Clinical neuropsychology

Clinical neuropsychology is a sub-specialty of clinical psychology that specialises in the diagnostic assessment and treatment of patients with brain injury or neurocognitive deficits.

Typically, a clinical neuropsychologist will hold an advanced degree in clinical psychology and will have completed further studies in neuropsychology, or in some countries, neurology.

In the USA, a neuropsychologist is a clinical psychologist, who, in addition to completing a Doctoral Degree in Psychology, also completes a Clinical Internship (1 year) and specialized Post-Doctoral training in Clinical Neuropsychology. Such Post-Doctoral training (i.e. Fellowship/Residency) currently ranges from 2 to 4 years. Neuropsychologists use models of brain-behavior relationships to determine whether expected neurobehavioral function has changed to a degree that is consistent with impairment. Such relationships are demonstrated through the interpretation of performance that is derived from a variety of specialized assessment procedures. Thus, the domain of neuropsychologists is expressed brain function: for example, reasoning/problem-solving, learning/recall processes, selective attention/concentration processes, perception, sensation, language processes, controlled/directed movement processes. Serial neuropsychological examinations may be used to monitor deteriorating neurobehavioral performance (as with dementing disorders) or to monitor improving neurobehavioral function (as during the recovery after an acquired brain injury or in response to pharmacological or surgical intervention).

What distinguishes a clinical neuropsychologist from other clinical psychologists is an extensive knowledge of the brain, including an understanding of areas such as: neuroanatomy, neurobiology, psychopharmacology, neurological illness or injury, the use of neuropsychological tests to accurately assess cognitive deficits, and the management, treatment and rehabiliation of brain injured and neurocognitively impaired patients.

Clinical neuropsychologists perform a number of tasks, usually within a clinical setting. They are often involved in conducting neuropsychological assessments to assess a person's cognitive skills, usually after some sort of brain injury or neurological impairment. This may be for the purposes of planning treatments, to determine someone's neurocognitive functioning or mental capacity (often done for presentation as evidence in court cases or legal proceedings) or to detect changes over time.

A clinical neuropsychologist's typical caseload may include people with traumatic brain injury (TBI), cerebrovascular accidents (CVA) such as stroke and aneurysm ruptures, brain tumors, encephalitis, epilepsy/seizure disorders, dementias, mental illnesses (e.g. schizophrenia), and a wide range of developmental disorders, including attention-deficit/hyperactivity disorder (ADHD), learning disabilities, autism and Tourette's syndrome.

Clinical neuropsychologists' training has included methods of psychotherapy and counseling. They can also provide therapeutic services to patients in need of education and emotional support concerning their neurological injuries or illness. In two U.S. States (New Mexico and Louisiana) and the Territory of Guam, clinical neuropsychologists (as well as generalist clinical psychologists) who complete additional postdoctoral training in clinical psychopharmacology and pass a national examination may prescribe psychotropic medications.

Many clinical neuropsychologists are employed by medical schools and hospitals, especially neurology, psychiatry, and rehabilitation facilities. Some work in private practice. They are frequently active in teaching at the university level and conducting research into a wide range of issues concerning human brain-behavior relationships. Some clinical neuropsychologists are also employed by pharmaceutical companies to help develop and test neuropsychological assessment tools for use in clinical trials.

The practice of cognitive neuropsychology and cognitive neuropsychiatry involves studying the cognitive effects of injury or illness to understand normal psychological function. Because of their day-to-day contact with people with brain impairment, many clinical neuropsychologists are active in these research fields.

Neuropsychology

Neuropsychology is the applied scientific discipline that studies the structure and function of the brain related to specific psychological processes and overt behaviors. The term neuropsychology has been applied to lesion studies in humans and animals. It has also been applied to efforts to record electrical activity from individual cells (or groups of cells) in higher primates (including some studies of human patients).

It is scientific in its approach and shares an information processing view of the mind with cognitive psychology and cognitive science.

It is one of the more eclectic of the psychological disciplines, overlapping at times with areas such as neuroscience, philosophy (particularly philosophy of mind), neurology, psychiatry and computer science (particularly by making use of artificial neural networks).

In practice neuropsychologists tend to work in academia (involved in basic or clinical research), clinical settings (involved in assessing or treating patients with neuropsychological problems – see clinical neuropsychology), forensic settings (often assessing people for legal reasons or court cases or working with offenders, or appearing in court as expert witness) or industry (often as consultants where neuropsychological knowledge is applied to product design or in the management of pharmaceutical clinical-trials research for drugs that might have a potential impact on CNS functioning).

Approaches

Experimental neuropsychology is an approach which uses methods from experimental psychology to uncover the relationship between the nervous system and cognitive function. The majority of work involves studying healthy humans in a laboratory setting, although a minority of researchers may conduct animal experiments. Human work in this area often takes advantage of specific features of our nervous system (for example that visual information presented to a specific visual field is preferentially processed by the cortical hemisphere on the opposite side) to make links between neuroanatomy and psychological function.

Clinical neuropsychology is the application of neuropsychological knowledge to the assessment (see neuropsychological test and neuropsychological assessment), management and rehabilitation of people who have suffered illness or injury (particularly to the brain) which has caused neurocognitive problems. In particular they bring a psychological viewpoint to treatment, to understand how such illness and injury may affect and be affected by psychological factors. Clinical neuropsychologists typically work in hospital settings in an interdisciplinary medical team, although private practice work is not unknown.

Cognitive neuropsychology is a relatively new development and has emerged as a distillation of the complementary approaches of both experimental and clinical neuropsychology. It seeks to understand the mind and brain by studying people who have suffered brain injury or neurological illness. One model of neuropsychological functioning is known as functional localization. This is based on the principle that if a specific cognitive problem can be found after an injury to a specific area of the brain, it is possible that this part of the brain is in some way involved. However, there may be reason to believe that the link between mental functions and neural regions is not so simple. An alternative model of the link between mind and brain, such as parallel processing, may have more explanatory power for the workings and dysfunction of the human brain. Yet another approach investigates how the pattern of errors produced by brain-damaged individuals can constrain our understanding of mental representations and processes without reference to the underlying neural structure. A more recent but related approach is cognitive neuropsychiatry which seeks to understand the normal function of mind and brain by studying psychiatric or mental illness.

Connectionism is the use of artificial neural networks to model specific cognitive processes using what are considered to be simplified but plausible models of how neurons operate. Once trained to perform a specific cognitive task these networks are often damaged or 'lesioned' to simulate brain injury or impairment in an attempt to understand and compare the results to the effects of brain injury in humans.

Functional neuroimaging uses specific neuroimaging technologies to take readings from the brain, usually when a person is doing a particular task, in an attempt to understand how the activation of particular brain areas is related to the task. In particular, the growth of methodologies to employ cognitive testing within established functional magnetic resonance imaging (fMRI) techniques to study brain-behavior relations is having a notable influence on neuropsychological research.

In practice these approaches are not mutually exclusive and most neuropsychologists select the best approach or approaches for the task to be completed.

Methods and tools

• The use of standardized neuropsychological tests. These tasks have been designed so the performance on the task can be linked to specific neurocognitive processes. These tests are typically standardized, meaning that they have been administered to a specific group(s) of individuals before being used in individual clinical cases. The data resulting from standardization are known as normative data. After these data have been collected and analyzed, they are used as the comparative standard against which individual performances can be compared. Examples of neuropsychological tests include: the Wechsler Adult Memory Scale (WMS), the Wechsler Adult Intelligence Scale (WAIS), and the Wechsler Intelligence Scale for Children (WISC). Other tests include the Halstead-Reitan Neuropsychological Battery, the Boston Naming Test, the Wisconsin Card Sorting Test, the Benton Visual Retention Test, and the Controlled Oral Word Association. (The Woodcock Johnson and the Nelson-Denny are not neuropsychological tests per se. They are psycho-educational batteries of tests used to measure an individual's intra-disciplinary strengths and weakness in specific academic areas (writing, reading and arithmetic)).

• The use of brain scans to investigate the structure or function of the brain is common, either as simply a way of better assessing brain injury with high resolution pictures, or by examining the relative activations of different brain areas. Such technologies may include fMRI (functional Magnetic Resonance Imaging) and PET (Positron Emission Tomography), which yields data related to functioning, as well as MRI (Magnetic Resonance Imaging) and CAT (or CT) (Computed Axial Tomography), which yields structural data.

• The use of electrophysiological measures designed to measure the activation of the brain by measuring the electrical or magnetic field produced by the nervous system. This may include EEG (Electroencephalography) or MEG (Magneto-encephalography).

• The use of designed experimental tasks, often controlled by computer and typically measuring reaction time and accuracy on a particular tasks thought to be related to a specific neurocognitive process. An example of this is the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Neuroimaging

Para-sagittal MRI of the head in a patient with benign familial macrocephaly.

Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain. It is a relatively new discipline within medicine and neuroscience/psychology.

Overview

Neuroimaging falls into two broad categories:

• Structural imaging, which deals with the structure of the brain and the diagnosis of gross (large scale) intracranial disease (such as tumor), and injury, and
• functional imaging, which is used to diagnose metabolic diseases and lesions on a finer scale (such as Alzheimer's disease) and also for neurological and cognitive psychology research and building brain-computer interfaces.

Functional imaging enables, for example, the processing of information by centers in the brain to be visualized directly. Such processing causes the involved area of the brain to increase metabolism and "light up" on the scan.

History

In 1918 the American neurosurgeon Walter Dandy introduced the technique of ventriculography. X-ray images of the ventricular system within the brain were obtained by injection of filtered air directly into one or both lateral ventricles of the brain. Dandy also observed that air introduced into the subarachnoid space via lumbar spinal puncture could enter the cerebral ventricles and also demonstrate the cerebrospinal fluid compartments around the base of the brain and over its surface. This technique was called pneumoencephalography.

In 1927 Egas Moniz, professor of neurology in Lisbon and recipient of theNobel Prize for Physiology or Medicine in 1949, introduced cerebral angiography, whereby both normal and abnormal blood vessels in and around the brain could be visualized with great accuracy.

In the early 1970s, Allan McLeod Cormack and Godfrey Newbold Hounsfield introduced computerized axial tomography (CAT or CT scanning), and ever more detailed anatomic images of the brain became available for diagnostic and research purposes. Cormack and Hounsfield won the 1979 Nobel Prize for Physiology or Medicine for their work. Soon after the introduction of CAT in the early 1980s, the development of radioligands allowed single photon emission computed tomography (SPECT) and positron emission tomography (PET) of the brain.

More or less concurrently, magnetic resonance imaging (MRI or MR scanning) was developed by researchers including Peter Mansfield and Paul Lauterbur, who were awarded the Nobel Prize for Physiology or Medicine in 2003. In the early 1980s MRI was introduced clinically, and during the 1980s a veritable explosion of technical refinements and diagnostic MR applications took place. Scientists soon learned that the large blood flow changes measured by PET could also be imaged by the correct type of MRI. Functional magnetic resonance imaging (fMRI) was born, and since the 1990s, fMRI has come to dominate the brain mapping field due to its low invasiveness, lack of radiation exposure, and relatively wide availability. As noted above fMRI is also beginning to dominate the field of stroke treatment.

In early 2000s the field of neuroimaging reached the stage where limited practical applications of functional brain imaging have become feasible. The main application area is crude forms of brain-computer interface.

Brain imaging techniques

Computed Axial Tomography

Computed Tomography (CT) or Computed Axial Tomography (CAT) scanning uses a series of x-rays of the head taken from many different directions. Typically used for quickly viewing brain injuries, CT scanning uses a computer program that performs a numerical integral calculation (the inverse Radon transform) on the measured x-ray series to estimate how much of an x-ray beam is absorbed in a small volume of the brain. Typically the information is presented as cross sections of the brain.

In approximation, the more dense a material is, the whiter a volume of it will appear on the scan (just as in the more familiar "flat" X-rays). CT scans are primarily used for evaluating swelling from tissue damage in the brain and in assessment of ventricle size. Modern CT scanning can provide reasonably good images in a matter of minutes.

Diffuse Optical Imaging

Diffuse Optical Imaging (DOI) or Diffuse Optical Tomography (DOT) is a medical imaging modality which uses near infrared light to generate images of the body. The technique measures the optical absorption of haemoglobin, and relies on the absorption spectrum of haemoglobin varying with its oxygenation status.

Event Related Optical Signal

Event Related Optical Signal (EROS) is a brain-scanning technique which uses infrared light through optical fibers to measure changes in optical properties of active areas of the cerebral cortex. Whereas techniques such as diffuse optical imaging (DOT) and near infrared spectroscopy (NIRS) measure optical absorption of haemoglobin, and thus are based on blood flow, EROS takes advantage of the scattering properties of the neurons themselves, and thus provide a much more direct measure of cellular activity. EROS can pinpoint activity in the brain within millimeters (spatially) and within milliseconds (temporally). Its biggest downside is the inability to detect activity more than a few centimeters deep. EROS is a new, relatively inexpensive technique that is non-invasive to the test subject. It was developed at the University of Illinois at Urbana-Champaign where it is now used in the Cognitive Neuroimaging Laboratory of Dr. Gabriele Gratton and Dr. Monica Fabiani.

Magnetic Resonance Imaging

(Sagittal MRI slice at the midline)

Magnetic Resonance Imaging (MRI) uses magnetic fields and radio waves to produce high quality two- or three-dimensional images of brain structures without use of ionizing radiation (X-rays) or radioactive tracers. During an MRI, a large cylindrical magnet creates a magnetic field around the head of the patient through which radio waves are sent. When the magnetic field is imposed, each point in space has a unique radio frequency at which the signal is received and transmitted (Preuss). Sensors read the frequencies and a computer uses the information to construct an image. The detection mechanisms are so precise that changes in structures over time can be detected.

Using MRI, scientists can create images of both surface and subsurface structures with a high degree of anatomical detail. MRI scans can produce cross sectional images in any direction from top to bottom, side to side, or front to back. The problem with original MRI technology was that while it provides a detailed assessment of the physical appearance, water content, and many kinds of subtle derangements of structure of the brain (such as inflammation or bleeding), it fails to provide information about the metabolism of the brain (i.e. how actively it is functioning) at the time of imaging. A distinction is therefore made between "MRI imaging" and "functional MRI imaging" (fMRI), where MRI provides only structural information on the brain while fMRI yields both structural and functional data.

Functional Magnetic Resonance Imaging

(Axial MRI slice at the level of the basal ganglia, showing fMRI BOLD signal changes overlayed in red (increase) and blue (decrease) tones)

Functional Magnetic Resonance Imaging (fMRI) relies on the paramagnetic properties of oxygenated and deoxygenated hemoglobin to see images of changing blood flow in the brain associated with neural activity. This allows images to be generated that reflect which brain structures are activated (and how) during performance of different tasks.

Most fMRI scanners allow subjects to be presented with different visual images, sounds and touch stimuli, and to make different actions such as pressing a button or moving a joystick. Consequently, fMRI can be used to reveal brain structures and processes associated with perception, thought and action. The resolution of fMRI is about 2-3 millimeters at present, limited by the spatial spread of the hemodynamic response to neural activity. It has largely superseded PET for the study of brain activation patterns. PET, however, retains the significant advantage of being able to identify specific brain receptors (or transporters) associated with particular neurotransmitters through its ability to image radiolabelled receptor "ligands" (receptor ligands are any chemicals that stick to receptors).

As well as research on healthy subjects, fMRI is increasingly used for the medical diagnosis of disease. Because fMRI is exquisitely sensitive to blood flow, it is extremely sensitive to early changes in the brain resulting from ischemia (abnormally low blood flow), such as the changes which follow stroke. Early diagnosis of certain types of stroke is increasingly important in neurology, since substances which dissolve blood clots may be used in the first few hours after certain types of stroke occur, but are dangerous to use afterwards. Brain changes seen on fMRI may help to make the decision to treat with these agents. With between 72% and 90% accuracy where chance would achieve 0.8%, fMRI techniques can decide which of a set of known images the subject is viewing.

MagnetoEncephaloGraphy

Magnetoencephalography (MEG) is an imaging technique used to measure the magnetic fields produced by electrical activity in the brain via extremely sensitive devices such as superconducting quantum interference devices (SQUIDs). MEG offers a very direct measurement neural electrical activity (compared to fMRI for example) with very high temporal resolution but relatively low spatial resolution. The advantage of measuring the magnetic fields produced by neural activity is that they are not distorted by surrounding tissue, unlike the electric fields measured by EEG (particularly the skull and scalp).

There are many uses for the MEG, including assisting surgeons in localizing a pathology, assisting researchers in determining the function of various parts of the brain, neurofeedback, and others.

Positron Emission Tomography

(PET scan of a normal 20-year-old brain)

Positron Emission Tomography (PET) measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data are computer-processed to produce 2- or 3-dimensional images of the distribution of the chemicals throughout the brain (Nilsson 57). The positron emitting radioisotopes used are produced by a cyclotron, and chemicals are labelled with these radioactive atoms. The labeled compound, called a radiotracer, is injected into the bloodstream and eventually makes its way to the brain. Sensors in the PET scanner detect the radioactivity as the compound accumulates in various regions of the brain. A computer uses the data gathered by the sensors to create multicolored 2- or 3-dimensional images that show where the compound acts in the brain. Especially useful are a wide array of ligands used to map different aspects of neurotransmitter activity, with by far the most commonly used PET tracer being a labeled form of glucose (see FDG).

The greatest benefit of PET scanning is that different compounds can show blood flow and oxygen and glucose metabolism in the tissues of the working brain. These measurements reflect the amount of brain activity in the various regions of the brain and allow us to learn more about how the brain works. PET scans were superior to all other metabolic imaging methods in terms of resolution and speed of completion (as little as 30 seconds), when they first became available. The improved resolution permitted better study to be made as to the area of the brain activated by a particular task. The biggest drawback of PET scanning is that because the radioactivity decays rapidly, it is limited to monitoring short tasks (Nilsson 60). Before fMRI technology came online, PET scanning was the preferred method of functional (as opposed to structural) brain imaging, and it still continues to make large contributions to neuroscience.

PET scanning is also used for diagnosis of brain disease, most notably because brain tumors, strokes, and neuron-damaging diseases which cause dementia (such as Alzheimer's disease) all cause great changes in brain metabolism, which in turn causes easily detectable changes in PET scans. PET is probably most useful in early cases of certain dementias (with classic examples being Azheimer's disease and Pick's disease) where the early damage is too diffuse and makes too little difference in brain volume and gross structure to change CT and standard MRI images enough to be able to reliably differentiate it from the "normal" range of cortical atrophy which occurs with aging (in many but not all) persons, and which does not cause clinical dementia.

Single Photon Emission Computed Tomography

Single Photon Emission Computed Tomography (SPECT) is similar to PET and uses gamma ray emitting radioisotopes and a gamma camera to record data that a computer uses to construct two- or three-dimensional images of active brain regions (Ball). SPECT relies on an injection of radioactive tracer, which is rapidly taken up by the brain but does not redistribute. Uptake of SPECT agent is nearly 100% complete within 30 – 60s, reflecting cerebral blood flow (CBF) at the time of injection. These properties of SPECT make it particularly well suited for epilepsy imaging, which is usually made difficult by problems with patient movement and variable seizure types. SPECT provides a "snapshot" of cerebral blood flow since scans can be acquired after seizure termination (so long as the radioactive tracer was injected at the time of the seizure). A significant limitation of SPECT is its poor resolution (about 1 cm) compared to that of MRI.

Like PET, SPECT also can be used to differentiate different kinds of disease process which produce dementia, and it is increasingly used for this purpose. Neuro-PET has a disadvantage of requiring use of a tracers with half-lives of at most 110 minutes, such as FDG. These must be made in a cyclotron, and are expensive or even unavailable if necessary transport times are prolonged more than a few half-lives. SPECT, however, is able to make use of tracers with much longer half-lives, such as technetium-99m, and as a result, is far more widely available.

Hemofiltration

In medicine, hemofiltration, is a renal replacement therapy similar to hemodialysis which is used almost exclusively in the intensive care setting. Thus, it is almost always used for acute renal failure. It is a slow continuous therapy in which sessions usually last between 12 to 24 hours and are usually performed daily. During hemofiltration, a patient's blood is passed through a set of tubing (a filtration circuit) via a machine to a semipermeable membrane (the filter) where waste products and water are removed. Replacement fluid is added and the blood is returned to the patient.

The Principle of Hemofiltration

As in dialysis, in hemofiltration one achieves movement of solutes across a semi-permeable membrane. However, solute movement with hemofiltration is governed by convection rather than by diffusion. With hemofiltration, dialysate is not used. Instead, a positive hydrostatic pressure drives water and solutes across the filter membrane from the blood compartment to the filtrate compartment, from which it is drained. Solutes, both small and large, get dragged through the membrane at a similar rate by the flow of water that has been engineered by the hydrostatic pressure. So convection overcomes the reduced removal rate of larger solutes (due to their slow speed of diffusion) seen in hemodialysis.

Replacement fluid composition

An isotonic replacement fluid is added to the blood to replace fluid volume and electrolytes. The replacement fluid must be of high purity, because it is infused directly into the blood line of the extracorporeal circuit. The replacement hemofiltration fluid usually contains lactate or acetate as a bicarbonate-generating base, or bicarbonate itself. Use of lactate can occasionally be problematic in patients with lactic acidosis or with severe liver disease, because in such cases the conversion of lactate to bicarbonate can be impaired. In such patients use of bicarbonate as a base is preferred.

Hemodiafiltration

Hemofiltration is sometimes used in combination with hemodialysis, when it is termed hemodiafiltration. Blood is pumped through the blood compartment of a high flux dialyzer, and a high rate of ultrafiltration is used, so there is a high rate of movement of water and solutes from blood to dialysate that must be replaced by substitution fluid that is infused directly into the blood line. However, dialysis solution is also run through the dialysate compartment of the dialyzer. The combination is theoretically useful because it results in good removal of both large and small molecular weight solutes.

Intermittent vs. continuous modes of therapy

These treatments can be given intermittently, or continuously. The latter is usually done in an intensive care unit setting.

On-line intermittent hemofiltration (IHF) or hemodiafiltration (IHDF)

Either of these treatments can be given in outpatient dialysis units, three or more times a week, usually 3-5 hours per treatment. IHDF is used almost exclusively, with only a few centers using IHF. With both IHF or IHDF, the substitution fluid is prepared on-line from dialysis solution by running dialysis solution through a set of two membranes to purify it before infusing it directly into the blood line. In the United States, regulatory agencies have not yet approved on-line creation of substitution fluid because of concerns about its purity. For this reason, hemodiafiltration is almost never used in an outpatient setting in the United States as of 2007. Use of sterile, pre-packaged substitution fluid would be cost-prohibitive in the current economic environment.

Continuous hemofiltration (CHF) or hemodiafiltration (CHDF)

Hemofiltration is most commonly used in an intensive care unit setting, where it is either given as 8-12 hours treatments, so called SLEF (slow extended hemofiltration), or as CHF (continuous hemofiltration also sometimes called continuous veno-venous hemofiltration (CVVH)) or Continuous Renal Replacement Therapy (CRRT). Hemodiafiltration (SLED-F or CHDF or CVVHDF) also is widely used in this fashion. In the United States, the substitution fluid used in CHF or CHDF is commercially prepared, prepackaged, and sterile (or sometimes is prepared in the local hospital pharmacy), avoiding regulatory issues of on-line creation of replacement fluid from dialysis solution.

With slow continuous therapies, the blood flow rates are usually in the range of 100-200 ml/min, and access is usually achieved through a central venous catheter placed in one of the large central veins. In such cases a blood pump is used to drive blood flow through the filter. Native access for hemodialysis (eg AV fistulas or grafts) are unsuitable for CHF because the prolonged residence of the access needles required might damage such accesses.

Is on-line intermittent hemodiafiltration (IHDF) better than regular hemodialysis?

There is current controversy about whether intermittent on-line hemodiafiltration (IHDF) gives better results than hemodialysis in an outpatient setting. In Europe, several observational studies have compared outcomes in patients getting dialysis with those getting IHDF. These have suggested a lower mortality rate and other favorable outcomes in patients getting IHDF vs. those getting ordinary hemodialysis. However, the issue is not settled at this time, because the required randomized controlled clinical trials have not been done. Another problem has been that in several of the trials done, IHDF was compared to dialysis using low-flux (small pore) membranes, and the benefit found may have been due more to the use of a high-flux membrane than to the addition of convective transport (filtration) to dialysis. A recent Cochrane database review of available trials could not find a definite benefit of either IHF or IHDF vs. hemodialysis in terms of outcomes.

Peritoneal dialysis

Introduction

Current treatment options for patients with severe chronic kidney failure are dialysis and kidney transplantation. Dialysis is a treatment that removes substances such as water, salts, and waste products (from the body’s normal metabolism), which build up in patients with failing kidneys. There are two forms of dialysis. One is called hemodialysis (HD), where the blood is cleaned outside the body and then returned to the body. This treatment, done in a hospital, or a dialysis clinic, is normally done 3 times a week, where each session takes about 4 hours. In HD, a machine and a filter are required, as well as a system to get the blood out of the body, as well as returning the cleaned blood to the patient. In most patients, this so called access to the blood, is done by inserting two needles into blood vessels on the forearm. A few centers around the world can train patients for self- HD. In regard to transplantation, the new kidney can come from either a deceased person or a living donor.

