Monoclonal Antibody
A Novel Class of Therapeutics

Antibodies, also known as immunoglobulins, form a class of proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses.  Antibodies are produced by a kind of white blood cell called a B cell.  Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures to exist.  Each of these variants can specifically recognize a different target, e.g. a protein on the surface of a bacteria.  The huge diversity of antibodies allows the immune system to recognize an equally wide diversity of targets.  Recognition of a target by an antibody can neutralize the target directly by, for example, binding to a part of a pathogen that it needs to cause an infection.  Alternatively, binding of an antibody to its target can tag the target for attack by other parts of the immune system.

Monoclonal antibodies are antibodies that are 100% identical to each other because they are produced by cloned immune cells, meaning identical immune cells all made to be exact copies of a single parent cell.  Monoclonal antibodies are man-made via an experimental approach that first involves the injection of a mouse with the desired target protein.  Cells in the spleen of that mouse then start to produce antibodies against the target.  These antibody-producing spleen cells are then extracted from the mouse and fused with so-called myeloma cells, which are quasi-immortal cancer cells that can be cultured in the laboratory. Myeloma cells do not stop proliferating and keep growing indefinitely.  This capacity, which is the culprit of the unrestricted growth of cancerous tumors during disease, can be used in the lab as an experimental tool by fusing antibody-producing mouse spleen cells to myeloma cells. Since the mouse spleen cells produce antibodies against the target protein and the myeloma cells are quasi-immortal, the fused cell, called a hybridoma cell, produces antibodies against the desired target and keeps growing indefinitely, which makes it possible to harvest large amounts of antibodies from the same batch of cells.

Given almost any protein, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect that protein or to block its function by binding to it. This has become an important tool in biochemistry, molecular biology and medicine.  When used as medications, the generic name of the corresponding monoclonal antibody ends in –mab.  A recent example for a monoclonal antibody that  has received attention in the renal field is the drug rituximab.

Renin-Angiotensin System
Major Regulator of Blood Pressure

The renin-angiotensin system is a complex system that helps regulate long-term blood pressure in the body.  Activation of the renin-angiotensin system involves the chemical modification of a precursor protein called angiotensinogen I by the kidney-derived enzyme renin.  The product of angiotensinogen I processed by renin is called angiotensin I.  Angiotensin I can then further be converted by another enzyme, angiotensin-converting enzyme (ACE), into the angiotensin II hormone.  Both angiotensin I and II can help increase blood pressure, however, angiotensin II is much more potent in that role than angiotensin I.  Angiotensin II is therefore the major bioactive product of the renin-angiotensin system.  It plays a vital role in regulating blood pressure in the body.

   Components of the renin-angiotensin system are present in many tissues.  Yet, the primary site of renin release is the kidney.  Release of renin in the kidney is triggered, for example, by lowered blood pressure in the renal artery, or decreased sodium delivery to the renal tubule, both of which require an increase in blood pressure in order to restore normal body function.

   Many diseases are accompanied by elevated angiotensin II levels, a prime example being high blood pressure (hypertension).  T he renin-angiotensin system is often manipulated clinically to treat high blood pressure.  Inhibitors of angiotensin-converting enzyme (ACE inhibitors) are often used to reduce the formation of angiotensin II.  Alternatively, angiotensin receptor blockers (ARBs) can be used to prevent angiotensin II from acting on its targets in the body.  Both pharmacological interventions aim to lessen the effects of angiotensin II in the body, thereby reducing blood pressure.

   Podocytes, which are essential components of the glomerular filtration barrier, are especially sensitive to high blood pressure due to their location on the external surface of the glomerular capillaries.  They are thought to counteract pressure-mediated capillary expansion.  Therefore, these cells are increasingly challenged during increased blood pressure in the glomerulus.  The use of ACE inhibitors and ARBs have been shown to lessen glomerular blood pressure and by that protect podocyte function and reduce proteinuria.

Extracellular Matrix (ECM)
Mattress and Cushion for Cells

In biology, the  term extracellular matrix (ECM) designates the part of tissue that lies outside of the cells and usually provides structural support to the cells.  ECM includes interstitial matrices (i.e. matrices filling out the space in between neighboring cells) and basement membranes – such as the glomerular basement membrane as a part of the glomerular filtration barrier.  In contrast to interstitial matrices, which act as a compression buffer between cells, basement membranes are sheet-like sections of ECM, on which cells rest.