What is peritoneal dialysis (PD) and how does it work?

The other form of dialysis is called peritoneal dialysis (PD). More than 150,000 patients are currently receiving this lifesaving treatment around the world.

In PD, a dialysis fluid is entered into the patient’s abdominal (= peritoneal) cavity (the “belly”), which is covered by a thin membrane, containing many small blood vessels. This membrane, called the peritoneum, is like a big bag that keeps the stomach, intestines, liver, and other organs in place. The dialysis fluid will make water, salts, and the waste products move from the blood into the fluid (also called solution). This process is called dialysis, and means that the peritoneum works as a dialysis filter. As the fluid gets saturated after a while, the solution must be exchanged regularly.

The solutions

The fluids contain either sugar (glucose), amino acids, which are building blocks for proteins, or a compound called icodextrin, to remove the water. The sugar solution is the one most commonly used. The glucose “strength” (1.5%, 2.5% or 4.25%) of the solution determines how much water is removed from the blood; the higher the concentration, the greater the water removal. The amino acid solution is used to improve a patient’s nutritional condition (as the amino acids are taken up by the body, i.e. they move from the solution to the blood), and/ or to reduce the uptake of glucose from the solution. The benefits of the icodextrin fluid is that it removes more water than the glucose solution for longer exchange intervals, and that it is glucose- free, which is advantageous both for the peritoneum and the body as a whole.

There are two types of glucose solutions. The main difference is the pH, and the type of substance added to reduce the acidity of the blood, which is common in patients with kidney disease.

How can the solution be exchanged?

A small plastic tube, called a catheter, which has been placed through the abdominal wall in a small operation done before starting PD, is used to let the fluid go in to, and out from, the abdomen. The place where the catheter comes out is called the “exit site”. The catheter can normally be used for many years if so needed. In most cases two liters of fluid is entered each time, and is exchanged 4 times per day. In the beginning the patient may feel some discomfort when the solution goes in, but this normally disappears after a while. The bags are delivered to the patient’s home at regular intervals.

Preparation for the exchange

The recommended procedure varies somewhat between centers, but in most cases the patient wears a disposable surgical mask, and scrubs the hands for 3 minutes using soap and water. The solution should be warmed to body temperature before use, for example by using a heating pad or a heating plate. Many centers will provide the patients with an appropriate heating device to be used at home.

Two methods for the solution exchange/ types of PD

There are two types of PD: CAPD and APD. The difference is that in CAPD the exchanges are done manually, and in APD automatically by a small machine.

CAPD means: Continuous Ambulatory Peritoneal Dialysis

C- continuous: dialysis solution is always inside the “belly” cleansing the blood in a continuous manner.

A- ambulatory: ambulatory means that between exchanges, one can move about freely and continue normal activities like going for a drive, walking, golfing, studying or sleeping. In CAPD the solution exchanges are done manually at home, normally with 4 exchanges daily, seven days a week, by the patient him/herself.

P- peritoneal: this type of dialysis makes use of the peritoneal membrane that covers the peritoneal cavity in order to cleanse the blood of waste products and water.

D- dialysis: dialysis is the process of removing all wastes and excess water from the blood, in PD using the peritoneal membrane as a filter.

Steps in CAPD are

Step 1) Attach the new bag

Step 2) Drain: this means letting the solution go from the peritoneal cavity (by gravity) to the so-called drain bag, which takes 15-20 minutes

Step 3) Flush: this is when the system is ‘flushed’ with unused solution for approximately 10 seconds. This ensures your system is made clear of bacteria that may have entered the system when the new bag was connected

Step 4) Fill: this means filling the new solution into the peritoneal cavity. This normally takes less than 10 minutes

Step 5) Dwell time: this is when the dialysis solution is inside the peritoneal cavity

APD means: Automated Peritoneal Dialysis

A- Automated: automated means that the fluid exchanges are done automatically by a machine. In APD, the treatment is done at home at night while sleeping. Most patients are prescribed a continuous treatment, but in some cases it may be possible to have no dialysis during the day, which means no fluid in “the belly” at daytime.

The steps in APD are

Step 1) Start the machine

Step 2) Connect the new bags

Step 3) Connect to machine

Step 4) The fluid exchanges are done by the machine during the night

Step 5) Disconnect from the machine

Travel

Travel is possible with both CAPD and APD, as the bags can be delivered to the visiting areas. In APD the small size of the machine makes it easy to travel despite the PD treatment.

Disposing of the drained fluid

Patients can empty the bags containing the drained fluid into the toilet.

Advantages and disadvantages of peritoneal dialysis

Advantages

A. Compared to HD

• Treatment at home, which means no travel to a HD unit 3 times a week.
• Self control of the therapy
• No needles required
• Facilitates employment
• Easy travel
• Better preservation of the remaining kidney function, which is very important because it helps removing the water and the waste products. This reduces the need for a high dose of dialysis, and also improves patients’ survival and their quality of life.
• Lower doses of medication needed to treat anemia
• Lower risk for hepatitis B and C (liver infections caused by virus)
• Better results after kidney transplantation
• The removal of water is more gentle

B. General

• Easy to learn (3-5 days)
• High level of patient satisfaction and well-being

Disadvantages

• Peritonitis is an infection in the peritoneal cavity. This is in most cases caused by bacteria entering the fluid pass at a solution exchange procedure. The risk for such an infection is nowadays low (on average one episode every 3-5 years) due to improvements in the design of the products used. Also, following the instructions about how to exchange the fluids will further reduce the risk. Usually, a patient with peritonitis has fever, abdominal pain and a cloudy appearance of drained dialysis fluid. Peritonitis is treated, and normally cured, by using antibiotics. Sometimes a change of the catheter or a change of dialysis therapy (temporarily or permanently) may be necessary.
• Exit site infection is an infection of the “exit site” (=where the catheter comes out through the skin) and normally caused by bacteria. Common signs of such an infection are redness and secretion at the exit site. Antibiotics are given to cure the infection. There are also simple ways to prevent the occurrence of exit site infection, such as changing clothes daily, and always wash and dry hands before touching the catheter and exit site.
• Membrane function With time on PD, the peritoneal membrane may change its capability to remove enough water and wastes, which can require a need to change the prescription. In some cases, mainly after many years of PD (more than 5 years), this may not be sufficient, and a change to HD may be needed.

Summary

PD is a home- based therapy and widely used around the world. In general, it is easy, convenient, safe and effective for most patients with failing kidneys.

Hemodialysis

In medicine, hemodialysis is a method for removing waste products such as potassium and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies (the other two being renal transplant; peritoneal dialysis).

Hemodialysis can be an outpatient or inpatient therapy. Routine hemodialysis is conducted in a dialysis outpatient facility, either a purpose built room in a hospital or a dedicated, stand alone clinic. Less frequently hemodialysis is done at home. Dialysis treatments in a clinic are initiated and managed by specialized staff made up of nurses and technicians; dialysis treatments at home can be self initiated and managed or done jointly with the assistance of a trained helper who is usually a family member.

Principle

(Semipermeable membrane)

The principle of hemodialysis is the same as other methods of dialysis; it involves diffusion of solutes across a semipermeable membrane. Hemodialysis utilizes counter current flow, where the dialysate is flowing in the opposite direction to blood flow in the extracorporeal circuit. Counter-current flow maintains the concentration gradient across the membrane at a maximum and increases the efficiency of the dialysis.

Fluid removal (ultrafiltration) is achieved by altering the hydrostatic pressure of the dialysate compartment, causing free water and some dissolved solutes to move across the membrane along a created pressure gradient.

The dialysis solution that is used is a sterilized solution of mineral ions. Urea and other waste products, and also, potassium and phosphate, diffuse into the dialysis solution. However, concentrations of sodium and chloride are similar to those of normal plasma to prevent loss. Bicarbonate is added in a higher concentration than plasma to correct blood acidity. A small amount of glucose is also commonly used.

Note that this is a different process to the related technique of hemofiltration.

History

Many have played a role in developing dialysis as a practical treatment for renal failure, starting with Thomas Graham of Glasgow, who first presented the principles of solute transport across a semipermeable membrane in 1854. The artificial kidney was first developed by Abel, Rountree and Turner in 1913, the first hemodialysis in a human being was by Hass (February 28, 1924) and the artificial kidney was developed into a clinically useful apparatus by Kolff in 1943 - 1945. This research showed that life could be prolonged in patients dying of renal failure.

Dr. Willem Kolff was the first to construct a working dialyzer in 1943. The first successfully treated patient was a 67-year-old woman in uremic coma who regained consciousness after 11 hours of hemodialysis with Kolff’s dialyzer in 1945. At the time of its creation, Kolff’s goal was to provide life support during recovery from acute renal failure. After World War II ended, Kolff donated the five dialyzers he’d made to hospitals around the world, including Mount Sinai Hospital, New York. Kolff gave a set of blueprints for his hemodialysis machine to George Thorn at the Peter Bent Brigham Hospital in Boston. This led to the manufacture of the next generation of Kolff’s dialyzer, a stainless steel Kolff-Brigham dialysis machine.

By the 1950s, Willem Kolff’s invention of the dialyzer was used for acute renal failure, but it was not seen as a viable treatment for patients with stage 5 chronic kidney disease (CKD). At the time, doctors believed it was impossible for patients to have dialysis indefinitely for two reasons. Firstly, they thought no man-made device could replace the function of kidneys over the long term. In addition, a patient undergoing dialysis suffered from damaged veins and arteries, so that after several treatments, it became difficult to find a vessel to access the patient’s blood.

Dr. Nils Alwall: The original Kolff kidney was not very useful clinically, because it did not allow for removal of excess fluid. Dr. Nils Alwall encased a modified version of this kidney inside a stainless steel canister, to which a negative pressure could be applied, in this way effecting the first truly practical application of hemodialysis, which was done in 1946 at the University of Lund. Alwall also was arguably the inventor of the arteriovenous shunt for dialysis. He reported this first in 1948 where he used such an arteriovenous shunt in rabbits. Subsequently he used such shunts, made of glass, as well as his canister-enclosed dialyzer, to treat 1500 patients in renal failure between 1946 and 1960, as reported to the First International Congress of Nephrology held in Evian in September 1960. Alwall was appointed to a newly-created Chair of Nephrology at the University of Lund in 1957. Subsequently, he collaborated with Swedish businessman Holger Crafoord to found one of the key companies that would manufacture dialysis equipment in the past 40 years, Gambro, Inc. The early history of dialysis has been reviewed by Stanley Shaldon.

Dr. Belding H. Scribner working with a surgeon, Dr. Wayne Quinton, modified the glass shunts used by Alwall by making them from Teflon. Another key improvement was to connect them to a short piece of silicone elastomer tubing. This formed the basis of the so-called Scribner shunt, perhaps more properly called the Quinton-Scribner shunt. After treatment, the circulatory access would be kept open by connecting the two tubes outside the body using a small U-shaped Teflon tube, which would shunt the blood from the tube in the artery back to the tube in the vein.

In 1962, Scribner started the world’s first outpatient dialysis facility, the Seattle Artificial Kidney Center, later renamed the Northwest Kidney Centers. Immediately the problem arose of who should be given dialysis, since demand far exceeded the capacity of the six dialysis machines at the center. Scribner decided that the decision about who would receive dialysis and who wouldn’t, would not be made by him. Instead, the choices would be made by an anonymous committee, which could be viewed as one of the first bioethics committees.

Prescription

A prescription for dialysis by a nephrologist (a medical kidney specialist) will specify various parameters for a dialysis treatment. These include frequency (how many treatments per week), length of each treatment, and the blood and dialysis solution flow rates, as well as the size of the dialyzer. The composition of the dialysis solution is also sometimes adjusted in terms of its sodium and potassium and bicarbonate levels. In general, the larger the body size of an individual, the more dialysis he will need. In the North America and UK, 3-4 hour treatments (sometimes up to 5 hours for larger patients) given 3 times a week are typical. Twice-a-week sessions are limited to patients who have a substantial residual kidney function. Four sessions per week are often prescribed for larger patients, as well as patients who have trouble with fluid overload. Finally, there is growing interest in short daily home hemodialysis, which is 1.5 - 4 hr sessions given 5-7 times per week, usually at home. There also is interest in nocturnal dialysis, which involves dialyzing a patient, usually at home, for 8-10 hours per night, 3-6 nights per week. Nocturnal in-center dialysis, 3-4 times per week is also offered at a handful of dialysis units in the United States.

Side-effects and complications

Hemodialysis often involves fluid removal (through ultrafiltration), because most patients with renal failure pass little or no urine. Side effects caused by removing too much fluid and/or removing fluid too rapidly include low blood pressure, fatigue, chest pains, leg-cramps, nausea and headaches. These symptoms can occur during the treatment and can persist post treatment; they are sometimes collectively referred to as the dialysis hangover or dialysis washout. The severity of these symptoms are usually proportionate to the amount and speed of fluid removal. However, the impact of a given amount or rate of fluid removal can vary greatly from person to person and day to day. These side effects can be avoided and/or their severity lessened by limiting fluid intake between treatments or increasing the dose of dialysis e.g. dialyzing more often or longer per treatment than the standard three times a week, 3-4 hours per treatment schedule.

Since hemodialysis requires access to the circulatory system, patients undergoing hemodialysis may expose their circulatory system to microbes, which can lead to sepsis, an infection affecting the heart valves (endocarditis) or an infection affecting the bones (osteomyelitis). The risk of infection varies depending on the type of access used (see below). Bleeding may also occur, again the risk varies depending on the type of access used. Infections can be minimized by strictly adhering to infection control best practices.

Heparin is the most commonly used anticoagulant in hemodialysis, as it is generally well tolerated and can be quickly reversed with protamine sulfate. Heparin allergy can infrequently be a problem and can cause a low platelet count. In such patients, alternative anticoagulants can be used. In patients at high risk of bleeding, dialysis can be done without anticoagulation.

First Use Syndrome is a rare but severe anaphylactic reaction to the artificial kidney. Its symptoms include sneezing, wheezing, shortness of breath, back pain, chest pain, or sudden death. It can be caused by residual sterilant in the artificial kidney or the material of the membrane itself. In recent years, the incidence of First Use Syndrome has decreased, due to an increased use of gamma irradiation, steam sterilization, or electron-beam radiation instead of chemical sterilants, and the development of new semipermeable membranes of higher biocompatibility. New methods of processing previously acceptable components of dialysis must always been considered. For example, in 2008, a series of first-use type or reactions, including deaths occurred due to heparin contaminated during the manufacturing process with oversulfated chondroitin sulfate.

Longterm complications of hemodialysis include amyloidosis, neuropathy and various forms of heart disease. Increasing the frequency and length of treatments have been shown to improve fluid overload and enlargement of the heart that is commonly seen in such patients.

Listed below are specific complications associated with different types of hemodialysis access.

Access

In hemodialysis, three primary methods are used to gain access to the blood: an intravenous catheter, an arteriovenous (AV) fistula, or a synthetic graft. The type of access is influenced by factors such as the expected time course of a patient's renal failure and the condition of his or her vasculature. Patients may have multiple accesses, usually because an AV fistula or graft is maturing and a catheter is still being used.

Catheter

Catheter access, sometimes called a CVC (Central Venous Catheter), consists of a plastic catheter with two lumens (or occasionally two separate catheters) which is inserted into a large vein (usually the vena cava, via the internal jugular vein or the femoral vein) to allow large flows of blood to be withdrawn from one lumen, to enter the dialysis circuit, and to be returned via the other lumen. However, blood flow is almost always less than that of a well functioning fistula or graft.

Catheters are usually found in two general varieties, tunnelled and non-tunnelled.

Non-tunnelled catheter access is for short-term access (up to about 10 days, but often for one dialysis session only), and the catheter emerges from the skin at the site of entry into the vein.

Tunnelled catheter access involves a longer catheter, which is tunnelled under the skin from the point of insertion in the vein to an exit site some distance away. It is usually placed in the internal jugular vein in the neck and the exit site is usually on the chest wall. The tunnel acts as a barrier to invading microbes, and as such, tunnelled catheters are designed for short- to medium-term access (weeks to months only), because infection is still a frequent problem.

Aside from infection, venous stenosis is another serious problem with catheter access. The catheter is a foreign body in the vein and often provokes an inflammatory reaction in the vein wall. This results in scarring and narrowing of the vein, often to the point of occlusion. This can cause problems with severe venous congestion in the area drained by the vein and may also render the vein, and the veins drained by it, useless for creating a fistula or graft at a later date. Patients on long-term hemodialysis can literally 'run out' of access, so this can be a fatal problem.

Catheter access is usually used for rapid access for immediate dialysis, for tunnelled access in patients who are deemed likely to recover from acute renal failure, and for patients with end-stage renal failure who are either waiting for alternative access to mature or who are unable to have alternative access.

Catheter access is often popular with patients, because attachment to the dialysis machine doesn't require needles. However, the serious risks of catheter access noted above mean that such access should be contemplated only as a long-term solution in the most desperate access situation.

AV fistula

(A radiocephalic fistula)

AV (arteriovenous) fistulas are recognized as the preferred access method. To create a fistula, a vascular surgeon joins an artery and a vein together through anastomosis. Since this bypasses the capillaries, blood flows rapidly through the fistula. One can feel this by placing one's finger over a mature fistula. This is called feeling for "thrill" and produces a distinct 'buzzing' feeling over the fistula. Fistulas are usually created in the nondominant arm and may be situated on the hand (the 'snuffbox' fistula'), the forearm (usually a radiocephalic fistula, or so-called Brescia-Cimino fistula, in which the radial artery is anastomosed to the cephalic vein), or the elbow (usually a brachiocephalic fistula, where the brachial artery is anastomosed to the cephalic vein). A fistula will take a number of weeks to mature, on average perhaps 4-6 weeks. During treatment, two needles are inserted into the fistula, one to draw blood and one to return it.

The advantages of the AV fistula use are lower infection rates, because no foreign material is involved in their formation, higher blood flow rates (which translates to more effective dialysis), and a lower incidence of thrombosis. The complications are few, but if a fistula has a very high blood flow and the vasculature that supplies the rest of the limb is poor, a steal syndrome can occur, where blood entering the limb is drawn into the fistula and returned to the general circulation without entering the limb's capillaries. This results in cold extremities of that limb, cramping pains, and, if severe, tissue damage. One long-term complication of an AV fistula can be the development of an aneurysm, a bulging in the wall of the vein where it is weakened by the repeated insertion of needles over time. To a large extent the risk of developing an aneurysm can be reduced by careful needling technique. Aneurysms may necessitate corrective surgery and may shorten the useful life of a fistula. To prevent damage to the fistula and aneurysm or pseudoaneurysm formation, it is recommended that the needle be inserted at different points in a rotating fashion. Another approach is to cannulate the fistula with a blunted needle, in exactly the same place. This is called a 'buttonhole' approach. Often two or three buttonhole places are available on a given fistula. This also can prolong fistula life and help prevent damage to the fistula.

AV graft

(An arteriovenous graft)

AV (arteriovenous) grafts are much like fistulas in most respects, except that an artificial vessel is used to join the artery and vein. The graft usually is made of a synthetic material, often PTFE, but sometimes chemically treated, sterilized veins from animals are used. Grafts are inserted when the patient's native vasculature does not permit a fistula. They mature faster than fistulas, and may be ready for use several weeks after formation (some newer grafts may be used even sooner). However, AV grafts are at high risk to develop narrowing, especially in the vein just downstream from where the graft has been sewn to the vein. Narrowing often leads to clotting or thrombosis. As foreign material, they are at greater risk for becoming infected. More options for sites to place a graft are available, because the graft can be made quite long. Thus a graft can be placed in the thigh or even the neck.

Fistula First project

AV fistulas have a much better access patency and survival than do venous catheters or grafts. They also produce better patient survival and have far fewer complications compared to grafts or venous catheters. For this reason, the Centers for Medicare & Medicaid (CMS) has set up a Fistula First Initiative, whose goal is to increase the use of AV fistulas in dialysis patients.

Equipment

(Schematic of a hemodialysis circuit)

The hemodialysis machine pumps the patient's blood and the dialysate through the dialyzer. The newest dialysis machines on the market are highly computerized and continuously monitor an array of safety-critical parameters, including blood and dialysate flow rates; dialysis solution conductivity, temperature, and pH; and analysis of the dialysate for evidence of blood leakage or presence of air. Any reading that is out of normal range triggers an audible alarm to alert the patient-care technician who is monitoring the patient. Manufacturers of dialysis machines include companies such as Fresenius, Gambro, Baxter, B. Braun, and Bellco.

Water system

(A hemodialysis unit's dialysate solution tanks)

An extensive water purification system is absolutely critical for hemodialysis. Since dialysis patients are exposed to vast quantities of water, which is mixed with dialysate concentrate to form the dialysate, even trace mineral contaminants or bacterial endotoxins can filter into the patient's blood. Because the damaged kidneys cannot perform their intended function of removing impurities, ions introduced into the bloodstream via water can build up to hazardous levels, causing numerous symptoms or death. Aluminum, chloramine, fluoride, copper, and zinc, as well as bacterial fragments and endotoxins, have all caused problems in this regard.

For this reason, water used in hemodialysis is carefully purified before use. Initially it is filtered and temperature-adjusted and its pH is corrected by adding an acid or base. Then it is softened. Next the water is run through a tank containing activated charcoal to adsorb organic contaminants. Primary purification is then done by forcing water through a membrane with very tiny pores, a so-called reverse osmosis membrane. This lets the water pass, but holds back even very small solutes such as electrolytes. Final removal of leftover electrolytes is done by passing the water through a tank with ion-exchange resins, which remove any leftover anions or cations and replace them with hydroxyl and hydrogen molecules, respectively, leaving ultrapure water.

Even this degree of water purification may be insufficient. The trend lately is to pass this final purified water (after mixing with dialysate concentrate) through a dialyzer membrane. This provides another layer of protection by removing impurities, especially those of bacterial origin, that may have accumulated in the water after its passage through the original water purification system.

Once purified water is mixed with dialysate concentrate, its conductivity increases, since water that contains charged ions conducts electricity. During dialysis, the conductivity of dialysis solution is continuously monitored to ensure that the water and dialysate concentrate are being mixed in the proper proportions. Both excessively concentrated dialysis solution and excessively dilute solution can cause severe clinical problems.

Dialyzer

The dialyzer is the piece of equipment that actually filters the blood. Almost all dialyzers in use today are of the hollow-fiber variety. A cylindrical bundle of hollow fibers, whose walls are composed of semi-permeable membrane, is anchored at each end into potting compound (a sort of glue). This assembly is then put into a clear plastic cylindrical shell with four openings. One opening or blood port at each end of the cylinder communicates with each end of the bundle of hollow fibers. This forms the "blood compartment" of the dialyzer. Two other ports are cut into the side of the cylinder. These communicate with the space around the hollow fibers, the "dialysate compartment." Blood is pumped via the blood ports through this bundle of very thin capillary-like tubes, and the dialysate is pumped through the space surrounding the fibers. Pressure gradients are applied when necessary to move fluid from the blood to the dialysate compartment.

Membrane and flux

Dialyzer membranes come with different pore sizes. Those with smaller pore size are called "low-flux" and those with larger pore sizes are called "high-flux." Some larger molecules, such as beta-2-microglobulin, are not removed at all with low-flux dialyzers; lately, the trend has been to use high-flux dialyzers. However, such dialyzers require newer dialysis machines and high-quality dialysis solution to control the rate of fluid removal properly and to prevent backflow of dialysis solution impurities into the patient through the membrane.

Dialyzer membranes used to be made primarily of cellulose (derived from cotton linter). The surface of such membranes was not very biocompatible, because exposed hydroxyl groups would activate complement in the blood passing by the membrane. Therefore, the basic, "unsubstituted" cellulose membrane was modified. One change was to cover these hydroxyl groups with acetate groups (cellulose acetate); another was to mix in some compounds that would inhibit complement activation at the membrane surface (modified cellulose). The original "unsubstituted cellulose" membranes are no longer in wide use, whereas cellulose acetate and modified cellulose dialyzers are still used. Cellulosic membranes can be made in either low-flux or high-flux configuration, depending on their pore size.

Another group of membranes is made from synthetic materials, using polymers such as polyarylethersulfone, polyamide, polyvinylpyrrolidone, polycarbonate, and polyacrylonitrile. These synthetic membranes activate complement to a lesser degree than unsubstituted cellulose membranes. Synthetic membranes can be made in either low- or high-flux configuration, but most are high-flux.

Nanotechnology is being used in some of the most recent high-flux membranes to create a uniform pore size. The goal of high-flux membranes is to pass relatively large molecules such as beta-2-microglobulin (MW 11,600 daltons), but not to pass albumin (MW ~66,400 daltons). Every membrane has pores in a range of sizes. As pore size increases, some high-flux dialyzers begin to let albumin pass out of the blood into the dialysate. This is thought to be undesirable, although one school of thought holds that removing some albumin may be beneficial in terms of removing protein-bound uremic toxins.

Membrane flux and outcome

Whether using a high-flux dialyzer improves patient outcomes is somewhat controversial, but several important studies have suggested that it has clinical benefits. The NIH-funded HEMO trial compared survival and hospitalizations in patients randomized to dialysis with either low-flux or high-flux membranes. Although the primary outcome (all-cause mortality) did not reach statistical significance in the group randomized to use high-flux membranes, several secondary outcomes were better in the high-flux group. A recent Cochrane analysis concluded that benefit of membrane choice on outcomes has not yet been demonstrated.

Membrane flux and beta-2-microglobulin amyloidosis

High-flux dialysis membranes and/or intermittent on-line hemodiafiltration (IHDF) may also be beneificial in reducing complications of beta-2-microglobulin accumulation. Because beta-2-microglobulin is a large molecule, with a molecular weight of about 11,600 daltons, it does not pass at all through low-flux dialysis membranes. Beta-2-M is removed with high-flux dialysis, but is removed even more efficiently with IHDF. After several years (usually at least 5-7), patients on hemodialysis begin to develop complications from beta-2-M accumulation, including carpal tunnel syndrome, bone cysts, and deposits of this amyloid in joints and other tissues. Beta-2-M amyloidosis can cause very serious complications, including a spondylarthropathy, and often is associated with shoulder joint problems. Observational studies from Europe and Japan have suggested that using high-flux membranes in dialysis mode, or IHDF, reduces beta-2-M complications in comparison to regular dialysis using a low-flux membrane.

Dialyzer size and efficiency

Dialyzers come in many different sizes. A larger dialyzer with a larger membrane area (A) will usually remove more solutes than a smaller dialyzer, especially at high blood flow rates. This also depends on the membrane permeability coefficient K₀ for the solute in question. So dialyzer efficiency is usually expressed as the K₀A - the product of permeability coefficient and area. Most dialyzers have membrane surface areas of 0.8 to 2.2 square meters, and values of K₀A ranging from about 500 to 1500 mL/min. K₀A, expressed in mL/min, can be thought of as the maximum clearance of a dialyzer at very high blood and dialysate flow rates.

Reuse of dialyzers

The dialyzer may either be discarded after each treatment or be reused. Reuse requires an extensive procedure of high-level disinfection. Reused dialyzers are not shared between patients. There was an initial controversy about whether reusing dialyzers worsened patient outcomes. The consensus today is that reuse of dialyzers, done carefully and properly, produces similar outcomes to single use of dialyzers

Dialysis

In medicine, dialysis is primarily used to provide an artificial replacement for lost kidney function (renal replacement therapy) due to renal failure. Dialysis may be used for very sick patients who have suddenly but temporarily, lost their kidney function (acute renal failure) or for quite stable patients who have permanently lost their kidney function (stage 5 chronic kidney disease). When healthy, the kidneys maintain the body's internal equilibrium of water and minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate) and the kidneys remove from the blood the daily metabolic load of fixed hydrogen ions. The kidneys also function as a part of the endocrine system producing erythropoietin and 1,25-dihydroxycholecalciferol (calcitriol). Dialysis is an imperfect treatment to replace kidney function because it does not correct the endocrine functions of the kidney. Dialysis treatments replace some of these functions through the diffusion (waste removal) and convection (fluid removal).

Principle

Dialysis works, on the principles of the diffusion of solutes and convection of fluid across a semi-permeable membrane. Blood flows by one side of a semi-permeable membrane, and a dialysate or fluid flows by the opposite side. Smaller solutes and fluid pass through the membrane. The blood flows in one direction and the dialysate flows in the opposite. The concentrations of undesired solutes (for example potassium, calcium, and urea) are high in the blood, but low or absent in the dialysis solution and constant replacement of the dialysate ensures that the concentration of undesired solutes is kept low on this side of the membrane. The dialysis solution has levels of minerals like potassium and calcium that are similar to their natural concentration in healthy blood. For another solute, bicarbonate, dialysis solution level is set at a slightly higher level than in normal blood, to encourage diffusion of bicarbonate into the blood, to neutralise the metabolic acidosis that is often present in these patients.

Types

There are two primary types of dialysis, hemodialysis and peritoneal dialysis, and a third investigational type, intestinal dialysis.

Hemodialysis

Hemodialysis schematic

In hemodialysis, the patient's blood is pumped through the blood compartment of a dialyzer, exposing it to a semipermeable membrane. The cleansed blood is then returned via the circuit back to the body. Ultrafiltration occurs by increasing the hydrostatic pressure across the dialyzer membrane. This usually is done by applying a negative pressure to the dialysate compartment of the dialyzer. This pressure gradient causes water and disso

lved solutes to move from blood to dialysate, and allows removal of several litres of excess fluid during a typical 3 to 5 hour treatment. In the US, hemodialysis treatments are typically given in a dialysis center three times per week, however, as of 2007 over 2,000 people in the US are dialyzing at home more frequently for various treatment lengths.Studies have demonstrated the clinical benefits of dialyzing 5 to 7 times a week, for 6 to 8 hours. These frequent long treatments are often done at home, while sleeping but home dialysis is a flexible modality and schedules can be changed day to day, week to week. In general, studies have shown that both increased treatment length and frequency are clinically beneficial.

Peritoneal dialysis

In peritoneal dialysis, a sterile solution containing minerals and glucose is run through a tube into the peritoneal cavity, the abdominal body cavity around the intestine, where the peritoneal membrane acts as a semipermeable membrane. The dialysate is left there for a period of time to absorb waste products, and then it is drained out through the tube and discarded. This cycle or "exchange" is normally repeated 4-5 times during the day, (sometimes more often overnight with an automated system). Ultrafiltration occurs via osmosis; the dialysis solution used contains a high concentration of glucose, and the resulting osmotic pressure causes fluid to move from the blood into the dialysate. As a result, more fluid is drained than was instilled.

Peritoneal dialysis is less efficient than hemodialysis, but because it is carried out for a longer period of time the net effect in terms of removal of waste products and of salt and water are similar to hemodialysis. Peritoneal dialysis is carried out at home by the patient and it requires motivation. Although support is helpful, it is not essential. It does free patients from the routine of having to go to a dialysis clinic on a fixed schedule multiple times per week, and it can be done while travelling with a minimum of specialized equipment.

Hemofiltration

Hemofiltration is a similar treatment to hemodialysis, but it makes use of a different principle. The blood is pumped through a dialyzer or "hemofilter" as in dialysis, but no dialysate is used. A pressure gradient is applied; as a result, water moves across the very permeable membrane rapidly, facilitating the transport of dissolved substances, importantly ones with large molecular weights, which are cleared less well by hemodialysis. Salts and water lost from the blood during this process are replaced with a "substitution fluid" that is infused into the extracorporeal circuit during the treatment. Hemodiafiltration is a term used to describe several methods of combining hemodialysis and hemofiltration in one process.

Intestinal dialysis

In intestinal dialysis, the diet is supplemented with soluble fibres such as acacia fibre, which is digested by bacteria in the colon. This bacterial growth increases the amount of nitrogen that is eliminated in fecal waste. An alternative approach utilizes the ingestion of 1 to 1.5 liters of non-absorbable solutions of polyethylene glycol or mannitol every fourth hour.

Starting indications

The decision to initiate dialysis or hemofiltration in patients with renal failure can depend on several factors, which can be divided into acute or chronic indications.

• Acute indications for dialysis/hemofiltration:

1. Hyperkalemia
2. Metabolic acidosis
   
3. Fluid overload (which usually manifests as pulmonary edema)
4. Uremic Serositis complications, such as uremic pericarditis and uremic encephalopathy
5. And in patients without renal failure, acute poisoning with a dialysable drug, such as lithium, or aspirin

• Chronic indications for dialysis:

1. Symptomatic renal failure
2. Low glomerular filtration rate (GFR) (RRT often recommended to commence at a GFR of less than 10-15 mls/min/1.73m2)
3. Difficulty in medically controlling serum phosphorus or anaemia when the GFR is very low

Chronic kidney disease

Chronic kidney disease (CKD), also known as chronic renal disease, is a progressive loss of renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.

Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a falling glomerular filtration rate (rate at which the kidneys filter blood) and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction. Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is also called established chronic kidney disease and is synonymous with the now outdated terms end-stage renal disease (ESRD), chronic kidney failure (CKF) or chronic renal failure (CRF).

There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly with treatments aimed to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires one of the forms of renal replacement therapy; this may be a form of dialysis, but ideally constitutes a kidney transplant.

Signs and symptoms

Initially it is without specific symptoms and can only be detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:

• blood pressure is increased due to fluid overload and production of vasoactive hormones, increasing one's risk of developing hypertension and/or suffering from congestive heart failure
• Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Urea is excreted by sweating and crystallizes on skin ("uremic frost").
• Potassium accumulates in the blood (known as hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias)
• Erythropoietin synthesis is decreased (potentially leading to anemia, which causes fatigue)
• Fluid volume overload - symptoms may range from mild edema to life-threatening pulmonary edema
• Hyperphosphatemia - due to reduced phosphate excretion, associated with hypocalcemia (due to vitamin D3 deficiency).
  • Later this progresses to tertiary hyperparathyroidism, with hypercalcaemia, renal osteodystrophy and vascular calcification that further impairs cardiac function.
• Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid etc. This may cause altered enzyme activity by excess acid acting on enzymes and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia)

People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with chronic kidney disease and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.

Diagnosis

In many CKD patients, previous renal disease or other underlying diseases are already known. A small number presents with CKD of unknown cause. In these patients, a cause is occasionally identified retrospectively.

It is important to differentiate CKD from acute renal failure (ARF) because ARF can be reversible. Abdominal ultrasound is commonly performed, in which the size of the kidneys are measured. Kidneys with CKD are usually smaller (<>

Additional tests may include nuclear medicine MAG3 scan to confirm blood flows and establish the differential function between the two kidneys. DMSA scans are also used in renal imaging; with both MAG3 and DMSA being used chelated with the radioactive element Technetium-99.

In chronic renal failure treated with standard dialysis, numerous uremic toxins accumulate. These toxins show various cytotoxic activities in the serum, have different molecular weights and some of them are bound to other proteins, primarily to albumin. Such toxic protein bound substances are receiving the attention of scientists who are interested in improving the standard chronic dialysis procedures used today.

Stages

All individuals with a Glomerular filtration rate (GFR) <60>

of complications.

All individuals with kidney damage are classified as having chronic kidney disease, irrespective of the level of GFR. The rationale for including individuals with GFR 60 mL/min/1.73 m2 is that GFR may be sustained at normal or increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk of the two major outcomes of chronic kidney disease: loss of kidney function and development of cardiovascular disease.

The loss of protein in the urine is regarded as an independent marker for worsening of renal function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if there is significant protein loss.

Stage 1 CKD

Slightly diminished function; Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2). Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.

Stage 2 CKD

Mild reduction in GFR (60-89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.

Stage 3 CKD

Moderate reduction in GFR (30-59 mL/min/1.73 m2). British guidelines distinguish between stage 3A (GFR 45-59) and stage 3B (GFR 30-44) for purposes of screening and referral.

Stage 4 CKD

Severe reduction in GFR (15-29 mL/min/1.73 m2)

Stage 5 CKD

Established kidney failure (GFR <15>

Causes

The most common causes of CKD are diabetic nephropathy, hypertension, and glomerulonephritis. Together, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephrop

athy.

Historically, kidney disease has been classified according to the part of the renal anatomy that is involved, as:

• Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
• Glomerular, comprising a diverse group and subclassified into
  • Primary Glomerular disease suc h as focal segmen tal glomerulosclerosis and IgA nephritis
  • Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis

    

• Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
• Obstructive such as with bilateral kidney stones and diseases of the prostate

Treatment

The goal of therapy is to slow down or halt the otherwise relentless progression of CKD to stage 5. Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression of CKD to stage 5.

Replacement of erythropoietin and vitamin D3, two hormones processed by the kidney, is usually necessary, as is calcium. Phosphate binders are used to control the serum phosphate levels, which are usually elevated in chronic kidney disease.

When one reaches stage 5 CKD, renal replacement therapy is required, in the form of either dialysis or a transplant.

In some cases, dietary modifications have been proven to slow and even reverse further progression. Generally this includes limiting a persons intake of animal protein.

Prognosis

The prognosis of patients with chronic kidney disease is guarded as epidemiological data has shown that all cause mortality (the overall death rate) increases as kidney function decreases. The leading cause of death in patients with chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.

While renal replacement therapies can maintain patients indefinitely and prolong life, the quality of life is severely affected. Renal transplantation increases the survival of patients with stage 5 CKD significantly when compared to other therapeutic options; however, it is associated with an increased short-term mortality (due to complications of the surgery). Transplantation aside, high intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional three times a week hemodialysis and peritoneal dialysis.

Organizations

In the USA, the National Kidney Foundation is a national organization representing patients and professionals who treat kidney diseases. The Renal Support Network (RSN) is a nonprofit, patient-focused, patient-run organization that provides non-medical services to those affected by CKD. The American Association of Kidney Patients (AAKP) is a non-profit, patient-centric group focused on improving the health and well-being of CKD and dialysis patients. The Renal Physicians Association (RPA) is an association representing nephrology professionals.

In the United Kingdom, the National Kidney Federation represents patients, and the Renal Association represents renal physicians and works closely with the National Service Framework for kidney disease.

The International Society of Nephrology is an international body representing specialists in kidney diseases.

Acute renal failure

Acute renal failure (ARF), also known as acute kidney failure, is a rapid loss of renal function due to damage to the kidneys, resulting in retention of nitrogenous (urea and creatinine) and non-nitrogenous waste products that are normally excreted by the kidney. Depending on the severity and duration of the renal dysfunction, this accumulation is accompanied by metabolic disturbances, such as metabolic acidosis (acidification of the blood) and hyperkalaemia (elevated potassium levels), changes in body fluid balance, and effects on many other organ systems. It can be characterised by oliguria or anuria (decrease or cessation of urine production), although nonoliguric ARF may occur. It is a serious disease and treated as a medical emergency.

Causes

Acute renal failure is usually categorised according to pre-renal, renal and post-renal causes.

Acute Renal Failure

Pre-renal

Renal

Post-renal

• Pre-renal (causes in the blood supply):
  • hypovolemia (decreased blood volume), usually from shock or dehydration and fluid loss or excessive diuretics use.
  • hepatorenal syndrome in which renal perfusion is compromised in liver failure
  • vascular problems, such as atheroembolic disease and renal vein thrombosis (which can occur as a complication of the nephrotic syndrome)
  • infection usually sepsis, systemic inflammation due to infection
  • 

• Renal (damage to the kidney itself):
  • toxins or medication (e.g. some NSAIDs, aminoglycoside antibiotics, iodinated contrast, lithium, phosphate nephropathy due to bowel preparation for colonoscopy with sodium phosphates)
  • rhabdomyolysis (breakdown of muscle tissue) - the resultant release of myoglobin in the blood affects the kidney; it can be caused by injury (especially crush injury and extensive blunt trauma), statins, stimulants and some other drugs
  • hemolysis (breakdown of red blood cells) - the hemoglobin damages the tubules; it may be caused by various conditions such as sickle-cell disease, and lupus erythematosus
  • multiple myeloma, either due to hypercalcemia or "cast nephropathy" (multiple myeloma can also cause chronic renal failure by a different mechanism)
  • acute glomerulonephritis which may be due to a variety of causes, such as anti glomerular basement membrane disease/Goodpasture's syndrome, Wegener's granulomatosis or acute lupus nephritis with systemic lupus erythematosus

• Post-renal (obstructive causes in the urinary tract) due to:
  • medication interfering with normal bladder emptying (e.g. anticholinergics).
  • benign prostatic hypertrophy or prostate cancer.
  • kidney stones.
  • due to abdominal malignancy (e.g. ovarian cancer, colorectal cancer).
  • obstructed urinary catheter.

Diagnosis

In general, renal failure is diagnosed when either creatinine or blood urea nitrogen tests are markedly elevated in an ill patient, especially when oliguria is present. Previous measurements of renal function may offer comparison, which is especially important if a patient is known to have chronic renal failure as well. If the cause is not apparent, a large amount of blood tests and examination of a urine specimen is typically performed to elucidate the cause of acute renal failure, medical ultrasonography of the renal tract is essential to rule out obstruction of the urinary tract.

Consensus criteria for the diagnosis of ARF are:

• Risk: serum creatinine increased 1.5 times OR urine production of <0.5>
• Injury: creatinine 2.0 times OR urine production <0.5>
• Failure: creatinine 3.0 times OR creatinine >355 μmol/l (with a rise of >44) or urine output below 0.3 ml/kg for 24 h
• Loss: persistent ARF or more than four weeks complete loss of kidney function

Kidney biopsy may be performed in the setting of acute renal failure, to provide a definitive diagnosis and sometimes an idea of the prognosis, unless the cause is clear and appropriate screening investigations are reassuringly negative.

Treatment

Acute renal failure may be reversible if treated promptly and appropriately. Resuscitation to normotension and a normal cardiac output is key. The main interventions are monitoring fluid intake and output as closely as possible; insertion of a urinary catheter is useful for monitoring urine output as well as relieving possible bladder outlet obstruction, such as with an enlarged prostate. In the absence of fluid overload, administering intravenous fluids is typically the first step to improve renal function. Fluid administration may be monitored with the use of a central venous catheter to avoid over- or under-replacement of fluid. If the cause is obstruction of the urinary tract, relief of the obstruction (with a nephrostomy or urinary catheter) may be necessary. Metabolic acidosis and hyperkalemia, the two most serious biochemical manifestations of acute renal failure, may require medical treatment with sodium bicarbonate administration and antihyperkalemic measures, unless dialysis is required.

Should hypotension prove a persistent problem in the fluid replete patient, inotropes such as norepinephrine or dobutamine may be given to improve cardiac output and hence renal perfusion. While a useful pressor, there is no evidence to suggest that dopamine is of any specific benefit, and at least a suggestion of possible harm. A Swan-Ganz catheter may be used, to measure pulmonary artery occlusion pressure to provide a guide to left atrial pressure (and thus left heart function) as a target for inotropic support.

The use of diuretics such as furosemide, while widespread and sometimes convenient in ameliorating fluid overload, does not reduce the risk of complications and death. In practice, diuretics may simply mask things, making it more difficult to judge the adequacy of resuscitation.

Lack of improvement with fluid resuscitation, therapy-resistant hyperkalemia, metabolic acidosis, or fluid overload may necessitate artificial support in the form of dialysis or hemofiltration. Depending on the cause, a proportion of patients will never regain full renal function, thus having end stage renal failure requiring lifelong dialysis or a kidney transplant.

History

Before the advancement of modern medicine, acute renal failure might be referred to as uremic poisoning. Uremia was the term used to describe the contamination of the blood with urine. Starting around 1847 this term was used to describe reduced urine output, now known as oliguria, which was thought to be caused by the urine's mixing with the blood instead of being voided through the urethra.

Acute renal failure due to acute tubular necrosis (ATN) was recognised in the 1940s in the United Kingdom, where crush victims during the Battle of Britain developed patchy necrosis of renal tubules, leading to a sudden decrease in renal function. During the Korean and Vietnam wars, the incidence of ARF decreased due to better acute management and intravenous infusion of fluids.

Renal failure

Renal failure or kidney failure is a situation in which the kidneys fail to function adequately. It is divided in acute and chronic forms; either form may be due to a large number of other medical problems.

Biochemically, it is typically detected by an elevated serum creatinine. In the science of physiology, renal failure is described as a decrease in the glomerular filtration rate. When the kidneys malfunction, problems frequently encountered are abnormal fluid levels in the body, deranged acid levels, abnormal levels of potassium, calcium, phosphate, hematuria (blood in the urine) and (in the longer term) anemia. Long-term kidney problems have significant repercussions on other diseases, such as cardiovascular disease.

Classification

Renal failure can broadly be divided into two categories: acute or chronic renal failure. The type of renal failure is determined by the trend in the serum creatinine. Other factors which may help differentiate acute and chronic kidney disease include the presence of anemia and the kidney size on ultrasound. Chronic kidney disease generally leads to anemia and small kidney size.

Acute renal failure

Acute renal failure (ARF) is, as the name implies, a rapidly progressive loss of renal function, generally characterized by oliguria (decreased urine production, quantified as less than 400 mL per day in adults, less than 0.5 mL/kg/h in children or less than 1 mL/kg/h in infants); body water and body fluids disturbances; and electrolyte derangement. An underlying cause must be identified to arrest the progress, and dialysis may be necessary to bridge the time gap required for treating these fundamental causes. ARF can result from a large number of causes.

Chronic kidney disease

Stage 5 Chronic Kidney Disease (CKD) can either develop slowly and show few initial symptoms, be the long term result of irreversible acute disease or be part of a disease progression.

Acute on chronic renal failure

Acute renal failure can be present on top of chronic renal failure. This is called acute-on-chronic renal failure (AoCRF). The acute part of AoCRF may be reversible and the aim of treatment, as with ARF, is to return the patient to their baseline renal function, which is typically measured by serum creatinine. AoCRF, like ARF, can be difficult to distinguish from chronic renal failure, if the patient has not been monitored by a physician and no baseline (i.e., past) blood work is available for comparison.

Causes

Causes of Acute Renal Failure

Acute kidney failure usually occurs as the result of a sudden interruption in the blood supply to the kidney, or as a result of a toxic overload of the kidneys. Some causes of acute failure include accidents, injuries or complications from surgery where the kidneys are deprived of normal blood flow for an extended period of time. Heart-bypass surgery is an example of a situation in which the kidneys receive reduced blood flow.

Drug overdoses, whether accidental or from chemical overloads of drugs such as antibiotics or chemotherapy, may also cause the onset of acute kidney failure. Unlike in chronic kidney disease, however, the kidneys can often recover from acute failure, allowing the patient to resume a normal life. People suffering from acute failure require supportive treatment until their kidneys recover function, and they often remain at an increased risk of developing future kidney failure.

Causes of Chronic Kidney Disease

There are many causes of CKD. The most common cause is diabetes mellitus. The second most common cause is long-standing, uncontrolled, hypertension. Polycystic kidney diease is also a well known cause of chronic kidney disease. The majority of people afflicted with polycystic kidney disease have a family history of the disease. Many other genetic illnesses also affect kidney function. Overuse of some common drugs, such as aspirin, ibuprofen and acetaminophen can also cause chronic kidney damage.

Investigation

Methods of Measurement for CKD

Stages of Kidney Failure

Chronic kidney failure is measured in five stages, which are calculated using a patient’s GFR, or glomerular filtration rate. Stage 1 CKD is mildly diminished renal function, with few overt symptoms. Stages 2 and 3 need increasing levels of supportive care from their medical providers to slow and treat their renal dysfunction. Patients in stages 4 and 5 usually require preparation of the patient towards active treatment in order to survive.Stage 5 CKD is considered a severe illness and requires some form of renal replacement therapy (dialysis) or kidney transplant whenever feasible.

Glomerular Filtration Rate

A normal GFR varies according to many factors, including sex, age, body size and ethnicity. Renal professionals consider the glomerular filtration rate (GFR) to be the best overall index of kidney function. The National Kidney Foundation offers an easy to use on-line GFR calculator at the following webpage for anyone who is interested in knowing their glomerular filtration rate.(A serum creatinine level, a simple blood test, is needed to use the calculator).

Use of the term uremia

Before the advancement of modern medicine, renal failure was often referred to as uremic poisoning. Uremia was the term used to describe the contamination of the blood with urine. Starting around 1847, this term was used to describe reduced urine output, that was thought to be caused by the urine mixing with the blood instead of being voided through the urethra. The term uremia is now used to loosely describe the illness accompanying kidney failure.

Pyelonephritis

Pyelonephritis is an ascending urinary tract infection that has reached the pyelum (pelvis) of the kidney. If the infection is severe, the term "urosepsis" is used interchangeably (sepsis being a systemic inflammatory response syndrome due to infection). It requires antibiotics as therapy, and treatment of any underlying causes to prevent recurrence. It is a form of nephritis. It can also be called pyelitis.

Signs and symptoms

It presents with dysuria (painful voiding of urine), abdominal pain (radiating to the back on the affected side) and tenderness of the bladder area and the side of the involved kidney ("renal angle tenderness") which may be elicited by performing the kidney punch. In many cases there are systemic symptoms in the form of fever, rigors (violent shivering while the temperature rises), headache and vomiting. In severe cases, delirium may be present.

Diagnosis

The presence of nitrite and leukocytes (white blood cells) on a urine dipstick test in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Formal diagnosis is with culture of the urine; blood cultures may be needed if the source of the infection is initially doubtful.

If a kidney stone is suspected (e.g. on the basis of characteristic colicky pain, disproportionate amount of blood in the urine), X-rays of the kidneys, ureters and bladder (KUB) may assist in identifying radioopaque stones.

In patients with recurrent ascending urinary tract infections, it may be necessary to exclude an anatomical abnormality, such as vesicoureteral reflux (urine from the bladder flowing back into the ureter) or polycystic kidney disease. Investigations that are commonly used in this setting are ultrasound of the kidneys or voiding cystourethrography.