   Due to its diverse nature and composition, the ECM can serve many functions, such as providing support and anchorage for cells, segregating tissues from one another, and regulating intercellular communication and signaling.  When these vital functions of the ECM are compromised, severe disease can develop.  A prominent example in a renal context is membranous glomerulonephritis (also known as membranous kidney disease), which represent one of the most common causes for proteinuria and end-stage renal disease (ESRD) in the adult population.

Apoptosis
Programmed Cell Death

In contrast to necrosis, which is the name given to accidental, unwanted death of cells and living tissue as a consequence of acute injury, apoptosis represents a programmed cell death, which can be seen as the deliberate suicide of a cell.  Apoptosis involves a tightly-controlled and orchestrated series of intracellular biochemical events that eventually lead to the death of the cell.  The process of apoptosis has an important physiological role in that it is executed in such a way as to safely dispose of cell corpses and fragments, thereby disposing efficiently of unwanted cells without interfering with the normal function of other cells and tissues.  Defects in apopotic processes can have severe consequences and ultimately lead to cancer: a cancerogenic cell that is not able to commit suicide due to blockade of apoptosis may instead start to divide in an uncontrolled fashion, eventually resulting in the development of a cancerous tumor.

Enzymes
Molecular Machines

Cellular function depends on thousands of biochemical reactions that are occuring permanently in every cell.  A plethora of different molecules have to be constantly generated, modified, converted, and destroyed to ensure that a cell can properly carry out its function in the body.  The molecular machinery behind these events is constituted by specialized proteins called enzymes.  Enzymes are able to catalyze biochemical reactions, i.e. the formation and disruption of covalent chemical bonds.  Like all catalysts, enzymes work by lowering the energy threshold required for triggering a reaction, thus dramatically accelerating the rate of the reaction: most enzyme reaction rates are millions of times faster than those of comparable uncatalyzed reactions.

Nucleus
A Cell's Brain

Just as the human body is composed of a number of different organs,  a single cell is composed of different functional entities.  While components of an entire organism are called organs, the entities inside a single cell are names organelles.  Prominent examples of organelles are the mitochondria, which are the power-plants of the cell that produce energy, or the lysosomes, which can be seen as the waste processing plants of the cell where defective or unwanted proteins are destroyed.  One of the most important organelles in the nucleus: it is the core of a cell and can be considered as its brain, where (in higher organisms) the genetic code in form of DNA is stored and processed.  In the nucleus, the genetic code is read and deciphered, so the cell ultimately can interpret and act upon this information.  It may, for example,  manufacture certain proteins or initiate cellular events such as proliferation (cells division), differentiation (cells specialization), or apoptosis (cell suicide).  Although the nucleus is separated from the rest of the cell by a specialized membrane (the nuclear envelope), there is a constant transfer of molecules between the nucleus and the surrounding compartments.  The purpose of this nuclear trafficking is to make the information processed in the nucleus available to the rest of the cell, and to enable signaling from the extranuclear space into the nucleus.

Signaling
Cellular Signal Transduction

In biology, signaling or signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another, most often involving ordered sequences of biochemical reactions inside the cell that are carried out by enzymes and linked through specialized signaling molecules.  In many signal transduction processes, the number of enzymes and other molecules participating in these events increases as the process emanates from the initial stimulus, resulting in a so-called signal cascade.  This explains why even relatively small stimuli are able to elicite large responses.  A signal cascade usually occurs extremely rapidly, lasting on the order of milliseconds in the case of ion flux, to minutes for the activation of protein-mediated signaling cascades.

Kidney Filtration
What the Kidneys are And What They Do

The two kidneys are bean-shaped organs located near the middle of the back, just below the rib cage to the left and right of the spine. Each about the size of a fist, these organs act as sophisticated filters for the body. They process about 200 quarts of blood a day to sift out about 2 quarts of waste products such as potassium, acid and urea, and extra water that eventually leave the body as urine. The adverb renal designates that something has to do with or is happening in the kidney, e.g. renal filtration, or renal disease.