Causes

Most cases of "community-acquired" pyelonephritis are due to bowel organisms that enter the urinary tract. Common organisms are E. coli (70-80%) and Enterococcus faecalis. Hospital-acquired infections may be due to coliforms and enterococci, as well as other organisms uncommon in the community (e.g. Klebsiella spp., Pseudomonas aeruginosa). Most cases of pyelonephritis start off as lower urinary tract infections, mainly cystitis and prostatitis.

Risk is increased in the following situations:

• Mechanical: any structural abnormalities to the kidneys and the urinary tract, vesicoureteral reflux (VUR) especially in young children, calculi (kidney stones), urinary tract catheterisation, urinary tract stents or drainage procedures (e.g. nephrostomy), pregnancy, neurogenic bladder (e.g. d ue to spinal cord damage, spina bifida or multiple sclerosis) and prostate disease (e.g. benign prostatic hyperplasia) in men
• Constitutional: diabetes mellitus, immunocompromised states
• Behavioural: change in sexual partner within the last year, spermicide use
• Positive family history (close family members with frequent urinary tract infections)

Pathology

Acute pyelonephritis is an exudative purulent localized inflammation of the renal pelvis (collecting system) and kidney. The renal parenchyma presents in the interstitium abscesses (suppurative necrosis), consisting in purulent exudate (pus): neutrophils, fibrin, cell debris and central germ colonies (hematoxylinophils). Tubules are damaged by exudate and may contain neutrophil casts. In the early stages, glomeruli and vessels are normal. Gross pathology often reveals pathognomonic radiations of hemorrhage and suppuration through the renal pelvis to the renal cortex. Chronic infections can result in fibrosis and scarring.

Treatment

As practically all cases of pyelonephritis are due to bacterial infections, antibiotics are the mainstay of treatment. Mild cases may be treated with oral therapy, but generally intravenous antibiotics are required for the initial stages of treatment. The type of antibiotic depends on local practice, and may include fluoroquinolones (e.g. ciprofloxacin), beta-lactam antibiotics (e.g. amoxicillin or a cephalosporin), trimethoprim (or co-trimoxazole) or nitrofurantoin. Aminoglycosides are avoided due to their toxicity, but may be added for a short duration.

All acute cases with spiking fevers and leukocytosis should be admitted to the hospital for IV fluids hydration and IV antibiotic treatment immediately. ciprofloxacin IV 400mg every 12 hours is the first line treatment of choice. Alternatively, ampicillin IV 2g every 6 hours plus gentamicin IV 1mg/kg every 8 hours also provide excellent coverage. If the patient is pregnant, ampicillin/gentamicin combination is the treatment of choice, as ciprofloxacin is contraindicated. During the course of antibiotic treatment, serial white blood count and temperature should be closely monitored. Typically, the IV antibiotics should be continued till the patient is afebrile for at least 24 to 48 hours, then equivalent oral antibiotic agents can be given for a total of 2-week duration of treatment.

If the patient is unwell and septic, intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to maximise urine output.

In recurrent infections, additional investigations may identify an underlying abnormality. Occasionally, surgical intervention is necessary to improve chances of recurrence. If no abnormality is identified, some studies suggest long-term preventative (prophylactic) treatment with antibiotics, either daily or after sexual intercourse. In children at risk of recurrent UTIs, meta-analysis of the present literature indicates that not enough studies have been performed to conclude prescription of long-term antibiotics have a net positive benefit. Ingestion of cranberry juice has been studied as a prophylactic measure; while studies are heterogeneous, many suggest a benefit.

Some recommend other nutritional approaches to prevent recurrence of UTIs. Increasing fluid intake, consuming cranberry juice, blueberry juice, and fermented milk products containing probiotic bacteria, have been shown to inhibit adherence of bacteria to the epithelial cells of the urinary tract.

Epidemiology

Pyelonephritis is very common, with 12-13 cases annually per 10,000 population in women and 3-4 cases per 10,000 in men. Young women are most likely to be affected, traditionally reflecting sexual activity in that age group. Infants and the elderly are also at increased risk, reflecting anatomical abnormalities and hormonal status.

Nephrotic Syndrome

Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein (at least 3.5 grams per day per 1.73m2 body surface area) from the blood into the urine.

Presentation

It is characterised by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia and edema. A few other characteristics are:

• The most common sign is excess fluid in the body. This may take several forms:
  • Puffiness around the eyes, characteristically in the morning.
  • Edema over the legs which is pitting (i.e. leaves a little pit when the fluid is pressed out, which resolves over a few seconds).
  • Fluid in the pleural cavity causing pleural effusion.
  • Fluid in the peritoneal cavity causing ascites.
• Hypertension (rarely)
• Some patients may notice foamy urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as hematuria or oliguria are uncommon, and are seen commonly in nephritic syndrome.
• May have features of the underlying cause, such as the rash associated with Systemic Lupus Erythematosus, or the neuropathy associated with diabetes.
• Examination should also exclude other causes of gross edema—especially the cardiovascular and hepatic system.

Investigations

The following are baseline, essential investigations

• Urine sample shows proteinuria (>3.5 per 1.73 m2 per 24 hour). It is also examined for urinary casts; which is more a feature of active nephritis.
• Comprehensive metabolic panel (CMP) shows Hypoalbumi nemia: albumin level ≤2.5g/dL (normal=3.5-5g/dL).
• High levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly elevated VLDL
• Electrolytes, urea and creatinine (EUCs): to evaluate renal function

Further investigations are indicated if the cause is not clear

• Biopsy of kidney
• Auto-immune markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis)

Classification and causes

Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney, called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.

Etiologic classification

A broad classification of nephrotic syndrome based on etiology:

Nephrotic syndrome

Primary

Secondary

Histologic classification

Nephrotic syndrome is often classified histologically:

Nephrotic syndrome

MCD

FSGS

MN

MPGN

Primary causes

Primary causes of nephrotic syndrome are usually described by the histology, i.e. minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN).

They are considered to be "diagnoses of exclusion", i.e. they are diagnosed only after secondary causes have been excluded.

Secondary causes

Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though may exhibit some differences suggesting a secondary cause, such as inclusion bodies.

They are usually described by the underlying cause.

Secondary causes by histologic pattern

Membranous nephropathy (MN)

• Hepatitis B
  
• Sjogren's syndrome
• Systemic lupus erythematosus(SLE)
• Diabetes mellitus
• Sarcoidosis
• Syphilis
• Drugs
• Malignancy (cancer)

Focal segmental glomerulosclerosis (FSGS)

• Hypertensive Nephrosclerosis
• Human immunodeficiency virus (HIV)
• Diabetes mellitus
• Obesity
  
• Kidney loss

Minimal change disease (MCD)

• Drugs
• Malignancy, especially Hodgkin's lymphoma

Differential diagnosis of gross edema

When someone presents with generalized edema, the following causes should be excluded:

1. Heart failure: The patient is older, with a history of heart disease. Jugular venous pressure is elevated on examination, might hear heart murmurs. An echocardiogram is the gold standard investigation.
2. Liver failure: History suggestive of hepatitis/ cirrhosis: alcoholic, IV drug user, some hereditary causes.
   Stigmata of liver disease are seen: jaundice (yellow skin and eyes), dilated veins over umbilicus (caput medusae), scratch marks (due to widespread itching, known as "pruritus"), enlarged spleen, spider angiomata, encephalopathy, bruising, nodular liver
3. Acute fluid overload in someone with kidney failure: These people are known to have kidney failure, and have either drunk too much or missed their dialysis.
4. Metastatic cancer: When cancer seeds the lungs or abdomen it causes effusions and fluid accumulation due to obstruction of lymphatics and veins as well as serous exudation.

Diagnosis

Diagnosis is based on blood and urine tests and sometimes imaging of the kidneys, a biopsy of the kidneys, or both.

Treatment

Treatment includes:

General measures (supportive)

• Monitoring and maintaining euvolemia (the correct amount of fluid in the body):
  • monitoring urine output, BP regularly
  • fluid restrict to 1L
  • diuretics (IV furosemide)

• Monitoring kidney function:
  • do EUCs daily and calculating GFR

• Prevent and treat any complications

• Albumin infusions are generally not used because their effect lasts only transiently.

Specific treatment of underlying cause

Immunosupression for the glomerulonephritides (Corticosteroids, cyclosporin).

Standard ISKDC Regime for first episode:Prednisolone -60mg/m² /day in 3 divided doses for 4weeks followed by 40mg/m²/day in a single dose on every alternate day for 4 weeks.

Relapses by prednisolone 2mg/kg/day till urine becomes negative for protein.Then,1.5mg/kg/day for 4 weeks.

Frequent Relapses treated by:cyclophosphamide or nitrogen mustard or cyclosporin or levamisole.

Achieving stricter blood glucose control if diabetic.

Blood pressure control. ACE inhibitors are the drug of choice. Independent of their blood pressure lowering effect, they have been shown to decrease protein loss.

Dietary recommendations

Reduce sodium intake to 1000-2000 milligrams daily. Foods high in sodium include salt used in cooking and at the table, seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods, fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to calories per serving. Sodium should be less than or equal to calories per serving.

Eat a moderate amount of high protein animal food: 3-5 oz per meal (preferably lean cuts of meat, fish, and poultry)

Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and nuts. Eat low-fat desserts.

Increase intake of fruits and vegetables. There is no potassium or phosphorus restriction necessary.

Monitor fluid intake, which includes all fluids and foods that are liquid at room temperature. Fluid management in nephrotic syndrome is tenuous, especially during an acute flare.

Complications

• Venous thrombosis: due to leak of anti-thrombin 3, which helps prevent thrombosis. This often occurs in the renal veins. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin 3 which is lost in the proteinuria so it will be ineffective.)

• Infection: due to leakage of immunoglobulins, encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumonia can cause infection.

• Acute renal failure is due to hypovolemia. Despite the excess of fluid in the tissues, there is less fluid in the vasculature. Decreased blood flow to the kidneys causes them to shutdown. Thus it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia.

• Pulmonary edema: again due to fluid leak, sometimes it leaks into lungs causing hypoxia and dyspnoea.

• Growth retardation: does not occur in MCNS.It occurs in cases of relapses or resistance to therapy. Causes of growth retardation are protein deficiency from the loss of protein in urine, anorexia (reduced protein intake), and steroid therapy (catabolism).

• Vitamin D deficiency can occur. Thyroxine is reduced due to decreased thyroid binding globulin.

• Microcytic hypochromic anaemia is typical. It is iron-therapy resistant.

Prognosis

The prognosis depends on the cause of nephrotic syndrome. It is usually good in children, because minimal change disease responds very well to steroids and does not cause chronic renal failure. However other causes such as focal segmental glomerulosclerosis frequently lead to end stage renal disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood pressure control and kidney function (GFR).

Minimal change disease

Minimal change disease or nil disease (lipoid nephrosis) is a disease of the kidney which causes nephrotic syndrome and usually affects children (peak incidence at 2-3 years of age).

Minimal change disease is most common in very young children, but can occur in older children and adults. It is by far the most common cause of nephrotic syndrome (NS) in children under 10 years of age, accounting for the majority (about 90%) of these diagnoses. Among teenagers who develop NS, it is caused by minimal change disease about half the time. It can also occur in adults, but accounts for less than 20% of adults diagnosed with NS. Among children less than 10 years of age, boys seem to be more likely to develop minimal change disease than girls.

Symptoms

The symptoms are proteinuria (leakage of protein into the urine) and edema (water retention). Nephrotic syndrome (NS) is a general term that refers to the loss of protein in the urine. Many conditions are categorized as nephrotic syndromes -- minimal change disease is unique, because it is the only one lacking any evidence of pathology on light microscopy. When viewed with an electron microscope, it discloses diffuse loss of visceral epithelial cells (podocyte) foot processes.

When protein is lost in the urine, its blood concentration decreases, allowing water to move into other areas of the body, which leads to swelling known as edema. Edema is commonly observed in the feet and legs, in the belly or abdomen, and around the eyes, but can occur anywhere, especially in response to gravity. Additionally, because of this extra fluid that stays in the body, people often gain weight and experience fatigue -- in many patients, for example, their usual clothes and shoes will no longer fit. Some people notice that their urine becomes more frothy, and may find that they urinate less often.

Causes

Minimal change disease can be associated with food allergies, medications, or hematologic malignancies, or it can occur idiopathically. The pathology does not appear to involve complement, immunoglobulins, or immune complex deposition. Rather, an altered cell-mediated immunologic response with abnormal secretion of lymphokines by T cells is thought to reduce the production of anions in the glomerular basement membrane, thereby increasing the glomerular permeability to serum albumin through a reduction of electrostatic repulsion. The loss of anionic charges is also thought to favor foot process fusion. With minimal change disease the kidney tissue appears normal under a light microscope, but shows podocyte foot process effacement under an electron microscope.

Treatment

Prednisone is prescribed along with a blood pressure medication, typically an ACE inhibitor such as lisinopril. Some nephrologists will start out with the ACE inhibitor first in an attempt to reduce the blood pressure's force which pushes the protein through the cell wall in order to lower the proteinuria. In some cases a corticosteroid may not be necessary if the case of minimal change disease is mild enough to be treated just with the ACE Inhibitor. Often the liver is overactive with minimal change disease in an attempt to replace lost protein and over produces cholesterol. Therefore a statin drug is often prescribed for the duration of the treatment. When the urine is clear of protein, the drugs can be discontinued. 50% of patients will relapse and need further treatment.

Minimal change disease usually responds well to initial treatment, with the symptoms of nephrotic syndrome (NS) typically going away, but this can take weeks to months. Younger children, who are more likely to develop minimal change disease, usually respond faster than adults. In 2 out of 3 children with minimal change diease, however, the symptoms of NS can reoccur, called a Relapse, particularly after an infection or an allergic reaction. This is typical, and usually requires additional treatment. Many children experience 3 to 4 Relapses before the disease starts to go away. Some children require longer term therapy to keep MCD under control. It appears that the more time one goes without a Relapse, the better the chances are that a Relapse will not occur. In most children with minimal change disease, particularly among those who respond typically, there is minimal to no permanent damage observed in their kidneys.

With steroid treatment, the symptoms of nephrotic syndrome (NS) will go away, called remission, in the majority of children with minimal change disease. This typically occurs faster, over 2 to 8 weeks, in younger children, but can take up to 3 or 4 months in adults. Typically the dose of steroids will initially be fairly high, lasting 1or 2 months. At some point after the urine protein levels have become normal again, the dose of steroids might be switched to an every-other-day schedule, then very slowly reduced over the course of several months. It is very important to taper, or gradually reduce, the dose of steroids. The body does not respond well to a sudden discontinuation of steroids, and this might also trigger a relapse, or return of NS symptoms. Giving steroids initially for a longer period of time is thought to reduce the likelihood of relapse. The majority of children with minimal change disease will respond to this treatment.

Even among those who respond well to steroids initially, it is common to observe periods of relapse (return of NS symptoms). Because of the potential for relapse, your physician might prescribe and teach you how to use a tool to have you check urine protein levels at home. Two out of 3 children who initially responded to steroids will experience this at least once. Typically the steroids will be restarted when this occurs, although the total duration of steroid treatment is usually shorter during relapses than it is during the initial treatment of the disease.

Though steroids are the first-line therapy for minimal change disease, they have a significant number of side effects, inlcuding, but not limited to, suppression of the immune system, increase risk for diabetes, weight gain, increased risk for high blood pressure, osteoporosis, and cataract formation. Steroids also raise a person's cholesterol.

If steroids are not successful, or are contraindicated for various reasons, alternate therapies exist, including cyclosporine, tacrolimus, and mycophenilate mofetil (Cellcept). Of these, Cellcept offers the best "bang for buck", in terms of least side effects, and allowance of reducation in steroid dosage. It must be noted, however, that the immune system of suppresion of Cellcet and Prednisone are ADDITIVE, and place the person at significant risk of infection.

Lupus nephritis

Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus (SLE), a disease of the immune system. Apart from the kidneys, SLE can also damage the skin, joints, nervous system and virtually any organ or system in the body.

Signs and symptoms

Sufferers of lupus nephritis may or may not have symptoms of kidney disease, but it can manifest itself through weight gain, high blood pressure, darker foamy urine or swelling around the eyes, legs, ankles or fingers.

Histologically a wire-loop lesion will be present. The wire loop lesion is a glomerular capillary loop with subendothelial immune complex deposition that is circumferential around the loop.

Furthermore, patients may suffer from other symptoms of lupus unrelated to kidney function. Such symptoms can include arthritis, fevers, gastro-intestinal disturbances, headaches, fatigue, and fluid in the joints.

Diagnosis

The diagnosis of lupus nephritis depends on blood tests, urinalysis, X-rays, ultrasound scans of the kidneys, and a kidney biopsy.

The World Health Organization has divided lupus nephritis into five classes based on the biopsy. This classification was defined in 1982

and revised in 1995.

• Class I is minimal mesangial glomerulonephritis which is histologically normal on light microscopy but with mesangial deposits on electron microscopy.
• Class II is based on a finding of mesangial p roliferative lupus nephritis. This form typically responds completely to treatment with corticosteroids.
• Class III is focal proliferative nephritis and often successfully responds to treatment with high doses of corticosteroids.
• Class IV is diffuse proliferative nephritis. This form is mainly treated with corticosteroids and immunosuppressant drugs.
• Class V is membranous nephritis and is characterized by extreme edema and protein loss.
• Class VI Glomerulosclerosis

Medicines that decrease swelling, lower blood pressure, and decrease inflammation by suppressing the immune system: Patients may need to monitor intake of protein, sodium, and potassium. Patients with severe disease should restrict their sodium intake to 2 grams per day and limit fluid as well. Depending on the histology, renal function and degree of proteinuria, patients may require steroid therapy or chemotherapy regimens such as cyclophosphamide, azathioprine, mycophenolate mofetil, or cyclosporine.

(Lupus Nephritis -- Diffuse Proliferative)

The medical therapy for lupus nephritis depends on the severity of the disease. For mild disease, corticosteroids are, in general, prescribed. More severe disease requires treatment with immunosuppressant agents. The two most commonly-used agents are mycophenolate mofetil and intravenous cyclophosphamide. One recent study compared these two drugs. The authors showed that patients with Class III or IV disease are more likely to benefit from mycophenolate mofetil as compared to cyclophosphamide. However, a larger study by the same authors that directly compared these therapies did not show that Mycophenolate was superiour to cyclophosphamide except in non-caucasian non-asian patients. In caucasian or asian patients both treatments worked equally well. There was no overall difference in safety in this trial, although cyclophosphamide may induce permanent infertility in young women, which is a significant drawback. As a result, mycophenolate mofetil is now considered to be an alternative therapy for this disease.

Kidney Tumors

Wilms' tumor

Wilms' tumor or nephroblastoma is a tumor of the kidneys that typically occurs in children, rarely in adults. Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon (1867-1918) who first described this kind of tumor.

Approximately 500 cases are diagnosed in the U.S. annually. The majority (75%) occur in otherwise normal children; a minority (25%) is associated with other developmental abnormalities. It is highly responsive to treatment, with about 90% of patients surviving at least five years.

Pathology

Pathologically, a triphasic nephroblastoma comprises three elements:

• blastema
  
• mesenchyme
• epithelium

Wilms' tumor is a malignant tumor containing metanephric blastema, stromal and epithelial derivatives. Characteristic is the presence of abortive tubules and glomeruli surrounded by a spindled cell stroma. The stroma may include striated muscle, cartilage, bone, fat tissue, fibrous tissue. The tumor is compressing the normal kidney parenchyma.

The mesenchymal component may include cells showing rhabdomyoid differentiation. The rhabdomyoid component may itself show features of malignancy (rhabdomyosarcomatous Wilms).

Wilms tumor may be separated into 2 prognostic groups based on pathologic characteristics:

• Favorable - Contains well developed components mentioned above
• Anaplastic - Contains diffuse anaplasia (poorly developed cells)

Molecular biology

Mutations of the WT1 gene on chromosome 11 are observed in approximately 20% of Wilms tumors. At least half of the Wilms tumors with mutations in WT1 also carry mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin.

A gene on the X chromosome, WTX, is inactivated in up to 30% of Wilms tumor cases.

Many cases do not have mutations in any of these genes.

Staging and treatment

Staging is determined by combination of imaging studies, and pathologic findings if the tumor is operable. Treatment strategy is determined by the stage:

Stage I (43% of patients)

For stage I Wilms' tumor, 1 or more of the following criteria must be met:

• Tumor is limited to the kidney and is completely excised.
• The surface of the renal capsule is intact.
• The tumor is not ruptured or biopsied (open or needle) prior to removal.
• No involvement of renal sinus vessels.
• No residual tumor apparent beyond the margins of excision.

Treatment: Nephrectomy + 18 weeks of chemotherapy

Outcome: 98% 4-year survival; 85% 4-year survival if anaplastic

Stage II (23% of patients)

For Stage II Wilms' tumor, 1 or more of the following criteria must be met:

• Tumor extends beyond the kidney but is completely excised.
• No residual tumor apparent at or beyond the margins of excision.
• Any of the following conditions may also exist:
  • Tumor involvement of the blood vessels of the renal sinus and/or outside the renal parenchyma.
  • The tumor has been biopsied prior to removal or there is local spillage of tumor during surgery, confined to the flank.

Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy

Outcome: 96% 4-year survival; 70% 4-year survival if anaplastic

Stage III (23% of patients)

For Stage III Wilms' tumor, 1 or more of the following criteria must be met:

• Unresectable primary tumor.
• Lymph node metastasis.
• Positive surgical margins.
• Tumor spillage involving peritoneal surfaces either before or during surgery, or transected tumor thrombus.

Treatment: Abdominal radiation + 24 weeks of chemotherapy + nephrectomy after tumor shrinkage

Outcome: 95% 4-year survival; 56% 4-year survival if anaplastic

Stage IV (10% of patients)

Stage IV Wilms' tumor is defined as the presence of hematogenous metastases (lung, liver, bone, or brain), or lymph node metastases outside the abdomenopelvic region.

Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy + radiation of metastatic site as appropriate

Outcome: 90% 4-year survival; 17% 4-year survival if anaplastic

Stage V (5% of patients)

Stage V Wilms’ tumor is defined as bilateral renal involvement at the time of initial diagnosis. Note: For patients with bilateral involvement, an attempt should be made to stage each side according to the above criteria (stage I to III) on the basis of extent of disease prior to biopsy. The 4-year survival was 94% for those patients whose most advanced lesion was stage I or stage II; 76% for those whose most advanced lesion was stage III.

Treatment: Individualized therapy based on tumor burden

Stage I-IV Anaplasia

Children with stage I anaplastic tumors have an excellent prognosis (80-90% five-year survival). They can be managed with the same regimen given to stage I favorable histology patients.

Children with stage II through stage IV diffuse anaplasia, however, represent a higher-risk group. These tumors are more resistant to the chemotherapy traditionally used in children with Wilms’ tumor (favorable histology), and require more aggressive regimens.

Treatment

Once a kidney tumor is found, surgery can find out whether or not the tumor is cancer. A sample of tissue from the tumor is sent to a pathologist, who looks at it under a microscope to check for signs of cancer. If the tumor is only in the kidney, it can be removed along with the whole kidney (a process called nephrectomy). If there are tumors in both kidneys or if the tumor has spread outside the kidney, a piece of the tumor will be removed.

Renal cell carcinoma

Renal cell carcinoma (RCC) is the most common form of kidney cancer arising from the renal tubule. It is the most common type of kidney cancer in adults. Initial treatment is most commonly a radical or partial nephrectomy. Where the tumour is confined to the renal parenchyma, the 5-year survival rate is 60-70%, but this is lowered considerably where metastases have spread. It is resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib have improved the outlook for RCC, although they have not yet demonstrated improved survival.

Signs and symptoms

The classic triad is hematuria (blood in the urine), flank pain and an abdominal mass. This is now known as the 'too late triad' because by the time patients present with symptoms, their disease is often advanced beyond a curative stage. In addition, whilst this triad is highly suggestive of RCC, it only occurs in around 15% of the sufferers. Today, the majority of renal tumors are asymptomatic and are detected incidentally on imaging, usually for an unrelated cause.

Signs may include:

• Abnormal urine color (dark, rusty, or brown) due to blood in the urine (found in 60% of cases)
• Loin pain (found in 40% of cases)
• Abdominal mass (25% of cases)
• Malaise, weight loss or anorexia (30% of cases)
• Polycthemia (5% of cases)
• Anaemia resulting from depression of erythropoietin (5% of cases)
• The presenting symptom may be due to metastatic disease, such as a pathologic fracture of the hip due to a metastasis to the bone
• Enlargement of one testicle known as varicocele (usually the left, due to blockage of the left gonadal vein by tumor invasion of the left renal vein -- the right gonadal vein drains directly into the inferior vena cava)
• Vision abnormalities
• Pallor or plethora
• Hirsutism - Excessive hair growth (females)
• Constipation
• Hypertension (high blood pressure) resulting from secretion of renin by the tumour (30% of cases)
Elevated calcium levels (Hypercalcemia)
Paraneoplastic disease

Causes

Renal cell carcinoma affects about three in 10,000 people, resulting in about 31,000 new cases in the US per year. Every year, about 12,000 people in the US die from renal cell carcinoma. It is more common in men than women, usually affecting men older than 55.

Kidney cancer both RCC & TCC currently is diagnosed in some 6,600 people in Britain/UK per annum and some 3,600 people who die are recorded as having died of kidney cancer in a given year. The morbidity rate recorded is thought to underestimate the percentage who die of kidney cancer. Often the cause of death recorded on the death certificate may not mention kidney cancer but the subsequent metastases. It is clear that well over 50% of those diagnosed with kidney cancer in Britain will die as a result of the disease.

Why the cells become cancerous is not known. A history of smoking greatly increases the risk for developing renal cell carcinoma. Some people may also have inherited an increased risk to develop renal cell carcinoma, and a family history of kidney cancer increases the risk.

Increasingly there is a belief that inhalation of a diversity of chemicals may be causal and it is also noted that there is a steady increase in diagnosis in women. That a disproportionate percentage of those diagnosed with kidney cancer are obese is increasingly believed to be a significant factor.

People with von Hippel-Lindau disease, a hereditary disease that also affects the capillaries of the brain, commonly also develop renal cell carcinoma, specifically the clear cell type of RCC. Kidney disorders that require dialysis for treatment also increase the risk for developing renal cell carcinoma.

Pathology

(Renal cell carcinoma)

Gross examination shows a yellowish, multilobulated tumor in the renal cortex, which frequently contains zones of necrosis, hemorrhage and scarring.

Light microscopy shows tumor cells forming cords, papillae, tubules or nests, and are atypical, polygonal and large. Because these cells accumulate glycogen and lipids, their cytoplasm appear "clear", lipid-laden, the nuclei remain in the middle of the cells, and the cellular membrane is evident. Some cells may be smaller, with eosinophilic cytoplasm, resembling normal tubular cells. The stroma is reduced, but well vascularized. The tumor compresses the surrounding parenchyma, producing a pseudocapsule.

Secretion of vasoactive substances (e.g. renin) may cause arterial hypertension, and release of erythropoietin may cause erythrocytosis (increased production of red blood cells).

Radiology

(Renal cell carcinoma)

The characteristic appearance of renal cell carcinoma (RCC) is a solid renal lesion which disturbs the renal contour. It will frequently have an irregular or lobulated margin. 85% of solid renal masses will be RCC. 10% of RCC will contain calcifications, and some contain macroscopic fat (likely due to invasion and encasement of the perirenal fat). Following intravenous contrast administration (computed tomography or magnetic resonance imaging), enhancement will be noted, and will increase the conspicuity of the tumor relative to normal renal parenchyma.

A list of solid renal lesions includes:

• renal cell carcinoma
• metastasis from an extra-renal primary neoplasm
• renal lymphoma
• squamous cell carcinoma
• juxtaglomerular tumor (reninoma)
• transitional cell carcinoma
  
• angiomyolipoma
• oncocytoma
• Wilm's tumor

In particular, reliably distinguishing renal cell carcinoma from an oncocytoma (a benign lesion) is not possible using current medical imaging or percutaneous biopsy.

Renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, hemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one. A classification system for cystic renal lesions that classifies them based specific imaging features into groups that are benign and those that need surgical resection is available. At diagnosis, 30% of renal cell carcinoma has spread to that kidney's renal vein, and 5-10% has continued on into the inferior vena cava.

Percutaneous biopsy can be performed by a radiologist using ultrasound or computed tomography to guide sampling of the tumor for the purpose of diagnosis. However this is not routinely performed because when the typical imaging features of renal cell carcinoma are present, the possibility of an incorrectly negative result together with the risk of a medical complication to the patient make it unfavorable from a risk-benefit perspective.This is not completely accurate, there are new experimental treatments.

Treatment

If it is only in the kidneys, which is about 40% of cases, it can be cured roughly 90% of the time with surgery. If it has spread outside of the kidneys, often into the lymph nodes or the main vein of the kidney, then it must be treated with adjunctive therapy, including cytoreductive surgery.

Watchful waiting

Small renal tumors represent the majority of tumors that are treated today by way of partial nephrectomy. The average growth of these masses is about 4-5 mm per year, and a significant proportion (up to 40%) of tumors less than 4cm in diameter are benign. More centers of excellence are incorporating needle biopsy to confirm the presence of malignant histology prior to recommending definitive surgical extirpation. In the elderly, patients with co-morbidities and in poor surgical candidates, small renal tumors may be monitored carefully with serial imaging. Most clinicians conservatively follow tumors up to a size threshold between 3-5 cm, beyond which the risk of distant spread (metastases) is about 5%.

Surgery

Surgical removal of all or part of the kidney (nephrectomy) is recommended.This may include removal of the adrenal gland, retroperitoneal lymph nodes, and possibly tissues involved by direct extension (invasion) of the tumor into the surrounding tissues. In cases where the tumor has spread into the renal vein, inferior vena cava, and possibly the right atrium (angioinvasion), this portion of the tumor can be surgically removed, as well. In case of metastases surgical resection of the kidney ("cytoreductive nephrectomy") may improve survival, as well as resection of a solitary metastatic lesion.

Percutaneous therapies

Percutaneous, image-guided therapies, usually managed by radiologists, are being offered to patients with localized tumor, but who are not good candidates for a surgical procedure. This sort of procedure involves placing a probe through the skin and into the tumor using real-time imaging of both the probe tip and the tumor by computed tomography, ultrasound, or even magnetic resonance imaging guidance, and then destroying the tumor with heat (radiofrequency ablation) or cold (cryotherapy). These modalities are at a disadvantage compared to traditional surgery in that pathologic confirmation of complete tumor destruction is not possible.

Medications

RCC "elicits an immune response, which occasionally results in dramatic spontaneous remissions." This has encouraged a strategy of using immunomodulating therapies, such as cancer vaccines and interleukin-2 (IL-2), to reproduce this response. IL-2 has produced "durable remissions" in a small number of patients, but with substantial toxicity. Another strategy is to restore the function of the VHL gene, which is to destroy proteins that promote inappropriate vascularization. Bevacizumab, an antibody to VEGF, has significantly prolonged time to progression, but phase 3 trials have not been published. Sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus, which are small-molecule inhibitors of proteins, have been approved by the U.S. F.D.A.

Sorafenib was FDA approved in December 2005 for treatment of advanced renal cell cancer, the first receptor tyrosine kinase (RTK) inhibitor indicated for this use.

A month later, Sunitinib was approved as well. Sunitinib—an oral, small-molecule, multi-targeted (RTK) inhibitor—and sorafenib both interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation. Sunitinib appears to offer greater potency against advanced RCC, perhaps because it inhibits more receptors than sorafenib. However, these agents have not been directly compared against one another in a single trial.

Temsirolimus (CCI-779) is an inhibitor of mTOR kinase (mamallian target of rapamycin) that was shown to prolong overall survival vs. interferon-α in patients with previously untreated metastatic renal cell carcinoma with three or more poor prognostic features. The results of this Phase III randomized study were presented at the 2006 annual meeting of the American Society of Clinical Oncology.

Chemotherapy

Chemotherapy may be used in some cases, but cure is unlikely unless all the cancer can be removed with surgery. The use of Tyrosine Kinase (TK) inhibitors, such as Sunitinib and Sorafenib, and Temsirolimus are described in a different section.

Vaccine

Cancer vaccines, such as TroVax, are in phase 3 trials for treatment of renal cell carcinoma.

Cryoablation

This involves destroying the kidney tumor without surgery, by freezing the tumor. The process can remove 95% of tumors in one treatment and can be tolerated by patients who are not good candidates for surgery (older or weak patients).

The outcome varies depending on the size of the tumor, whether it is confined to the kidney or not, and the presence or absence of metastatic spread. The Fuhrman grading, which measures the aggressiveness of the tumor, may also affect survival, though the data is not as strong to support this.

The five year survival rate is around 90-95% for tumors less than 4 cm. For larger tumors confined to the kidney without venous invasion, survival is still relatively good at 80-85%. For tumors that extend through the renal capsule and out of the local fascial investments, the survivability reduces to near 60%. If it has metastasized to the lymph nodes, the 5-year survival is around 5 % to 15 %. If it has spread metastatically to other organs, the 5-year survival rate is less than 5 %.

For those that have tumor recurrence after surgery, the prognosis is generally poor. Renal cell carcinoma does not generally respond to chemotherapy or radiation. Immunotherapy, which attempts to induce the body to attack the remaining cancer cells, has shown promise. Recent trials are testing newer agents, though the current complete remission rate with these approaches are still low, around 12-20% in most series.

Kidney stones

Kidney stones, also called renal calculi, are solid concretions (crystal aggregations) of dissolved minerals in urine; calculi typically form inside the kidneys or bladder. The terms nephrolithiasis and urolithiasis refer to the presence of calculi in the kidneys and urinary tract, respectively.

Overview

The kidneys are a pair of organs that are primarily responsible for filtering metabolites and minerals from the circulatory system. These secretions are then passed to the bladder and out of the body as urine. Some of the substances found in urine are able to crystalize, and in a concentrated form these chemicals can precipitate into a solid deposit attached to the kidney walls. These crystals can grow through a process of accretion to form a kidney stone. In medical terminology these deposits are known as renal calculi.

Renal calculi can vary in size from as small as grains of sand to as large as a golf ball. Kidney stones typically leave the body by passage in the urine stream, and many stones are formed and passed without causing symptoms. If stones grow to sufficient size before passage—on the order of at least 2-3 millimeters—they can cause obstruction of the ureter. The resulting obstruction with dilation or stretching of the upper ureter and renal pelvis as well as spasm of muscle, trying to move the stone, can cause severe episodic pain, most commonly felt in the flank, lower abdomen and groin (a condition called renal colic). Renal colic can be associated with nausea and vomiting due to the embryological association of the kidneys with the intestinal tract. Hematuria (bloody urine) is commonly present due to damage to the lining of the urinary tract.

The incidence rate increases to 20–25%, because of increased risk of dehydration in hot climates.Men are affected approximately 4 times more often than women. Recent evidence has shown an increase in pediatric cases.

Causes

(Staghorn calculus)

Kidney stones can be due to underlying metabolic conditions, such as renal tubular acidosis, Dent's disease and medullary sponge kidney. Many health facilities will screen for such disorders in patients with recurrent kidney stones. This is typically done with a 24 hour urine collection that is chemically analyzed for deficiencies and excesses that promote stone formation. Kidney stones are also more common in patients with Crohn's disease.

There has been some evidence that water fluoridation may increase the risk of kidney stone formation. In one study, patients with symptoms of skeletal fluorosis were 4.6 times as likely to develop kidney stones. However, fluoride may also be an inhibitor of urinary stone formation.

There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which may be based on little science. Although some individual recent studies have found a relationship there is no clear relationship between excess ascorbic acid intake and kidney stone formation.

Calcium oxalate stones

The most common type of kidney stone is composed of calcium oxalate crystals, occurring in about 80% of cases, and the factors that promote the precipitation of crystals in the urine are associated with the development of these stones.

Common sense has long held that consumption of too much calcium could promote the development of calcium kidney stones. However, current evidence suggests that the consumption of low-calcium diets is actually associated with a higher overall risk for the development of kidney stones. This is perhaps related to the role of calcium in binding ingested oxalate in the gastrointestinal tract. As the amount of calcium intake decreases, the amount of oxalate available for absorption into the bloodstream increases; this oxalate is then excreted in greater amounts into the urine by the kidneys. In the urine, oxalate is a very strong promoter of calcium oxalate precipitation, about 15 times stronger than calcium.

Uric acid (urate)

About 5–10% of all stones are formed from uric acid. Uric acid stones form in association with conditions that cause hyperuricosuria with or without high blood serum uric acid levels (hyperuricemia); and with acid/base metabolism disorders where the urine is excessively acidic (low pH) resulting in uric acid precipitation. A diagnosis of uric acid nephrolithiasis is supported if there is a radiolucent stone, a persistent undue urine acidity, and uric acid crystals in fresh urine samples.

Other types

Other types of kidney stones are composed of struvite (magnesium, ammonium and phosphate); calcium phosphate; and cystine.

The formation of struvite stones is associated with the presence of urea-splitting bacteria, most commonly Proteus mirabilis (but also Klebsiella, Serratia, Providencia species). These organisms are capable of splitting urea into ammonia, decreasing the acidity of the urine and resulting in favorable conditions for the formation of struvite stones. Struvite stones are always associated with urinary tract infections.

The formation of calcium phosphate stones is associated with conditions such as hyperparathyroidism and renal tubular acidosis.

Formation of cystine stones is uniquely associated with people suffering from cystinuria, who accumulate cystine in their urine.

Symptoms

Symptoms of kidney stones include:

• Colicky pain: "loin to groin". Often described as "the worst pain ever experienced".
• Hematuria: blood in the urine, due to minor damage to inside wall of kidney, ureter and/or urethra.
• Pyuria: pus in the urine.
• Dysuria: burning on urination when passing stones (rare). More typical of infection.
• Oliguria: reduced urinary volume caused by obstruction of the bladder or urethra by stone, or extremely rarely, simultaneous obstruction of both ureters by a stone.
• Abdominal distention.
• Nausea/vomiting: embryological link with intestine – stimulates the vomiting center.
• Fever and chills.
• Hydronephrosis
• Postrenal azotemia: when kidney stone blocks ureter

Diagnosis

(Star shaped bladder urolith on an X-ray of the pelvis)

Clinical diagnosis is usually made on the basis of the location and severity of the pain, which is typically colic in nature (comes and goes in spasmodic waves). Pain in the back occurs when calculi produce an obstruction in the kidney.

Imaging is used to confirm the diagnosis and a number of other tests can be undertaken to help establish both the possible cause and consequences of the stone. Ultrasound imaging is also useful as it will give details about the presence of hydronephrosis (swelling of the kidney). It can also be used to show the kidneys during pregnancy when standard x-rays are discouraged. About 10% of stones do not have enough calcium to be seen on standard x-rays (radiolucent stones) and may show up on ultrasound although they typically are seen on CT scans.

The relatively dense calcium renders these stones radio-opaque and they can be detected by a traditional X-ray of the abdomen that includes the Kidneys, Ureters and Bladder—KUB. This may be followed by an IVP (Intravenous Pyelogram; (IntraVenous Urogram (IVU) is the same test by another name)) which requires about 50 ml of a special dye to be injected into the bloodstream that is excreted by the kidneys and by its density helps outline any stone on a repeated X-ray. These can also be detected by a Retrograde pyelogram where similar "dye" is injected directly into the ureteral opening in the bladder by a surgeon, usually a urologist.

Computed tomography (CT or CAT scan), a specialized X-ray, is considered the gold-standard diagnostic test for the detection of kidney stones, and in this setting does not require the use of intravenous contrast, which carries some risk in certain people (eg, allergy, kidney damage). All stones are detectable by CT except very rare stones composed of certain drug residues in the urine. The non-contrast "renal colic study" CT scan has become the standard test for the immediate diagnosis of flank pain typical of a kidney stone. If positive for stones, a single standard x-ray of the abdomen (KUB) is recommended. This additional x-ray provides the physicians with a clearer idea of the exact size and shape of the stone as well as its surgical orientation. Further, it makes it simple to follow the progress of the stone without the need for the much more expensive CT scan just by doing another single x-ray at some point in the future.

Other investigations typically carried out include:

• Microscopic study of urine, which may show proteins, red blood cells, bacteria, cellular casts and crystals.
• Culture of a urine sample to exclude urine infection (either as a differential cause of the patient's pain, or secondary to the presence of a stone)
• Blood tests: Full blood count for the presence of a raised white cell count (Neutrophilia) suggestive of infection, a check of renal function and to look for abnormally high blood calcium blood levels (hypercalcaemia).
• 24 hour urine collection to measure total daily urinary volume, magnesium, sodium, uric acid, calcium, citrate, oxalate and phosphate.
• Catching of passed stones at home (usually by urinating through a tea strainer) for later examination and evaluation by a doctor.

Treatment

Temporizing

About 90% of stones 4 mm or less in size usually will pass spontaneously, however 99% of stones larger than 6 mm will require some form of intervention. There are various measures that can be used to encourage the passage of a stone. These can include increased hydration, medication for treating infection and reducing pain, and diuretics to encourage urine flow and prevent further stone formation. Eating starfruit can be effective at reducing pain and improving urination. However caution should be exercised due to other concerns with the ingestion of starfruit.

In most cases, a smaller stone that is not symptomatic is often given up to four weeks to move or pass before consideration is given to any surgical intervention as it has been found that waiting longer tends to lead to additional complications. Immediate surgery may be required in certain situations such as in people with only one working kidney, intractable pain or in the presence of an infected kidney blocked by a stone which can rapidly cause severe sepsis and toxic shock.

Analgesia

Management of pain from kidney stones varies from country to country and even from physician to physician, but usually requires intravenous administration of narcotics in an emergency room setting for acute situations. Similar classes of drugs may be reasonably effective orally in an outpatient setting for less severe discomfort where nonsteroidal anti-inflammatories or narcotics like codeine can be prescribed. Some doctors will give patients with recurring passing of small stones a small supply prescription for hydrocodone to avoid a future visit to the ER when the next episode occurs. Taken at the first sign of pain, hydrocodone can eliminate much of the acute pain, nausea and vomiting which necessitates the hospital visit and still facilitate stone passage, although a follow-up with a physician is still necessary.

Patients who are to be treated non-surgically, may also be started on an alpha adrenergic blocking agent (such as Flomax, Uroxatral, terazosin or doxazosin), which acts to reduce the muscle tone of the ureter and facilitate stone passage. For smaller stones near the bladder, this type of medical treatment can increase the spontaneous stone passage rate by about 30%.

After treatment, the pain may return if the stone moves but re-obstructs in another location. Patients are encouraged to strain their urine so they can collect the stone when it eventually passes and send it for chemical composition analysis which will be used along with a 24 hour urine chemical analysis test to establish preventative options.

Urologic interventions

(A kidney stone at the tip of an ultrasonic instrument)

(Bladder stones incidentally found in a bladder diverticulum during transvesical prostatectomy)

Most kidney stones do not require surgery and will pass on their own. Surgery is necessary when the pain is persistent and severe, in renal failure and when there is a kidney infection. It may also be advisable if the stone fails to pass or move after 30 days. Finding a significant stone before it passes into the ureter allows physicians to fragment it surgically before it causes any severe problems. In most of these cases, non-invasive Extracorporeal Shock Wave Lithotripsy (ESWL) will be used. Otherwise some form of invasive procedure is required; with approaches including ureteroscopic fragmentation (or simple basket extraction if feasible) using laser, ultrasonic or mechanical (pneumatic, shock-wave) forms of energy to fragment the larger stones. Percutaneous nephrolithotomy or rarely open surgery may ultimately be necessary for large or complicated stones or stones which fail other less invasive attempts at treatment.

A single retrospective study in the USA, at the Mayo Clinic, has suggested that lithotripsy may increase subsequent incidence of diabetes and hypertension, but it has not been felt warranted to change clinical practice at the clinic.

More common complications related to ESWL are bleeding, pain related to passage of stone fragments, failure to fragment the stone, and the possible requirement for additional or alternative interventions.

Ureteral (double-J) stents

Three-dimensional reconstructed CT scan image of a ureteral stent in the left kidney (indicated by yellow arrow).

One modern medical technique uses a ureteral stent (a small tube between the bladder and the inside of the kidney) to provide immediate relief of a blocked kidney. This is especially useful in saving a failing kidney due to swelling and infection from the stone. Ureteral stents vary in length and width but most have the same shape usually called a "double-J" or "double pigtail", because of the curl at both ends. They are designed to allow urine to drain around any stone or obstruction. They can be retained for some length of time as infections recede and as stones are dissolved or fragmented with ESWL or other treatment. The stents will gently dilate or stretch the ureters which can facilitate instrumentation and they will also provide a clear landmark to help surgeons see the stones on x-ray. Discomfort levels from stents typically range from minimal associated pain to moderate discomfort.

Prevention

Preventive strategies include dietary modifications and sometimes also taking drugs with the goal of reducing excretory load on the kidneys:

• Drinking enough water to make 2 to 2.5 liters of urine per day.
• A diet low in protein, nitrogen and sodium intake.
• Restriction of oxalate-rich foods, such as chocolate, nuts, soybeans, rhubarb and spinach, plus maintenance of an adequate intake of dietary calcium. There is equivocal evidence that calcium supplements increase the risk of stone formation, though calcium citrate appears to carry the lowest, if any, risk.
• Taking drugs such as thiazides, potassium citrate, magnesium citrate and allopurinol, depending on the cause of stone formation.
• Some fruit juices, such as orange, blackcurrant, and cranberry, may be useful for lowering the risk factors for specific types of stones.
• Avoidance of cola beverages.
• Avoiding large doses of vitamin C.

For those patients interested in optimizing their kidney stone prevention options, it's essential to have a 24 hour urine test performed. This should be done with the patient on his or her regular diet and activities. The results can then be analyzed for abnormalities and appropriate treatment given.

Interstitial nephritis

Interstitial nephritis is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules. This disease can be either acute, which means it occurs suddenly or chronic, meaning it is ongoing and eventually ending in kidney failure.


causes

Common causes include infection, or reaction to medication (such as an analgesic or antibiotics). 71% to 92% of cases are reported to be caused by drugs. This disease is also caused by other diseases and toxins that do damage to the kidney. Both acute and chronic tubulointerstitial nephritis can be caused by a bacterial infection in the kidneys, known as pyelonephritis. The most common cause is by an allergic reaction to a drug. The drugs that are known to cause this sort of reaction are antibiotics such as penicillin, and nonsteroidal anti-inflammatory drugs, such as aspirin. The time between exposure to the drug and the development of acute tubulointerstitial nephritis can be anywhere from 5 days to 5 weeks.

Diagnosis

At times there are no symptoms of this disease, but when they do occur they are widely varied and can occur rapidly or gradually. When caused by an allergic reaction, the symptoms of acute tubulointerstitial nephritis are fever (27% of patients)[1], rash (15% of patients), and enlarged kidneys. Some people experience dysuria, and lower back pain. In chronic tubulointerstitial nephritis the patient can experience symptoms such as nausea, vomiting, fatigue, and weight loss. Other conditions that may develop include hyperkalemia, metabolic acidosis, and kidney failure.

Blood tests

About 23% of patients have eosinophilia.

Urinary findings

Urinary findings include:

• Eosinophiluria: sensitivity is 67% and specificity is 83%. The sensitivity is higher in patients with interstitial nephritis induced by methicillin or when the Hansel's stain is used.
• Isosthenuria

Gallium scan

The sensitivity of an abnormal gallium scan has been reported to range from 60% to 100%.

Treatment

Remove the etiology such as an offending drug. Corticosteroids do not clearly help. Nutrition therapy consists of adequate fluid intake, which can require several liters of extra fluid including Food, Nutrition, & Diet Therapy.

Prognosis

The kidneys are the only body system that is directly affected by tubulointerstitial nephritis. Kidney function is usually reduced; the kidneys can be just slightly dysfunctional, or fail completely.

In chronic tubulointerstitial nephritis the most serious long term effect is kidney failure. When the proximal tube is injured sodium, potassium, bicarbonate, uric acid, and phosphate intake may be reduced or changed, resulting in low bicarbonate, known as metabolic acidosis, low potassium, low uric acid known as hypouricemia, and low phosphate known as hypophosphatemia. Damage to the distal tubule may cause loss of urine concentrating ability and polyuria.

In most cases of acute tubulointerstitial nephritis, the function of the kidneys will return after the harmful drug is not taken anymore, or when the underlying disease is cured by treatment. If the illness is caused by an allergic reaction, a corticosteroid may speed the recovery kidney function, however this is often not the case. Chronic tubulointerstitial nephritis has no cure. Some patients may require dialysis. Eventually, a kidney transplant may be needed.

Hydronephrosis

Hydronephrosis is distention and dilation of the renal pelvis and calyces, usually caused by obstruction of the free flow of urine from the kidney, leading to progressive atrophy of the kidney.

Signs and symptoms

Specimen of a kidney that has undergone extensive dilation due to hydronephrosis. Note the extensive atrophy and thinning of the renal cortex.

The signs and symptoms of hydronephrosis depend upon whether the obstruction is acute or chronic, partial or complete, unilateral or bilateral. Unilateral hydronephrosis may occur without any symptoms, while acute obstruction can cause intense pain.

Blood tests can show raised creatinine and electrolyte imbalance. Urinalysis may show an elevated pH due to the secondary destruction of nephrons within the affected kidney.

Symptoms that occur regardless of where the obstruction lies include loin or flank pain. An enlarged kidney may be palpable on examination.

Where the obstruction occurs in the lower urinary tract, suprapubic tenderness (with or without a history of bladder outflow obstruction) along with a palpable bladder are strongly suggestive of acute urinary retention, which left untreated is highly likely to cause hydronephrosis.

Upper urinary tract obstruction is characterised by pain in the flank, often radiating to either the abdomen or the groin. Where the obstruction is chronic, renal failure may also be present. If the obstruction is complete, an enlarged kidney is often palpable on examination.