Glomerulus
Where Filtration Takes Place

Blood enters the kidney through arteries that branch inside the kidneys into tiny clusters or tufts of tiny looping blood vessels (capillaries). Each cluster is a major component of one glomerulus, which comes from the Greek word meaning filter. The plural form of the word is glomeruli. In the human, there are approximately 1 million glomeruli, or filters, in each kidney. The adverb glomerular designates that something has to do with or is happening in the glomerulus, e.g. glomerular blood vessels, or glomerular filtration. Kidney diseases originating in the glomerulus are therefore referred to as glomerular diseases.

Tubules
Where Reabsorption Takes Place

Each glomerulus is attached to the opening of a small fluid-collecting tube called a tubule. Blood is filtered in the glomerulus, and extra water and wastes pass into the tubule as primary urine.

In the tubules, the major part of the filtered solutes and water return to the bloodstream during a process called reabsorption, leaving the waste products concentrated in a solution that finally becomes urine. Eventually, the urine drains from the kidneys into the bladder through larger tubes called ureters. Like Bowman’s Capsules, tubules are part of the urinary space.

Nephron
Basic Functional Unit of the Kidney

Each glomerulus-and- tubule unit is called a nephron. Whereas the glomerulus is the actual site of filtration, the tubules are the site of reabsorption, allowing the major part of filtrate or primary urine to return to the bloodstream, leaving the actual waste products concentrated as urine.

Each kidney is composed of about 1 million nephrons in the human. In healthy nephrons, the glomerular filtration barrier that separates the blood vessels from the tubule allows waste products and extra water to pass into the tubule while keeping blood cells and protein in the bloodstream.

Glomerular Filtration Barrier
Filter Membrane of the Kidney

The tiny looping blood vessels (capillaries) in the glomerulus are each wrapped with a filter membrane. This filter membrane, which separates the bloodstream from the urinary space, is often referred to as glomerular filtration barrier.

The membrane is composed of three distinct layers: (1) A layer of cells decorating the inner surface of the blood vessels in the glomerulus, called fenestrated endothelium. (2) The glomerular basement membrane, a structure composed of several different proteins. (3) A layer of cells called podocytes sitting on top of the glomerular basement membrane on the outer surface of the blood vessels in the glomerulus.

Bowman's Capsule
On the Other Side of the Glomerular Filter I

The three-layered glomerular filtration barrier is a membrane wrapped around each of the capillaries (blood vessels) in the glomerulus. Waste materials and extra water leave the bloodstream and pass through the glomerular filtration barrier into the urinary space. Once this has happened, the filtrate is referred to as primary urine.

The first structure inside the glomerulus that the filtrate (primary urine) enters after it has passed the glomerular filtration barrier is called Bowman’s Capsule. Bowman’s Capsule is the cavity or chamber that contains the central cluster of glomerular capillaries through which primary urine spills into the cavity. Bowman’s Capsule has an outer shell of so-called mesangial cells encapsulating the glomerulus.

An analogy: if the glomerulus were a peach and the blood vessel cluster the core, the mesangial cells would be the outside peel and Bowman’s Capsule would comprise a cavity where the peach pulp normally is located. Once it has reached Bowman’s Capsule, the primary urine is collected in a drain, the tubule, similar to the drain of a sink.

Every glomerulus has exactly one tubule, in which the primary urine undergoes further processing. As they extend, the countless tubules from all glomeruli merge, finally forming one large channel called the ureter. There is one ureter for each kidney that leads to the bladder. In summary, the filtrate makes its way step by step, from Bowman’s Capsule into the tubule, then into one of the ureters, and eventually into the bladder. What is eventually excreted from the bladder, is simply called urine.

Urinary Space
On the Other Side of the Glomerular Filter II

The glomerular filtration barrier is wrapped around the blood vessels in the glomerulus. Waste materials and extra water leave the bloodstream and pass through the glomerular filtration barrier. Once this has happened, the filtrate is referred to as primary urine. The primary urine then makes its way from Bowman’s Capsule into the tubule, where it undergoes further processing. As they extend, the countless tubules from all glomeruli merge, finally forming one large channel called the ureter. What is exiting the tubules and entering one of the ureters is no longer referred to as primary urine – it’s simply urine since, after the tubule, there is no more processing going on. The ureter itself is located outside the kidney and leads to the bladder. The term Urinary Space designates the entirety of all Bowman’s Capsules and tubules, in other words the entirety of structures the primary urine passes through inside the kidney before exiting the kidney as (final) urine into one of the ureters, and eventually ending up in the bladder.