Etiology

The obstruction may be either partial or complete and can occur anywhere from the urethral meatus to the calyces of the renal pelvis.

The obstruction may arise from either inside or outside the urinary tract or may come from the wall of the urinary tract itself. Intrinsic obstructions (those that occur within the tract) include blood clots, stones, sloughed papilla along with tumours of the kidney, ureter and bladder. Extrinsic obstructions (those that are caused by factors outside of the urinary tract) include pelvic or abdominal tumours or masses, retroperitoneal fibrosis or neurological deficits. Strictures of the ureters (congenital or acquired), neuromuscular dysfunctions or schistosomiasis are other causes which originate from the wall of the urinary tract.

Tests

(Ultrasound picture of hydronephrosis caused by a left ureteral stone)

Blood (U&E, creatinine) and urine (MSU, pH) tests should be taken. IVUs, ultrasounds, CTs and MRIs are also important tests. Ultrasound allows for visualisation of the ureters and kidneys and can be used to assess the presence of hydronephrosis and/or hydroureter. An IVU is useful for assessing the position of the obstruction. Antegrade or retrograde pyelography will show similar findings to an IVU but offer a therapeutic option as well.

The choice of imaging depends on the clinical presentation (history, symptoms and examination findings). In the case of renal colic (one sided loin pain usually accompanied by a trace of blood in the urine) the initial investigation is usually an intravenous urogram. This has the advantage of showing whether there is any obstruction of flow of urine causing hydronephrosis as well as demonstrating the function of the other kidney. Many stones are not visible on plain xray or IVU but 99% of stones are visible on CT and therefore CT is becoming a common choice of initial investigation. MRI is less commonly used, often when there is a reason to avoid radiation exposure, e.g. in pregnancy.

Complications

Left untreated, bilateral obstruction (obstruction occurring to both kidneys rather than one) has a poor prognosis.

Treatment

Treatment of hydronephrosis focuses upon the removal of the obstruction and drainage of the urine that has accumulated behind the obstruction. Therefore, the specific treatment depends upon where the obstruction lies, and whether it is acute or chronic.

Acute obstruction of the upper urinary tract is usually treated by the insertion of a nephrostomy tube. Chronic upper urinary tract obstruction is treated by the insertion of a ureteric stent or a pyeloplasty.

Lower urinary tract obstruction (such as that caused by bladder outflow obstruction secondary to prostatic hypertrophy) is usually treated by insertion of a urinary catheter or a suprapubic catheter.

Glomerulonephritis

Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys. It may present with isolated hematuria and/or proteinuria (blood resp. protein in the urine); or as a nephrotic syndrome, a nephritic syndrome, acute renal failure, or chronic renal failure. They are categorised into several different pathological patterns, which are broadly grouped into non-proliferative or proliferative types. Diagnosing the pattern of GN is important because the outcome and treatment differs in different types. Primary causes are one which are intrinsic to the kidney, whilst secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis) or cancers.

Thin Basement Membrane Disease

This is an autosomal dominant inherited disease characterised by thin glomerular basement membranes on electron microscopy. It is a benign condition that causes persistent microscopic haematuria.

Non Proliferative

This is characterised by low numbers of cells (lack of hypercellularity) in the glomeruli. They usually cause nephrotic syndrome. This includes the following types:

Minimal change GN

This form of GN causes 80% of nephrotic syndrome in children, but only 20% in adults. As the name indicates, there are no changes visible on simple light microscopy, but on electron microscopy there is fusion of podocytes (supportive cells in the glomerulus). Immunohistochemistry staining is negative. Treatment consists of supportive care for the massive fluid accumulation in the patients body (= oedema) and as well as steroids to halt the disease process (typically Prednisone 1 mg/kg). Over 90% of children respond well to steroids, being essentially cured after 3 months of treatment.

Adults have a lower response rate (80%). Failure to respond to steroids ('steroid resistant') or return of the disease when steroids are stopped ('steroid dependent') may require cytotoxic therapy (such as cyclosporin) which is associated with many side-effects.

Focal Segmental Glomerulosclerosis (FSGS)

FSGS may be primary or secondary to reflux nephropathy, Alport syndrome, heroin abuse or HIV. FSGS presents as a nephrotic syndrome with varying degrees of impaired renal function (seen as a rising serum creatinine, hypertension). As the name suggests, only certain foci of glomeruli within the kidney are affected, and then only a segment of an individual glomerulus. The pathological lesion is sclerosis (fibrosis) within the glomerulus and hyalinisation of the feeding arterioles, but no increase in the number of cells (hence non-proliferative). The hyaline is an amorphous material, pink, homogeneous, resulting from combination of plasma proteins, increased mesangial matrix and collagen. Staining for antibodies and complement is essentially negative. Steroids are often tried but not shown to be effective. 50% of people with FSGS continue to have progressive deterioration of kidney function, ending in renal failure.

Membranous glomerulonephritis

Membranous glomerulonephritis (MPGN), a relatively common type of glomerulonephritis in adults, frequently produces a mixed nephrotic and nephritic picture. It is usually idiopathic, but may be associated with cancers of the lung and bowel, infection such as hepatitis and malaria, drugs including penicillamine, and connective tissue diseases such as systemic lupus erythematosus. Individuals with cerebral shunts are at risk of developing shunt nephritis, which frequently produces MPGN.

Microscopically, MPGN is characterized by a thickened glomerular basement membrane without a hypercellular glomerulus. Immunofluorescence demonstrates diffuse granular uptake of IgG. The basement membrane may completely surround the granular deposits, forming a "spike and dome" pattern.

Prognosis follows the rule of thirds: one-third remain with MPGN indefinitely, one-third remit, and one-third progress to end-stage renal failure. As the glomerulonephritis progresses, the tubules of the kidney become infected, leading to atrophy and hyalinisation. The kidney appears to shrink. Treatment with corticosteroids is attempted if the disease progresses.

Proliferative

This type is characterised by increased number of cells in the glomerulus (hypercellular). Usually present as a nephritic syndrome and usually progress to end-stage renal failure (ESRF) over weeks to years (depending on type).

IgA nephropathy (Berger's disease)

IgA nephropathy is the most common type of glomerulonephritis in adults world-wide. It usually presents as macroscopic haematuria ( visibly bloody urine). It occasionally presents as a nephrotic syndrome. It often affects young males within days (24-48hrs) after an upper respiratory tract or gastrointestinal infection. Microscopic examination of biopsy specimens shows increased number of mesangial cells with increased matrix (the 'cement' which holds everything together). Immuno-staining is positive for immunoglobulin A deposits within the matrix. Prognosis is variable, 20% progress to ESRF. Steroids and immunosuppression are not effective treatments for this disease; ACE inhibitors are the mainstay of treatment.

Henoch-Schönlein purpura

Henoch-Schönlein purpura (HSP) is a systemic variant of IgA nephropathy which causes a small-vessel vasculitis and associated glomerulonephritis.

Post-infectious

Post-infectious glomerulonephritis can occur after essentially any infection, but classically occurs after infection with Streptococcus pyogenes. It typically occurs 10-14 days after a skin or pharyngeal infection with this bacterium.

Patients present with signs and symptoms of glomerulonephritis. Diagnosis is made based on these findings in an individual with a history of recent streptococcal infection. Streptococcal titers in the blood (antistreptolysin O titers) may support the diagnosis.

Light microscopy demonstrates diffuse hypercellularity due to proliferation of endothelial and mesangial cells, as well as an influx of neutrophils and monocytes. The Bowman space is compressed, in some cases to the extent that this produces a crescent formation characteristic of crescentic glomerulonephritis.

Biopsy is seldom done as the disease usually regresses without complications. Treatment is supportive, and the disease generally resolves in 2-4 weeks.

Mesangiocapillary GN

This is primary, or secondary to SLE, viral hepatitis, hypocomplementemia. One sees 'hypercellular and hyperlobular' glomeruli due to proliferation of both cells and the matrix within the mesangium. Presents usually with as a nephrotic syndrome but can be nephritic, with inevitable progression to ESRF.

Rapidly progressive glomerulonephritis (Crescentic GN)

As the name suggests, this type has a poor prognosis, with rapid progression to kidney failure over weeks. Any of the above types of GN can be rapidly progressive. Additionally two further causes present as solely RPGN. One is Goodpasture's syndrome, an autoimmune disease whereby antibodies are directed against basal membrane antigens found in the kidney and lungs. As well as kidney failure, patient have hemoptysis (cough up blood). High dose immunosuprresion is required (intavenous Methylprednisolone) and cyclophosphamide, plus plasmapheresis. Immunohistochemistry staining of tissue specimens shows linear IgG deposits. The second cause is vasculitic disorders such as Wegener's granulomatosis and polyarteritis. There is a lack of immune deposits on staining, but blood tests are positive for ANCA antibody. Histopathology: The majority of glomeruli present "crescents". Formation of crescents is initiated by passage of fibrin into the Bowman space as a result of increased permeability of glomerular basement membrane. Fibrin stimulates the proliferation of parietal cells of Bowman capsule, and an influx of monocytes. Rapid growing and fibrosis of crescents compresses the capillary loops and decreases the Bowman space which leads to renal failure within weeks or months.

Diabetic nephropathy

Diabetic nephropathy (nephropatia diabetica), is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and nodular glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime cause for dialysis in many Western countries.

History

The syndrome was discovered by British physician Clifford Wilson (1906-1997) and Germany-born American physician Paul Kimmelstiel (1900-1970) and was published for the first time in 1936.

Epidemiology

The syndrome can be seen in patients with chronic diabetes (15 years or more after onset), so patients are usually of older age (between 50 and 70 years old). The disease is progressive and may cause death two or three years after the initial lesions, and is more frequent in men. Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease. People with both type 1 and type 2 diabetes are at risk. The risk is higher if blood-glucose levels are poorly controlled. Further, once nephropathy develops, the greatest rate of progression is seen in patients with poor control of their blood pressure. Also people with high cholesterol level in their blood have much more risk than others.

Etiopathology

The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus. At this stage, the kidney may start allowing more serum albumin (plasma protein) than normal in the urine (albuminuria), and this can be detected by sensitive medical tests for albumin. This stage is called "microalbuminuria". It can appear 5 to 10 years before other symptoms develop. As diabetic nephropathy progresses, increasing numbers of glomeruli are destroyed by nodular glomerulosclerosis. Now the amounts of albumin being excreted in the urine increases, and may be detected by ordinary urinalysis techniques. At this stage, a kidney biopsy clearly shows diabetic nephropathy.

Signs and symptoms

Kidney failure provoked by glomerulosclerosis leads to fluid filtration deficits and other disorders of kidney function. There is an increase in blood pressure (hypertension) and of fluid retention in the body (oedema). Other complications may be arteriosclerosis of the renal artery and proteinuria (nephrotic syndrome).

Throughout its early course, diabetic nephropathy has no symptoms. They develop in late stages and may be a result of excretion of high amounts of protein in the urine or due to renal failure:

• oedema: swelling, usually around the eyes in the mornings; later, general body swelling may result, such as swelling of the legs
• foamy appearance or excessive frothing of the urine
• unintentional weight gain (from fluid accumulation)
• anorexia (poor appetite)
• nausea and vomiting
• malaise (general ill feeling)
• fatigue
  
• headache
• frequent hiccups
• generalized itching

The first laboratory abnormality is a positive microalbuminuria test. Most often, the diagnosis is suspected when a routine urinalysis of a person with diabetes shows too much protein in the urine (proteinuria). The urinalysis may also show glucose in the urine, especially if blood glucose is poorly controlled. Serum creatinine and BUN may increase as kidney damage progresses.

A kidney biopsy confirms the diagnosis, although it is not always necessary if the case is straightforward, with a documented progression of proteinuria over time and presence of diabetic retinopathy on examination of the retina of the eyes.

Treatment

The goals of treatment are to slow the progression of kidney damage and control related complications. The main treatment, once proteinuria is established, is ACE inhibitor drugs, which usually reduces proteinuria levels and slows the progression of diabetic nephropathy. Several effects of the ACEIs that may contribute to renal protection have been related to the association of rise in Kinins which is also responsible for some of the side effects associated with ACEIs therapy such as dry cough. The renal protection effect is related to the antihypertensive effects in normal and hypertensive patients, renal vasodilatation resulting in increased renal blood flow and dilatation of the efferent arterioles. Many studies have shown that related drugs, angiotensin receptor blockers (ARBs), have a similar benefit. In fact, a combination may be best.

Blood-glucose levels should be closely monitored and controlled. This may slow the progression of the disorder, especially in the very early stages. Medications to manage diabetes include oral hypoglycemic agents and insulin injections. As kidney failure progresses, less insulin is excreted, so smaller doses may be needed to control glucose levels.

The diet may be modified to help control blood-sugar levels. Modification of protein intake can effect hemodynamic and nonhemodynamic injury. High blood pressure should be aggressively treated with antihypertensive medications, in order to reduce the risks of kidney, eye, and blood vessel damage in the body. It is also very important to control lipid levels, maintain a healthy weight, and engage in regular physical activity.

Patients with diabetic nephropathy should avoid taking the following drugs:

• Contrast agents containing iodine
• Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, or COX-2 inhibitors like Celebrex, because they may injure the weakened kidney.

Urinary tract and other infections are common and can be treated with appropriate antibiotics.

Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplantation must be considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.

C-peptide, a by-product of insulin production, may provide new hope for patients sufering from diabetic nephropathy.

Prognosis

Diabetic nephropathy continues to get gradually worse. Complications of chronic kidney failure are more likely to occur earlier, and progress more rapidly, when it is caused by diabetes than other causes. Even after initiation of dialysis or after transplantation, people with diabetes tend to do worse than those without diabetes.

Complications

Possible complications include:

• hypoglycemia (from decreased excretion of insulin)
• rapidly progressing chronic kidney failure
• end-stage kidney disease
  
• hyperkalemia
• 
  
• severe hypertension
• complications of hemodialysis
• complications of kidney transplant
• coexistence of other diabetes complications
• peritonitis (if peritoneal dialysis used)
• increased infections

Human Kidney

The kidneys are complicated organs that have numerous biological roles. Their primary role is to maintain the homeostatic balance of bodily fluids by filtering and secreting metabolites (such as urea) and minerals from the blood and excreting them, along with water, as urine. Because the kidneys are poised to sense plasma concentrations of ions such as sodium, potassium, hydrogen, oxygen, and compounds such as amino acids, creatinine, bicarbonate, and glucose, they are important regulators of blood pressure, glucose metabolism, and erythropoiesis (the process by which red blood cells (erythrocytes) are produced). The medical field that studies the kidneys and diseases of the kidney is called nephrology.

Anatomy

In humans, the kidneys are located in the posterior part of the abdominal cavity. There are two, one on each side of the spine; the right kidney sits just below the diaphragm and posterior to the liver, the left below the diaphragm and posterior to the spleen. Above each kidney is an adrenal gland (also called the suprarenal gland). The asymmetry within the abdominal cavity caused by the liver results in the right kidney being slightly lower than the left one while the left kidney is located slightly more medial. The bulk of water re-absorption in the vertebrate kidney takes place in the loop of henle.

The kidneys are retroperitoneal and range from 9 to 13 cm in diameter; the left slightly larger than the right. They are approximately at the vertebral level T12 to L3. The upper parts of the kidneys are partially protected by the eleventh and twelfth ribs, and each whole kidney and adrenal gland are surrounded by two layers of fat (the perirenal and pararenal fat) and the renal fascia which help to cushion it. Congenital absence of one or both kidneys, known as unilateral (on one side) or bilateral (on both the sides) renal agenesis, can occur.

The kidneys receive unfiltered blood directly from the heart through the abdominal aorta which then branches to the left and right renal arteries. Filtered blood then returns by the left and right renal veins to the inferior vena cava and then the heart. Renal blood flow accounts for up to a third of the cardiac output.

Functions

Excretion of waste products

The kidneys excrete a variety of waste products produced by metabolism, including the nitrogenous wastes: urea (from protein catabolism) and uric acid (from nucleic acid metabolism) and water.

Homeostasis

The kidney is one of the major organs involved in whole-body homeostasis. Among its homeostatic functions are acid-base balance, regulation of electrolyte concentrations, control of blood volume, and regulation of blood pressure. The kidneys accomplish these homeostatic functions independently and through coordination with other organs, particularly those of the endocrine system. The kidney communicates with these organs through hormones secreted into the bloodstream.

Acid-base balance

The kidneys regulate the pH of blood by adjusting H⁺ ion levels, referred as augmentation of mineral ion concentration, as well as water composition of the blood.

Blood pressure

Sodium ions are controlled in a homeostatic process involving aldosterone which increases sodium ion reabsorption in the distal convoluted tubules.

Plasma volume

Any significant rise or drop in plasma osmolality is detected by the hypothalamus, which communicates directly with the posterior pituitary gland. A rise in osmolality causes the gland to secrete antidiuretic hormone, resulting in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return the plasma osmolality to its normal levels.

Hormone secretion

The kidneys secrete a variety of hormones, including erythropoietin, urodilatin, and vitamin D.

Embryology

The mammalian kidney develops from intermediate mesoderm. Kidney development, also called nephrogenesis, proceeds through a series of three successive phases, each marked by the development of a more advanced pair of kidneys: the pronephros, mesonephros, and metanephros.

Pronephros

During approximately day 22 of human gestation, the paired pronephroi appear towards the cranial end of the intermediate mesoderm. In this region, epithelial cells arrange themselves in a series of tubules called nephrotomes and join laterally with the pronephric duct, which does not reach the outside of the embryo. Thus the pronephros is considered nonfunctional in mammals because it cannot excrete waste from the embryo.

Mesonephros

Each pronephric duct grows towards the tail of the embryo, and in doing so induces intermediate mesoderm in the thoracolumbar area to become epithelial tubules called mesonephric tubules. Each mesonephric tubule receives a blood supply from a branch of the aorta, ending in a capillary tuft analogous to the glomerulus of the definitive nephron. The mesonephric tubule forms a capsule around the capillary tuft, allowing for filtration of blood. This filtrate flows through the mesonephric tubule and is drained into the continuation of the pronephric duct, now called the mesonephric duct or Wolffian duct. The nephrotomes of the pronephros degenerate while the mesonephric duct extends towards the most caudal end of the embryo, ultimately attaching to the cloaca. The mammalian mesonephros is similar to the kidneys of aquatic amphibians and fishes.

Metanephros

During the fifth week of gestation, the mesonephric duct develops an outpouching, the ureteric bud, near its attachment to the cloaca. This bud, also called the metanephrogenic diverticulum, grows posteriorly and towards the head of the embryo. The elongated stalk of the ureteric bud, the metanephric duct, later forms the ureter. As the cranial end of the bud extends into the intermediate mesoderm, it undergoes a series of branchings to form the collecting duct system of the kidney. It also forms the major and minor calyces and the renal pelvis.

The portion of undifferentiated intermediate mesoderm in contact with the tips of the branching ureteric bud is known as the metanephrogenic blastema. Signals released from the ureteric bud induce the differentiation of the metanephrogenic blastema into the renal tubules. As the renal tubules grow, they come into contact and join with connecting tubules of the collecting duct system, forming a continuous passage for flow from the renal tubule to the collecting duct. Simultaneously, precursors of vascular endothelial cells begin to take their position at the tips of the renal tubules. These cells differentiate into the cells of the definitive glomerulus.

Terms

(Microscopic photograph of the renal cortex)

(Microscopic photograph of the renal medulla)

• renal capsule: The membranous covering of the kidney.
• cortex: The outer layer over the internal medulla. It contains blood vessels, glomeruli (which are the kidneys' "filters") and urine tubes and is supported by a fibrous matrix.
• hilum: The opening in the middle of the concave medial border for nerves and blood vessels to pass into the renal sinus.
• renal column: The structures which support the cortex. They consist of lines of blood vessels and urinary tubes and a fibrous material.
• renal sinus: The cavity which houses the renal pyramids.
• calyces: The recesses in the internal medulla which hold the pyramids. They are used to subdivide the sections of the kidney. (singular - calyx)
• papillae: The small conical projections along the wall of the renal sinus. They have openings through which urine passes into the calyces. (singular - papilla)
• renal pyramids: The conical segments within the internal medulla. They contain the secreting apparatus and tubules and are also called malpighian pyramids.
• renal artery: Two renal arteries come from the aorta, each connecting to a kidney. The artery divides into five branches, each of which leads to a ball of capillaries. The arteries supply (unfiltered) blood to the kidneys. The left kidney receives about 60% of the renal bloodflow.
• renal vein: The filtered blood returns to circulation through the renal veins which join into the inferior vena cava.
• renal pelvis: Basically just a funnel, the renal pelvis accepts the urine and channels it out of the hilus into the ureter.
• ureter: A narrow tube 40 cm long and 4 mm in diameter. Passing from the renal pelvis out of the hilus and down to the bladder. The ureter carries urine from the kidneys to the bladder by means of peristalsis.
• renal lobe: Each pyramid together with the associated overlying cortex forms a renal lobe

Medical terminology

• Medical terms related to the kidneys involve the prefixes renal- and nephro-.
• Surgical removal of the kidney is a nephrectomy, while a radical nephrectomy is removal of the kidney, its surrounding tissue, lymph nodes, and potentially the adrenal gland. A radical nephrectomy is performed for the removal of the cancers.

Diseases and disorders

Congenital

• Congenital hydronephrosis
  
• Congenital obstruction of urinary tract
• Duplicated ureter
• Horseshoe kidney
• Polycystic kidney disease
• Renal dysplasia
• Unilateral small kidney
• Multicystic dysplastic kidney

Acquired

(drawing of an enlarged kidney)

• Diabetic nephropathy
  
• Glomerulonephritis
• 
  
• Hydronephrosis is the enlargement of one or both of the kidneys caused by obstruction of the flow of urine.
• Interstitial nephritis
• Kidney stones are a relatively common and particularly painful disorder.
• Kidney tumors
  • Wilms tumor
  • Renal cell carcinoma
• Lupus nephritis
  
• Minimal change disease
• 
  
• In nephrotic syndrome, the glomerulus has been damaged so that a large amount of protein in the blood enters the urine. Other frequent features of the nephrotic syndrome include swelling, low serum albumin, and high cholesterol.
• Pyelonephritis is infection of the kidneys and is frequently caused by complication of a urinary tract infection.
• Renal failure
  
  • Acute renal failure
  • Stage 5 chronic kidney disease
  
  

The failing kidney

Generally, humans can live normally with just one kidney, as one has more functioning renal tissue than is needed to survive. Only when the amount of functioning kidney tissue is greatly diminished will Stage 5 Chronic Kidney Disease develop. If the glomerular filtration rate (a measure of renal function) has fallen very low ( Stage 5 Chronic Kidney Disease), or if the renal dysfunction leads to severe symptoms, then renal replacement therapy is indicated, either dialysis or kidney transplantation.

Histology

Human cell types found in the kidney include:

• Kidney glomerulus parietal cell
  
• Kidney glomerulus podocyte
• Kidney proximal tubule brush border cell
• Loop of Henle thin segment cell
• Thick ascending limb cell
• Kidney distal tubule cell
• Kidney collecting duct cell
  
  • Cortical collecting duct cell
  • Medullary collecting duct cell
• Interstitial kidney cell, which do not participate in the filtration process.

Lung pinprick condition

Lung Pinprick Condition (LPC) is a rare, autosomal recessive, respirative condition. It is estimated that less than 2% of humans carry the gene for LPC. LPC is distributed evenly throughout the world, but those of the East Asian populations exhibit slightly higher frequencies of the trait. Inheriting LPC results in microscopic holes appearing in the lungs of the afflicted. These openings usually begin to appear during the early stages of puberty, but are non-threatening. Symptoms are often noticeable, but they rarely cause discomfort to the individual.

Symptoms include:

• Unusually loud or heavy breathing
• Shortness of breath during strenuous aerobic exercise
• Loud and irregular snoring
• Enlarged veins and arteries, especially in the extremities

LPC does not result in sudden attacks, which are associated with asthma, and thus more than 80% of those with the condition are not aware of its effect upon them. Similarly, since LPC is not especially harmful, no medical research into gene therapy-related cures has been investigated.

Bronchitis

Bronchitis is an inflammation of the bronchi.

More specifically, it may refer to:

• Acute bronchitis, caused by viruses or bacteria and lasting several days or weeks
• Chronic bronchitis, a persistent, productive cough lasting at least three months in two consecutive years.

In bronchitis, the membranes lining the larger bronchial tubes become inflamed and an excessive amount of mucus is produced. The person with bronchitis develops a bad cough to get rid of the mucus.

Acute bronchitis

Bronchitis is an inflammation of the large bronchi (medium-sized airways) in the lungs. It can progress to pneumonia. Acute bronchitis is usually caused by viruses or bacteria and may last several days or weeks. Acute bronchitis is characterized by cough and sputum (phlegm) production and symptoms related to the obstruction of the airways by the inflamed airways and the phlegm, such as shortness of breath and wheezing. Diagnosis is by clinical examination and sometimes microbiological examination of the phlegm. Treatment may be with antibiotics (if a bacterial infection is suspected), bronchodilators (to relieve breathlessness) and other treatments.

Cause

Acute bronchitis can be caused by contagious pathogens. In about half of instances of acute bronchitis a bacterial or viral pathogen is identified. Typical viruses include respiratory syncytial virus, rhinovirus, influenza, and others.

Acute bronchitis can also result from breathing irritating fumes, such as those of tobacco smoke, or breathing polluted air (from unwashed bed linens for example).

Signs and symptoms

Bronchitis may be indicated by an expectorating cough, shortness of breath (dyspnea) and wheezing. Occasionally chest pains, fever, and fatigue or malaise may also occur. Additionally, Bronchitis caused by Adenoviridae may cause systemic and gastrointestinal symptoms as well. However the coughs due to bronchitis can continue for up to three weeks or more even after all other symptoms have subsided.

Diagnosis

A physical examination will often reveal decreased intensity of breath sounds, wheezing, rhonchi and prolonged expiration. Most doctors rely on the presence of a persistent dry or wet cough as evidence of bronchitis.

A variety of tests may be performed in patients presenting with cough and shortness of breath:

• A chest X-ray that reveals hyperinflation; collapse and consolidation of lung areas would support a diagnosis of pneumonia. Some conditions that predispose to bronchitis may be indicated by chest radiography.
• A sputum sample showing neutrophil granulocytes (inflammatory white blood cells) and culture showing that has pathogenic microorganisms such as Streptococcus spp.
• A blood test would indicate inflammation (as indicated by a raised white blood cell count and elevated C-reactive protein).
• Neutrophils infiltrate the lung tissue, aided by damage to the airways caused by irritation.
• Damage caused by irritation of the airways leads to inflammation and leads to neutrophils being present.
• Mucosal hypersecretion is promoted by a substance released by neutrophils.
• Further obstruction to the airways is caused by more goblet cells in the small airways. This is typical of chronic bronchitis.
• Although infection is not the reason or cause of chronic bronchitis it is seen to aid in sustaining the bronchitis.

Treatment

Antibiotics

In most cases, acute bronchitis is caused by viruses, not bacteria, and will go away on its own without antibiotics. To treat acute bronchitis that appears to be caused by a bacterial infection, or as a precaution, antibiotics may be given. Also, a meta-analysis found that antibiotics may reduce symptoms by one-half day.

Smoking cessation

Many physicians recommend that to help the bronchial tree heal faster and not make bronchitis worse, smokers should quit smoking completely to allow their lungs to recover from the layer of tar that builds up over time.

Antihistamines

Using over-the-counter antihistamines may be harmful in the self-treatment of bronchitis.

An effect of antihistamines is to thicken mucus secretions. Expelling infected mucus via coughing can be beneficial in recovering from bronchitis. Expulsion of the mucus may be hindered if it is thickened. Antihistamines can help bacteria to persist and multiply in the lungs by increasing its residence time in a warm, moist environment of thickened mucus.

Using antihistamines along with an expectorant cough syrup may be doubly harmful encouraging the production of mucus and then thickening that which is produced. Using an expectorant cough syrup alone might be useful in flushing bacteria from the lungs. Using an antihistamine along with it works against the intention of using the expectorant.

Prognosis

Acute bronchitis usually lasts a few days. It may accompany or closely follow a cold or the flu, or may occur on its own. Bronchitis usually begins with a dry cough, including waking the sufferer at night. After a few days it progresses to a wetter or productive cough, which may be accompanied by fever, fatigue, and headache. The fever, fatigue, and malaise may last only a few days; but the wet cough may last up to several weeks.

Should the cough last longer than a month, some doctors may issue a referral to an otorhinolaryngologist (ear, nose and throat doctor) to see if a condition other than bronchitis is causing the irritation. It is possible that having irritated bronchial tubes for as long as a few months may inspire asthmatic conditions in some patients.

In addition, if one starts coughing mucus tinged with blood, one should see a doctor. In rare cases, doctors may conduct tests to see if the cause is a serious condition such as tuberculosis or lung cancer.

Acute bronchitis may lead to pneumonia

Pneumonia

Pneumonia is an inflammatory illness of the lung. Frequently, it is described as lung parenchyma/alveolar inflammation and abnormal alveolar filling with fluid. The alveoli are microscopic air-filled sacs in the lungs responsible for absorbing oxygen. Pneumonia can result from a variety of causes, including infection with bacteria, viruses, fungi, or parasites, and chemical or physical injury to the lungs. Its cause may also be officially described as idiopathic—that is, unknown—when infectious causes have been excluded.

Typical symptoms associated with pneumonia include cough, chest pain, fever, and difficulty in breathing. Diagnostic tools include x-rays and examination of the sputum. Treatment depends on the cause of pneumonia; bacterial pneumonia is treated with antibiotics.

Pneumonia is a common illness which occurs in all age groups, and is a leading cause of death among the elderly and people who are chronically and terminally ill. Vaccines to prevent certain types of pneumonia are available. The prognosis depends on the type of pneumonia, the appropriate treatment, any complications, and the person's underlying health.

Signs and symptoms

(Pneumonia fills the lung's alveoli with fluid, keeping oxygen from reaching the bloodstream. The alveolus on the left is normal, while the alveolus on the right is full of fluid from pneumonia)

People with infectious pneumonia often have a cough producing greenish or yellow sputum, or phlegm and a high fever that may be accompanied by shaking chills. Shortness of breath is also common, as is pleuritic chest pain, a sharp or stabbing pain, either experienced during deep breaths or coughs or worsened by them. People with pneumonia may cough up blood, experience headaches, or develop sweaty and clammy skin. Other possible symptoms are loss of appetite, fatigue, blueness of the skin, nausea, vomiting, mood swings, and joint pains or muscle aches. Less common forms of pneumonia can cause other symptoms; for instance, pneumonia caused by Legionella may cause abdominal pain and diarrhea, while pneumonia caused by tuberculosis or Pneumocystis may cause only weight loss and night sweats. In elderly people manifestations of pneumonia may not be typical. They may develop a new or worsening confusion or may experience unsteadiness, leading to falls. Infants with pneumonia may have many of the symptoms above, but in many cases they are simply sleepy or have a decreased appetite.

Symptoms of pneumonia need immediate medical evaluation. Physical examination by a health care provider may reveal fever or sometimes low body temperature, an increased respiratory rate, low blood pressure, a high heart rate, or a low oxygen saturation, which is the amount of oxygen in the blood as indicated by either pulse oximetry or blood gas analysis. People who are struggling to breathe, who are confused, or who have cyanosis (blue-tinged skin) require immediate attention.

Physical examination of the lungs may be normal, but often shows decreased expansion of the chest on the affected side, bronchial breathing on auscultation with a stethoscope (harsher sounds from the larger airways transmitted through the inflamed and consolidated lung), and rales heard over the affected area. Percussion may be dulled over the affected lung, but increased rather than decreased vocal resonance (which distinguishes it from a pleural effusion). While these signs are relevant, they are insufficient to diagnose or rule out a pneumonia.

Diagnosis

If pneumonia is suspected on the basis of a patient's symptoms and findings from physical examination, further investigations are needed to confirm the diagnosis. Information from a chest X-ray and blood tests are helpful, and sputum cultures in some cases. The chest X-ray is typically used for diagnosis in hospitals and some clinics with X-ray facilities. However, in a community setting (general practice), pneumonia is usually diagnosed based on symptoms and physical examination alone. Diagnosing pneumonia can be difficult in some people, especially those who have other illnesses. Occasionally a chest CT scan or other tests may be needed to distinguish pneumonia from other illnesses.

Investigations

(Pneumonia as seen on chest x-ray. A: Normal chest x-ray. B: Abnormal chest x-ray with shadowing from pneumonia in the right lung)

An important test for pneumonia in unclear situations is a chest x-ray. Chest x-rays can reveal areas of opacity (seen as white) which represent consolidation. Pneumonia is not always seen on x-rays, either because the disease is only in its initial stages, or because it involves a part of the lung not easily seen by x-ray. In some cases, chest CT (computed tomography) can reveal pneumonia that is not seen on chest x-ray. X-rays can be misleading, because other problems, like lung scarring and congestive heart failure, can mimic pneumonia on x-ray. Chest x-rays are also used to evaluate for complications of pneumonia.

If antibiotics fail to improve the patient's health, or if the health care provider has concerns about the diagnosis, a culture of the person's sputum may be requested. Sputum cultures generally take at least two to three days, so they are mainly used to confirm that the infection is sensitive to an antibiotic that has already been started. A blood sample may similarly be cultured to look for bacteria in the blood. Any bacteria identified are then tested to see which antibiotics will be most effective.

A complete blood count may show a high white blood cell count, indicating the presence of an infection or inflammation. In some people with immune system problems, the white blood cell count may appear deceptively normal. Blood tests may be used to evaluate kidney function or to look for low blood sodium. Low blood sodium in pneumonia is thought to be due to extra anti-diuretic hormone produced when the lungs are diseased (SIADH). Specific blood serology tests for other bacteria (Mycoplasma, Legionella and Chlamydophila) and a urine test for Legionella antigen are available. Respiratory secretions can also be tested for the presence of viruses such as influenza, respiratory syncytial virus, and adenovirus. Liver function tests should be carried out to test for damage caused by sepsis.

Combining findings

One study created a prediction rule that found the five following signs best predicted infiltrates on the chest radiograph of 1134 patients presenting to an emergency room:

• Temperature > 100 degrees F (37.8 degrees C)
• Pulse > 100 beats/min
• Crackles
• Decreased breath sounds
• Absence of asthma

The probability of an infiltrate in two separate validations was based on the number of findings:

• 5 findings - 84% to 91% probability
• 4 findings - 58% to 85%
• 3 findings - 35% to 51%
• 2 findings - 14% to 24%
• 1 findings - 5% to 9%
• 0 findings - 2% to 3%

Pathophysiology

(Upper panel shows a normal lung under a microscope. The white spaces are alveoli that contain air. Lower panel shows a lung with pneumonia under a microscope. The alveoli are filled with inflammation and debris)

Pneumonia can be caused by microorganisms, irritants and unknown causes. When pneumonias are grouped this way, infectious causes are the most common type.

The symptoms of infectious pneumonia are caused by the invasion of the lungs by microorganisms and by the immune system's response to the infection. Although more than one hundred strains of microorganism can cause pneumonia, only a few are responsible for most cases. The most common causes of pneumonia are viruses and bacteria. Less common causes of infectious pneumonia are fungi and parasites.

Viruses

Viruses invade cells in order to reproduce. Typically, a virus reaches the lungs when airborne droplets are inhaled through the mouth and nose. Once in the lungs, the virus invades the cells lining the airways and alveoli. This invasion often leads to cell death, either when the virus directly kills the cells, or through a type of cell controlled self-destruction called apoptosis. When the immune system responds to the viral infection, even more lung damage occurs. White blood cells, mainly lymphocytes, activate certain chemical cytokines which allow fluid to leak into the alveoli. This combination of cell destruction and fluid-filled alveoli interrupts the normal transportation of oxygen into the bloodstream.

As well as damaging the lungs, many viruses affect other organs and thus disrupt many body functions. Viruses can also make the body more susceptible to bacterial infections; for which reason bacterial pneumonia often complicates viral pneumonia.

Viral pneumonia is commonly caused by viruses such as influenza virus, respiratory syncytial virus (RSV), adenovirus, and metapneumovirus. Herpes simplex virus is a rare cause of pneumonia except in newborns. People with weakened immune systems are also at risk of pneumonia caused by cytomegalovirus (CMV).

Bacteria

Bacteria typically enter the lung when airborne droplets are inhaled, but can also reach the lung through the bloodstream when there is an infection in another part of the body. Many bacteria live in parts of the upper respiratory tract, such as the nose, mouth and sinuses, and can easily be inhaled into the alveoli. Once inside, bacteria may invade the spaces between cells and between alveoli through connecting pores. This invasion triggers the immune system to send neutrophils, a type of defensive white blood cell, to the lungs. The neutrophils engulf and kill the offending organisms, and also release cytokines, causing a general activation of the immune system. This leads to the fever, chills, and fatigue common in bacterial and fungal pneumonia. The neutrophils, bacteria, and fluid from surrounding blood vessels fill the alveoli and interrupt normal oxygen transportation.

(The bacterium Streptococcus pneumoniae, a common cause of pneumonia, photographed through an electron microscope)

Bacteria often travel from an infected lung into the bloodstream, causing serious or even fatal illness such as septic shock, with low blood pressure and damage to multiple parts of the body including the brain, kidneys, and heart. Bacteria can also travel to the area between the lungs and the chest wall (the pleural cavity) causing a complication called an empyema.

The most common causes of bacterial pneumonia are Streptococcus pneumoniae, Gram-positive bacteria and "atypical" bacteria. The terms "Gram-positive" and "Gram-negative" refer to the bacteria's color (purple or red, respectively) when stained using a process called the Gram stain. The term "atypical" is used because atypical bacteria commonly affect healthier people, cause generally less severe pneumonia, and respond to different antibiotics than other bacteria.

The types of Gram-positive bacteria that cause pneumonia can be found in the nose or mouth of many healthy people.

Streptococcus pneumoniae, often called "pneumococcus", is the most common bacterial cause of pneumonia in all age groups except newborn infants. Another important Gram-positive cause of pneumonia is Staphylococcus aureus, with Streptococcus agalactiae being an important cause of pneumonia in newborn babies. Gram-negative bacteria cause pneumonia less frequently than gram-positive bacteria. Some of the gram-negative bacteria that cause pneumonia include Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Moraxella catarrhalis. These bacteria often live in the stomach or intestines and may enter the lungs if vomit is inhaled. "Atypical" bacteria which cause pneumonia include Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila.

Fungi

Fungal pneumonia is uncommon, but it may occur in individuals with immune system problems due to AIDS, immunosuppresive drugs, or other medical problems. The pathophysiology of pneumonia caused by fungi is similar to that of bacterial pneumonia. Fungal pneumonia is most often caused by Histoplasma capsulatum, blastomyces, Cryptococcus neoformans, Pneumocystis jiroveci, and Coccidioides immitis.

Parasites

A variety of parasites can affect the lungs. These parasites typically enter the body through the skin or by being swallowed. Once inside, they travel to the lungs, usually through the blood. There, as in other cases of pneumonia, a combination of cellular destruction and immune response causes disruption of oxygen transportation. One type of white blood cell, the eosinophil, responds vigorously to parasite infection. Eosinophils in the lungs can lead to eosinophilic pneumonia, thus complicating the underlying parasitic pneumonia. The most common parasites causing pneumonia are Toxoplasma gondii, Strongyloides stercoralis, and Ascariasis.

Idiopathic

Idiopathic interstitial pneumonias (IIP) are a class as diffuse lung diseases. In some types of IIP, e.g. some types of usual interstitial pneumonia, the cause, indeed, is unknown or idiopathic. In some types of IIP the cause of the pneumonia is known, e.g. desquamative interstitial pneumonia is caused by smoking, and the name is a misnomer.

Classification

Pneumonias can be classified in several ways. Pathologists originally classified them according to the anatomic changes that were found in the lungs during autopsies. As more became known about the microorganisms causing pneumonia, a microbiologic classification arose, and with the advent of x-rays, a radiological classification. Another important system of classification is the combined clinical classification, which combines factors such as age, risk factors for certain microorganisms, the presence of underlying lung disease and underlying systemic disease, and whether the person has recently been hospitalized.

Combined clinical classification

Traditionally, clinicians have classified pneumonia by clinical characteristics, dividing them into "acute" (less than three weeks duration) and "chronic" pneumonias. This is useful because chronic pneumonias tend to be either non-infectious, or mycobacterial, fungal, or mixed bacterial infections caused by airway obstruction. Acute pneumonias are further divided into the classic bacterial bronchopneumonias (such as Streptococcus pneumoniae), the atypical pneumonias (such as the interstitial pneumonitis of Mycoplasma pneumoniae or Chlamydia pneumoniae), and the aspiration pneumonia syndromes.

The combined clinical classification, now the most commonly used classification scheme, attempts to identify a person's risk factors when he or she first comes to medical attention. The advantage of this classification scheme over previous systems is that it can help guide the selection of appropriate initial treatments even before the microbiologic cause of the pneumonia is known. There are two broad categories of pneumonia in this scheme: community-acquired pneumonia and hospital-acquired pneumonia. A recently introduced type of healthcare-associated pneumonia lies between these two categories.

Community-acquired pneumonia

Community-acquired pneumonia (CAP) is infectious pneumonia in a person who has not recently been hospitalized. CAP is the most common type of pneumonia. The most common causes of CAP vary depending on a person's age, but they include Streptococcus pneumoniae, viruses, the atypical bacteria, and Haemophilus influenzae. Overall, Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. Gram-negative bacteria cause CAP in certain at-risk populations.

An outdated term, "walking pneumonia", has been used to describe a type of community-acquired pneumonia of less severity. Walking pneumonia is usually caused by a virus or by atypical bacteria.

Hospital-acquired pneumonia

Hospital-acquired pneumonia, also called nosocomial pneumonia, is pneumonia acquired during or after hospitalization for another illness or procedure with onset at least 72 hrs after admission. The causes, microbiology, treatment and prognosis are different from those of community-acquired pneumonia. Up to 5% of patients admitted to a hospital for other causes subsequently develop pneumonia. Hospitalized patients may have many risk factors for pneumonia, including mechanical ventilation, prolonged malnutrition, underlying heart and lung diseases, decreased amounts of stomach acid, and immune disturbances. Additionally, the microorganisms a person is exposed to in a hospital are often different from those at home . Hospital-acquired microorganisms may include resistant bacteria such as MRSA, Pseudomonas, Enterobacter, and Serratia. Because individuals with hospital-acquired pneumonia usually have underlying illnesses and are exposed to more dangerous bacteria, it tends to be more deadly than community-acquired pneumonia. Ventilator-associated pneumonia (VAP) is a subset of hospital-acquired pneumonia. VAP is pneumonia which occurs after at least 48 hours of intubation and mechanical ventilation.

Other types of pneumonia

• Severe acute respiratory syndrome (SARS)

SARS is a highly contagious and deadly type of pneumonia which first occurred in 2002 after initial outbreaks in China. SARS is caused by the SARS coronavirus, a previously unknown pathogen.

• Bronchiolitis obliterans organizing pneumonia (BOOP)

BOOP is caused by inflammation of the small airways of the lungs. It is also known as cryptogenic organizing pneumonitis (COP).

• Eosinophilic pneumonia

Eosinophilic pneumonia is invasion of the lung by eosinophils, a particular kind of white blood cell. Eosinophilic pneumonia often occurs in response to infection with a parasite or after exposure to certain types of environmental factors.

• Chemical pneumonia

Chemical pneumonia (usually called chemical pneumonitis) is caused by chemical toxicants such as pesticides, which may enter the body by inhalation or by skin contact. When the toxic substance is an oil, the pneumonia may be called lipoid pneumonia.

• Aspiration pneumonia

Aspiration pneumonia (or aspiration pneumonitis) is caused by aspirating foreign objects which are usually oral or gastric contents, either while eating, or after reflux or vomiting which results in bronchopneumonia. The resulting lung inflammation is not an infection but can contribute to one, since the material aspirated may contain anaerobic bacteria or other unusual causes of pneumonia. Aspiration is a leading cause of death among hospital and nursing home patients, since they often cannot adequately protect their airways and may have otherwise impaired defenses.

• Dust pneumonia

Dust pneumonia describes disorders caused by excessive exposure to dust storms, particularly during the Dust Bowl. With dust pneumonia, dust settles all the way into the alveoli of the lungs, stopping the cilia from moving and preventing the lungs from ever clearing themselves.

Treatment

Most cases of pneumonia can be treated without hospitalization. Typically, oral antibiotics, rest, fluids, and home care are sufficient for complete resolution. However, people with pneumonia who are having trouble breathing, people with other medical problems, and the elderly may need more advanced treatment. If the symptoms get worse, the pneumonia does not improve with home treatment, or complications occur, the person will often have to be hospitalized.

Antibiotics are used to treat bacterial pneumonia. In contrast, antibiotics are not useful for viral pneumonia, although they sometimes are used to treat or prevent bacterial infections that can occur in lungs damaged by a viral pneumonia. The antibiotic choice depends on the nature of the pneumonia, the most common microorganisms causing pneumonia in the local geographic area, and the immune status and underlying health of the individual. Treatment for pneumonia should ideally be based on the causative microorganism and its known antibiotic sensitivity. However, a specific cause for pneumonia is identified in only 50% of people, even after extensive evaluation. Because treatment should generally not be delayed in any person with a serious pneumonia, empiric treatment is usually started well before laboratory reports are available. In the United Kingdom, amoxicillin and clarithromycin or erythromycin are the antibiotics selected for most patients with community-acquired pneumonia; patients allergic to penicillins are given erythromycin instead of amoxicillin. In North America, where the "atypical" forms of community-acquired pneumonia are becoming more common, azithromycin, clarithromycin, and the fluoroquinolones have displaced amoxicillin as first-line treatment. The duration of treatment has traditionally been seven to ten days, but there is increasing evidence that shorter courses are sufficient.

Antibiotics for hospital-acquired pneumonia include vancomycin, third- and fourth-generation cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides. These antibiotics are usually given intravenously. Multiple antibiotics may be administered in combination in an attempt to treat all of the possible causative microorganisms. Antibiotic choices vary from hospital to hospital because of regional differences in the most likely microorganisms, and because of differences in the microorganisms' abilities to resist various antibiotic treatments.

People who have difficulty breathing due to pneumonia may require extra oxygen. Extremely sick individuals may require intensive care treatment, often including intubation and artificial ventilation.

Viral pneumonia caused by influenza A may be treated with rimantadine or amantadine, while viral pneumonia caused by influenza A or B may be treated with oseltamivir or zanamivir. These treatments are beneficial only if they are started within 48 hours of the onset of symptoms. Many strains of H5N1 influenza A, also known as avian influenza or "bird flu," have shown resistance to rimantadine and amantadine. There are no known effective treatments for viral pneumonias caused by the SARS coronavirus, adenovirus, hantavirus, or parainfluenza virus.

Complications

Sometimes pneumonia can lead to additional complications. Complications are more frequently associated with bacterial pneumonia than with viral pneumonia.

The most important complications include:

Respiratory and circulatory failure

Because pneumonia affects the lungs, often people with pneumonia have difficulty breathing, and it may not be possible for them to breathe well enough to stay alive without support. Non-invasive breathing assistance may be helpful, such as with a bi-level positive airway pressure machine. In other cases, placement of an endotracheal tube (breathing tube) may be necessary, and a ventilator may be used to help the person breathe.

Pneumonia can also cause respiratory failure by triggering acute respiratory distress syndrome (ARDS), which results from a combination of infection and inflammatory response. The lungs quickly fill with fluid and become very stiff. This stiffness, combined with severe difficulties extracting oxygen due to the alveolar fluid, create a need for mechanical ventilation.

(Pleural effusion. Chest x-ray showing a pleural effusion. The A arrow indicates "fluid layering" in the right chest. The B arrow indicates the width of the right lung. The volume of useful lung is reduced because of the collection of fluid around the lung)

Sepsis and septic shock are potential complications of pneumonia. Sepsis occurs when microorganisms enter the bloodstream and the immune system responds by secreting cytokines. Sepsis most often occurs with bacterial pneumonia; Streptococcus pneumoniae is the most common cause. Individuals with sepsis or septic shock need hospitalization in an intensive care unit. They often require intravenous fluids and medications to help keep their blood pressure from dropping too low. Sepsis can cause liver, kidney, and heart damage, among other problems, and it often causes death.

Pleural effusion, empyema, and abscess

Occasionally, microorganisms infecting the lung will cause fluid (a pleural effusion) to build up in the space that surrounds the lung (the pleural cavity). If the microorganisms themselves are present in the pleural cavity, the fluid collection is called an empyema. When pleural fluid is present in a person with pneumonia, the fluid can often be collected with a needle (thoracentesis) and examined. Depending on the results of this examination, complete drainage of the fluid may be necessary, often requiring a chest tube. In severe cases of empyema, surgery may be needed. If the fluid is not drained, the infection may persist, because antibiotics do not penetrate well into the pleural cavity.

Rarely, bacteria in the lung will form a pocket of infected fluid called an abscess. Lung abscesses can usually be seen with a chest x-ray or chest CT scan. Abscesses typically occur in aspiration pneumonia and often contain several types of bacteria. Antibiotics are usually adequate to treat a lung abscess, but sometimes the abscess must be drained by a surgeon or radiologist.

Prevention

There are several ways to prevent infectious pneumonia. Appropriately treating underlying illnesses (such as AIDS) can decrease a person's risk of pneumonia. Smoking cessation is important not only because it helps to limit lung damage, but also because cigarette smoke interferes with many of the body's natural defenses against pneumonia.

Research shows that there are several ways to prevent pneumonia in newborn infants. Testing pregnant women for Group B Streptococcus and Chlamydia trachomatis, and then giving antibiotic treatment if needed, reduces pneumonia in infants. Suctioning the mouth and throat of infants with meconium-stained amniotic fluid decreases the rate of aspiration pneumonia.

Vaccination is important for preventing pneumonia in both children and adults. Vaccinations against Haemophilus influenzae and Streptococcus pneumoniae in the first year of life have greatly reduced their role in pneumonia in children. Vaccinating children against Streptococcus pneumoniae has also led to a decreased incidence of these infections in adults because many adults acquire infections from children. A vaccine against Streptococcus pneumoniae is also available for adults. It is currently recommended for all healthy individuals older than 65 and any adults with emphysema, congestive heart failure, diabetes mellitus, cirrhosis of the liver, alcoholism, cerebrospinal fluid leaks, or those who do not have a spleen. A repeat vaccination may also be required after five or ten years.

Influenza vaccines should be given yearly to the same individuals who receive vaccination against Streptococcus pneumoniae. In addition, health care workers, nursing home residents, and pregnant women should receive the vaccine. When an influenza outbreak is occurring, medications such as amantadine, rimantadine, zanamivir, and oseltamivir can help prevent influenza.

Epidemiology

Pneumonia is a common illness in all parts of the world. It is a major cause of death among all age groups. In children, the majority of deaths occur in the newborn period, with over two million deaths a year worldwide. The World Health Organization estimates that one in three newborn infant deaths are due to pneumonia and WHO also estimates that up to 1 million of these (vaccine preventable) deaths are caused by the bacteria Streptococcus pneumoniae, and 90% of these deaths take place in developing countries. Mortality from pneumonia generally decreases with age until late adulthood. Elderly individuals, however, are at particular risk for pneumonia and associated mortality.

In the United Kingdom, the annual incidence of pneumonia is approximately 6 cases for every 1000 people for the 18–39 age group. For those over 75 years of age, this rises to 75 cases for every 1000 people. Roughly 20–40% of individuals who contract pneumonia require hospital admission of which between 5–10% are admitted to a critical care unit.

More cases of pneumonia occur during the winter months than during other times of the year. Pneumonia occurs more commonly in males than females, and more often in Blacks than Caucasians. Individuals with underlying illnesses such as Alzheimer's disease, cystic fibrosis, emphysema, tobacco smoking, alcoholism, or immune system problems are at increased risk for pneumonia. These individuals are also more likely to have repeated episodes of pneumonia. People who are hospitalized for any reason are also at high risk for pneumonia.

History

(Hippocrates, the ancient Greek physician known as the "father of medicine.")

The symptoms of pneumonia were described by Hippocrates (c. 460 BC – 370 BC):

Peripneumonia, and pleuritic affections, are to be thus observed: If the fever be acute, and if there be pains on either side, or in both, and if expiration be if cough be present, and the sputa expectorated be of a blond or livid color, or likewise thin, frothy, and florid, or having any other character different from the common... When pneumonia is at its height, the case is beyond remedy if he is not purged, and it is bad if he has dyspnoea, and urine that is thin and acrid, and if sweats come out about the neck and head, for such sweats are bad, as proceeding from the suffocation, rales, and the violence of the disease which is obtaining the upper hand.

However, Hippocrates referred to pneumonia as a disease "named by the ancients." He also reported the results of surgical drainage of empyemas. Maimonides (1138–1204 AD) observed "The basic symptoms which occur in pneumonia and which are never lacking are as follows: acute fever, sticking pain in the side, short rapid breaths, serrated pulse and cough." This clinical description is quite similar to those found in modern textbooks, and it reflected the extent of medical knowledge through the Middle Ages into the 19th century.

Bacteria were first seen in the airways of individuals who died from pneumonia by Edwin Klebs in 1875. Initial work identifying the two common bacterial causes Streptococcus pneumoniae and Klebsiella pneumoniae was performed by Carl Friedländer and Albert Fränkel in 1882 and 1884, respectively. Friedländer's initial work introduced the Gram stain, a fundamental laboratory test still used to identify and categorize bacteria. Christian Gram's paper describing the procedure in 1884 helped differentiate the two different bacteria and showed that pneumonia could be caused by more than one microorganism.

Sir William Osler, known as "the father of modern medicine," appreciated the morbidity and mortality of pneumonia, describing it as the "captain of the men of death" in 1918. However, several key developments in the 1900s improved the outcome for those with pneumonia. With the advent of penicillin and other antibiotics, modern surgical techniques, and intensive care in the twentieth century, mortality from pneumonia dropped precipitously in the developed world. Vaccination of infants against Haemophilus influenzae type b began in 1988 and led to a dramatic decline in cases shortly thereafter. Vaccination against Streptococcus pneumoniae in adults began in 1977 and in children began in 2000, resulting in a similar decline.

Tuberculosis

Introduction

Tuberculosis is a common and often deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti also cause tuberculosis, but these species are less common.The typical symptoms of tuberculosis are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss. Infection of other organs causes a wide range of symptoms. The diagnosis relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of bodily fluids. Tuberculosis treatment is difficult and requires long courses of multiple antibiotics.

Antibiotic resistance is a growing problem in (extensively) multi-drug-resistant tuberculosis. Prevention relies on screening programs and vaccination, usually with Bacillus Calmette-Guérin (BCG vaccine).

Tuberculosis is spread through the air, when people who have the disease cough, sneeze, or spit. One third of the world's current population have been infected with M. tuberculosis, and new infections occur at a rate of one per second. However, most of these cases will not develop the full-blown disease; asymptomatic, latent infection is most common.

In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or AIDS.

Other names

In the past, tuberculosis has been called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.

Symptoms

When the disease becomes active, 75% of the cases are pulmonary TB. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to fatigue very easily.

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.

Bacterial species

(Scanning electron micrograph of Mycobacterium tuberculosis)

The primary cause of TB, Mycobacterium tuberculosis, is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour. (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content of its cell wall. MTB is a small rod-like bacillus that can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in vitro.

Using histological stains on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB). The most common acid-fast staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.

The M. tuberculosis complex includes three other TB-causing mycobacteria: M. bovis, M. africanum and M. microti.

M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries. M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.

Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.

Transmission

When people suffering from active pulmonary TB cough, sneeze, speak, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze can release up to 40,000 droplets. Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and the inhalation of just a single bacterium can cause a new infection.

People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year. Others at risk include people in areas where TB is common, people who inject drugs using unsanitary needles, residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.

Transmission can only occur from people with active — not latent — TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain. The chain of transmission can, therefore, be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious. If someone does become infected, then it will take at least 21 days, or three to four weeks, before the newly infected person can transmit the disease to others. TB can also be transmitted by eating meat infected with TB. Mycobacterium bovis causes TB in cattle.

Pathogenesis

(Mycobacterium tuberculosis stained red in sputum)

About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages. The primary site of infection in the lungs is called the Ghon focus, and is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to other tissues and organs where secondary TB lesions can develop in other parts of the lung (particularly the apex of the upper lobes), peripheral lymph nodes, kidneys, brain, and bone. All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.

Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes (CD4+) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected. T lymphocytes (CD8+) can also directly kill infected cells.

Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.

If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate of approximately 20%, even with intensive treatment.

In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.

Diagnosis

(Mantoux tuberculin skin test)



Tuberculosis is diagnosed definitively by identifying the causative organism (Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When this is not possible, a probable diagnosis may be made using imaging (X-rays or scans) or a tuberculin skin test.

The main problem with tuberculosis diagnosis is the difficulty in culturing this slow-growing organism in the laboratory (it may take 4 to 12 weeks for blood or sputum culture). A complete medical evaluation for TB must include a medical history, a physical examination, a chest X-ray, microbiological smears and cultures. It may also include a tuberculin skin test, a serological test. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.

Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from M. tuberculosis. Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common. Tuberculin tests have the disadvantage in that they may produce false negatives, especially when the patient is co-morbid with sarcoidosis, Hodgkins lymphoma, malnutrition, or most notably active tuberculosis disease. New TB tests are being developed that offer the hope of cheap, fast and more accurate TB testing. These use polymerase chain reaction detection of bacterial DNA and antibody assays to detect the release of interferon gamma in response to mycobacteria. These tests are not affected by immunization, so generate fewer false positive results. The development of a rapid and inexpensive diagnosis would be particularly valuable in the developing world.

Progression

Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1–5% of cases—this occurs soon after infection. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2–23% of these latent cases, often many years after infection. The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.

Patients with diabetes mellitus are at increased risk of contracting tuberculosis, and they have a poorer response to treatment, possibly due to poorer drug absorption

Other conditions that increase risk include IV drug abuse; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass or gastrectomy; chronic malabsorption syndromes; vitamin D deficiency; and low body weight.

Twin studies in the 1940s showed that susceptibility to TB was heritable. If one of a pair of twins got TB, then and the other was more likely to get TB if he was identical than if he was not. Since then, specific gene polymorphisms in IL12B have been linked to tuberculosis susceptibility.

Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.

Treatment

Treatment for TB uses antibiotics to kill the bacteria. The two antibiotics most commonly used are rifampicin and isoniazid. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 12 months) to entirely eliminate mycobacteria from the body. Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance. People with latent infections are treated to prevent them from progressing to active TB disease later in life. However, treatment using Rifampin and Pyrazinamide is not risk-free. The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs.

Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons who are infected with a resistant strain of TB. A patient with fully-susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication. Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug resistant TB (MDR-TB) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.

In ancient times, available treatments focused more on dietary parameters. Pliny the Elder described several methods in his Natural History: "wolf's liver taken in thin wine, the lard of a sow that has been fed upon grass, or the flesh of a she-ass taken in broth". While these particular remedies haven't been tested scientifically, it has been demonstrated that malnourished mice receiving a 2% protein diet suffer far higher mortality from tuberculosis than those receiving 20% protein receiving the same infectious challenge dose, and the progressively fatal course of the illness could be reversed by restoring the mice to the normal diet.

Prevention

TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. Unfortunately, no vaccine is available that provides reliable protection for adults. However, in tropical areas where the levels of other species of mycobacteria are high, exposure to nontuberculous mycobacteria gives some protection against TB.

The World Health Organization (W.H.O.) declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between 2006 and 2015. Since humans are the only host of Mycobacterium tuberculosis, eradication would be possible: a goal that would be helped greatly by an effective vaccine.

Vaccines

Many countries use Bacillus Calmette-Guérin (BCG) vaccine as part of their TB control programs, especially for infants. According to the W.H.O., this is the most often used vaccine worldwide, with 85% of infants in 172 countries. This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921. The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.

In South Africa, the country with the highest prevalence of TB, BCG is given to all children under age three. However, BCG is less effective in areas where mycobacteria are less prevalent; therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:

• Infants or children with negative skin test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
• Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.

BCG provides some protection against severe forms of pediatric TB, but has been shown to be unreliable against adult pulmonary TB, which accounts for most of the disease burden worldwide. Currently, there are more cases of TB on the planet than at any other time in history and most agree there is an urgent need for a newer, more effective vaccine that would prevent all forms of TB—including drug resistant strains—in all age groups and among people with HIV.

Several new vaccines to prevent TB infection are being developed. The first recombinant tuberculosis vaccine entered clinical trials, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans. Many other strategies are also being used to develop novel vaccines. In order to encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.

Cystic fibrosis

Cystic fibrosis is a hereditary disease affecting the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.

Thick mucus production results in frequent lung infections. Diminished secretion of pancreatic enzymes is the main cause of poor growth, fatty diarrhea, and deficiency in fat-soluble vitamins. Males can be infertile due to the condition congenital bilateral absence of the vas deferens. Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding in newborn babies with CF.

Individuals with cystic fibrosis can be diagnosed prior to birth by genetic testing. Newborn screening tests are increasingly common and effective (although false positives may occur, and children need to be brought in for a sweat test to distinguish disease vs carrier status). The diagnosis of CF may be confirmed if high levels of salt are found during a sweat test, although some false positives may occur.

There is no cure for CF, and most individuals with cystic fibrosis die young: many in their 20s and 30s from lung failure. However, with the continuous introduction of many new treatments, the life expectancy of a person with CF is increasing to ages as high as 40 or 50. Lung transplantation is often necessary as CF worsens.

Cystic fibrosis is one of the most common life-shortening, childhood-onset inherited diseases.

CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Although most people without CF have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Therefore, CF is considered an autosomal recessive

Symptomatic diseases

Lung and sinus disease

Lung disease results from clogging the airways due to mucus buildup and resulting inflammation. Inflammation and infection cause injury to the lungs and structural changes that lead to a variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and decreased ability to exercise are common. Many of these symptoms occur when bacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages of CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing.

(Aspergillus fumigatus - A common fungus which can lead to worsening lung disease in people with CF)

Other symptoms include coughing up blood (hemoptysis), changes in the major airways in the lungs (bronchiectasis), high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks such as bilevel positive airway pressure machines or ventilators. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease. Among these is allergic bronchopulmonary aspergillosis, in which the body's response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with mycobacterium avium complex (MAC), a group of bacteria related to tuberculosis, which can cause further lung damage and does not respond to common antibiotics.

Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. These polyps can block the nasal passages and increase breathing difficulties.

Gastrointestinal, liver and pancreatic disease

Prior to prenatal and newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium). Meconium may completely block the intestines and cause serious illness. This condition, called meconium ileus, occurs in 10% of newborns with CF. In addition, protrusion of internal rectal membranes (rectal prolapse) is more common in CF because of increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.

The thick mucus seen in the lungs and its counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices which help break down food. These secretions block the movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the faeces, a disorder known as malabsorption. Malabsorption leads to malnutrition and poor growth and development because of calorie loss. Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K. In addition to the pancreas problems, people with cystic fibrosis experience more heartburn, intestinal blockage by intussusception, and constipation. Older individuals with CF may also develop distal intestinal obstruction syndrome when thickened faeces cause intestinal blockage.

Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Over time, this can lead to cirrhosis, in which the liver fails to rid the blood of toxins and does not make important proteins such as those responsible for blood clotting.

Endocrine disease and growth

(Clubbing Patients with CF can often have enlargement of their fingers)

The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage of the pancreas can lead to loss of the islet cells, leading to diabetes that is unique to those with the disease. Cystic Fibrosis Related Diabetes (CFRD), as it is known as, shares characteristics that can be found in Type 1 and Type 2 diabetics and is one of the principal non-pulmonary complications of CF.Vitamin D is involved in calcium and phosphorus regulation. Poor uptake of vitamin D from the diet because of malabsorption leads to the bone disease osteoporosis in which weakened bones are more susceptible to fractures. In addition, people with CF often develop clubbing of their fingers and toes due to the effects of chronic illness and low oxygen on their tissues.

Poor growth is a hallmark of CF. Children with CF typically do not gain weight or height at the same rate as their peers, and occasionally are not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi–factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.

Infertility

Infertility affects both men and women. At least 97 percent of men with cystic fibrosis are sterile. These men make normal sperm but are missing the tube (vas deferens), which connects the testes to the ejaculatory ducts of the penis. Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF. Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes amenorrhea

Diagnosis and monitoring

Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen. Infants with an abnormal newborn screen need a sweat test in order to confirm the CF diagnosis. Trypsinogen levels can be increased in individuals who have a single CF gene (carriers) or, in rare instances, even in individuals without a CF gene. Due to these false positives, CF screening in newborns is somewhat controversial. Therefore, most individuals are diagnosed after symptoms prompt an evaluation for cystic fibrosis. The most commonly-used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running electric current to a separate electrode on the skin. This process, called iontophoresis, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. CF can also be diagnosed by identification of mutations in the CFTR gene.

A multitude of tests are used to identify complications of CF and to monitor disease progression. X-rays and CAT scans are used to examine the lungs for signs of damage or infection. Examination of the sputum under a microscope is used to identify which bacteria are causing infection so that effective antibiotics can be given. Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy. Blood tests can identify liver problems, vitamin deficiencies, and the onset of diabetes. DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.

The role of chronic infection in lung disease

The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread amongst individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus encourages the development of bacterial microenvironments (biofilms) that are difficult for immune cells (and antibiotics) to penetrate. The lungs respond to repeated damage by thick secretions and chronic infections by gradually remodeling the lower airways (bronchiectasis), making infection even more difficult to eradicate.

Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as Staphylococcus aureus and Hemophilus influenzae colonize and infect the lungs. Eventually, however, Pseudomonas aeruginosa dominates. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people that do not have CF.

One way in which infection has spread is by passage between different individuals with CF. In the past, people with CF often participated in summer "CF Camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF in order to limit the spread of virulent bacterial strains. Often, patients with particularly damaging bacteria will attend clinics on different days and in different buildings than those without these infections.

Treatment

(A typical breathing treatment for cystic fibrosis, using a mask nebuliser and the ThAIRapy Vest)

The cornerstones of management are proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. The treatment for cystic fibrosis continues throughout a patient's life, and is aimed at maximizing organ function, and therefore quality of life. At best, current treatments delay the decline in organ function. Treatment typically occurs at specialist multidisciplinary centres, and is tailored to the individual, because of the wide variation in disease symptoms. Targets for therapy are the lungs, gastrointestinal tract (including insulin treatment), the reproductive organs (including Assisted Reproductive Technology (ART)) and psychological support. In addition, therapies such as transplantation and gene therapy aim to cure some of the effects of cystic fibrosis.

The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time consuming to the patient. One of the most important battles that CF patients face is finding the time to comply with all the prescribed treatments while balancing a normal life.

Antibiotics to treat lung disease

Many CF patients are on one or more antibiotics at all times, even when they are considered healthy, to suppress the infection as much as possible. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function. Antibiotics are usually chosen based on the results of a sputum analysis and the patients past response. Many bacteria common in cystic fibrosis are resistant to multiple antibiotics and require weeks of treatment with intravenous antibiotics such as vancomycin, tobramycin, meropenem, ciprofloxacin, and piperacillin. Inhaled therapy with antibiotics such as tobramycin and colistin is often given for months at a time in order to improve lung function by impeding the growth of colonized bacteria. Inhaled therapy with the antibiotic aztreonam is also being developed and clinical trials have shown great promise. Oral antibiotics such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection. Some individuals spend years between hospitalizations for antibiotics, whereas others require several antibiotic treatments each year.

Several common antibiotics such as tobramycin and vancomycin can cause hearing loss, damage to the balance system in the inner ear or kidney problems with long-term use. In order to prevent these side-effects, the amount of antibiotics in the blood are routinely measured and adjusted accordingly.

Other methods to treat lung disease

Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, physical therapy is utilized; a therapist pounds an individual's chest with his or her hands several times a day. Devices that recreate this percussive therapy include the ThAIRapy Vest and the intrapulmonary percussive ventilator (IPV). Newer methods such as Biphasic Cuirass Ventilation, and associated clearance mode available in such devices, now integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. Biphasic Cuirass Ventilation is also shown to provide a bridge to transplantation. These are portable and adapted for home use. Aerobic exercise is of great benefit to people with cystic fibrosis. Not only does exercise increase sputum clearance but it also improves cardiovascular and overall health.

Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline. Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity. N-Acetylcysteine may also decrease sputum viscosity, but research and experience have shown its benefits to be minimal. Albuterol and ipratropium bromide are inhaled to increase the size of the small airways by relaxing the surrounding muscles.

As lung disease worsens, breathing support from machines may become necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance. During severe illness, people with CF may need to have a tube placed in their throats and their breathing supported by a ventilator.

Treatment of other aspects of CF

(Intracytoplasmic sperm injection is used to provide fertility for men with cystic fibrosis)

Newborns with meconium ileus typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the faeces. Even so, most individuals with CF take additional amounts of vitamins A, D, E, and K and eat high-calorie meals. It should be noted, however, that nutritional advice given to patients is, at best, mixed: Often, literature encourages the eating of high-fat foods without differentiating between saturated, unsaturated fat, and trans-fats; this lack of clear information runs counter to health advice given to the general population, and creates the risk of further serious health problems for people with cystic fibrosis as they grow older. So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.

The diabetes common to many CF patients is typically treated with insulin injections or an insulin pump. Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates. Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone.

Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone are used to decrease nasal inflammation. Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility may be overcome with intracytoplasmic sperm injection. Third party reproduction is also a possibility for women with CF.

Transplantation and gene therapy

Lung transplantation often becomes necessary for individuals with cystic fibrosis as lung function and exercise tolerance declines. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung would contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time in order to alleviate liver disease and diabetes. Lung transplantation is considered when lung function approaches a point where it threatens survival or requires assistance from mechanical devices.

Gene therapy holds promise as a potential avenue to cure cystic fibrosis. Gene therapy attempts to place a normal copy of the CFTR gene into affected cells. Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR gene expression is needed. Many approaches have been theorized and several clinical trials have been initiated but, as of 2006, many hurdles still exist before gene therapy can be successful. In theory placing the normal CFTR gene into the affected epithelium cells using a viral component works perfectly. However the clinical theories have shown the practical faults in the gene therapy. It is extremly difficult to inject the right cells with the virus. Another problem is that even if the virus actually managed to intervene with the normal RNA translation and managed to implant its own RNA into the translation system the scientist were not able to influence which part of the viral information was translated. So the gene therapy could have even negative impact on the patient instead of a positive one.

Asthma

Introduction to asthama

Asthma is a chronic condition involving the respiratory system in which the airways occasionally constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more triggers. These episodes may be triggered by such things as exposure to an environmental stimulant such as an allergen, environmental tobacco smoke, cold or warm air, perfume, pet dander, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.

Signs and symptoms

In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, a tightness and itching of the chest or an inability for physical exertion. Some asthmatics who have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

An acute exacerbation of asthma is commonly referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor. Although the former is "often regarded as the sine qua non of asthma", some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode include wheezing, prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles.

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. The person's feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments, are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.

Cause

Asthma is caused by a complex interaction of environmental and genetic factors that researchers do not yet fully understand. These factors can also influence how severe a person’s asthma is and how well they respond to medication. As with other complex diseases, many environmental and genetic factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may affect asthma only when combined.

Environmental

Many environmental risk factors have been associated with asthma development and morbidity in children, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association.

Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections. Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research.

Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Cesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Cesarean section compared with vaginal birth, which modifies the immune system.

Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system.

Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context. Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis).

The hygiene hypothesis is an hypothesis about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products. All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

The pool chlorine hypothesis is another hypothesis, in which long-term attendance at chlorinated swimming pools was found to correlate strongly with the probability of children having asthma. The suspected causal link, nitrogen trichloride, is directly associated with asthma in lifeguards and lung damage in recreational swimmers.

Genetic

Over 100 genes have been associated with asthma in at least one genetic association study. However, such studies must be repeated to ensure the findings are not due to chance.

Many of these genes are related to the immune system or to modulating inflammation. However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested. This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma. One theory is that asthma is a collection of several diseases, and that genes might have a role in only subsets of asthma. For example, one group of genetic differences (single nucleotide polymorphisms in 17q21) was associated with asthma that develops in childhood.

Gene-environment Interactions

Research suggests that some genetic variants may only cause asthma when they are combined with specific environmental exposures, and otherwise may not be risk factors for asthma.

The genetic trait, CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) are a well-replicated example of a gene-environment interaction that is associated with asthma. Endotoxin exposure varies from person to person and can come from several environmental sources, including environmental tobacco smoke, dogs, and farms. Researchers have found that risk for asthma changes based on a person’s genotype at CD14 C-159T and level of endotoxin exposure.

Pathophysiology

In asthma, constriction of the airways occurs due to bronchoconstriction and bronchial inflammation. Bronchoconstriction is the narrowing of the airways in the lungs due to the tightening of surrounding smooth muscle. Bronchial inflammation also causes narrowing due to edema and swelling caused by an immune response to allergens.

Bronchoconstriction

(Inflamed airways and bronchoconstriction in asthma. Airways narrowed as a result of the inflammatory response cause wheezing.)

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.

The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli. It is usually classified as type I hypersensitivity. In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

The normal caliber of the bronchus is maintained by a balanced functioning of these systems, which both operate reflexively. The parasympathetic reflex loop consists of afferent nerve endings which originate under the inner lining of the bronchus. Whenever these afferent nerve endings are stimulated (for example, by dust, cold air or fumes) impulses travel to the brain-stem vagal center, then down the vagal afferent pathway to again reach the bronchus. Acetylcholine is released from the afferent nerve endings. This acetylcholine results in the excessive formation of cyclic Guanine Mono phosphate (GMP). This initiates bronchoconstriction.

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (TH0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack.

Stimuli

• Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;
• Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.
• Medications, including aspirin, β-adrenergic antagonists (beta blockers), and penicillin.
• Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.
• Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.
• Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH₂Cl), dichloramine (NHCl₂) and trichloramine (NCl₃)—in the air around them, which are known to induce asthma.
• Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. In many cases, significant asthma may not even occur until the respiratory infection is in its waning stage, and the person is seemingly improving. Eighty percent of asthma attacks in adults and 60% in children are caused by respiratory viruses.
• Exercise or intense use of respiratory system. The effects of which differ somewhat from those of the other triggers, since they are brief.
• Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.
• Emotional stress which is poorly understood as a trigger. Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
• Cold weather can make it harder for asthmatics to breathe. Whether high altitude helps or worsens asthma is debatable and may vary from person to person.

Pathogenesis

The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.

In 2006, Researchers at Harvard Medical School found evidence that asthma is caused by over-proliferation of a special type of natural "killer" cell.

Asthma and sleep apnea

It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated. CPAP is not effective in patients with nocturnal asthma only.

Asthma and gastro-esophageal reflux disease

If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.