Kidney Ultrafiltration
Primary Urine is the Result

In general terms, ultrafiltration is a variety of membrane filtration, in which hydrostatic pressure forces a liquid against a semi permeable membrane. Filtrations that use hydrostatic pressure are widely used; for example, making filtered coffee is nothing else than that, with the coffee filter being the filtration membrane, and coffee the filtrate. A semi permeable membrane is a membrane that allows flow of filtrate in only one direction – once filtrate has passed the filtration membrane, it cannot go back.

The prefix “ultra-” designates that the filtration deals with tiny substances such as proteins. In fact, other than in terms of the size of the molecules it retains, ultrafiltration is not fundamentally different from other filtration principles such as reverse osmosis, microfiltration or nanofiltration.

In the kidney, the hydrostatic pressure driving renal ultrafiltration is the blood pressure. The filtered liquid is the blood, which is forced against the glomerular filtration barrier, which is the semi permeable membrane. What passes through the glomerular filtration barrier is primary urine containing small solutes and excess water. Larger molecules such as the protein albumin can not pass through the barrier and are normally retained in the bloodstream.

Kidney Function
Assessing the Performance of the Kidney Filter Apparatus

To determine kidney function, doctors usually order blood tests to measure the levels of waste products such as creatinine and urea nitrogen. While healthy kidneys are able to clear the bloodstream of these waste products, damaged kidneys are hindered in their ability to do so, which eventually results in an accumulation of waste in the blood.

Other tests may detect the presence of protein or albumin in the urine (proteinuria or albuminuria, respectively), a sign that the kidney filters are leaking these important molecules into the urine. The best way to determine the level of kidney function is measuring the glomerular filtration rate (GFR).

Glomerular Filtration Rate (GFR)
Measuring Kidney Filtration Performance

Determining the glomerular filtration rate ( GFR ) is the best way to measure the level of kidney function or determine the stage of kidney disease. Doctors can calculate the GFR from the results of a blood test, taking into account age, race, gender and other factors.

A value of 90 or greater indicates a normal GFR and kidney function. Values of 60 to 89 indicate a mild decrease in GFR , values of 30 to 59 a moderate decrease in GFR , values of 15 to 29 a severe increase in GFR , and values of less than 15 are observed in patients with End-Stage Renal Disease(ESRD) requiring dialysis of a transplant.

Podocytes
Key Cells Involved in Kidney Filtration

Podocytes are part of the glomerular filtration barrier. They are located on top of the glomerular basement membrane on the outer surface of the blood vessels in the glomerulus. Podocytes have an octopus-like shape comprised of a larger cell body from which many tentacle-like extensions called processes branch out.

There are two kinds of extensions: First, major processes branching out from the podocyte cell body, and second, thinner foot processes branching out from the major processes. The foot processes of podocytes are the structures that attach the cell to the outer surface of the glomerular blood vessel – they are, as their name says, the “feet” of the cell. The foot processes are the reason podocytes are so named: Their nomenclature derives from the greek words for “foot” (podos) and ”hollow vessel” (kytos), meaning cell.

A “podos-kytos“, or podocyte, therefore designates the “cell with feet”. Podocyte foot processes are tiny structures that can only be seen with extremely high magnification under an electron microscope. Foot processes from neighboring podocytes combine to form a dense network around the glomerular blood vessels. However, they do not touch each other.

In fact, the gaps between foot processes are filled by a complex multi-protein structure called the slit diaphragm. Podocytes are key cells involved in the process of kidney filtration, and injury of podocytes can be observed in many forms of glomerular diseases. The most common symptom of podocyte injury is foot process effacement.

Slit Diaphragm
Making up the Pores of the Kidney Filter Membrane

The glomerular blood vessels are surrounded by highly specialized cells called podocytes. A podocyte is an octopus-shaped cell whose cell body branches out into many little extensions called foot processes.

Foot processes of neighboring podocytes join to form a dense network that is an important component of the glomerular filtration barrier. The many podocyte foot processes do not touch each other. In fact, the gaps between foot processes are filled by a complex multi-protein structure called the slit diaphragm. Slit diaphragms are thought to allow for the passage of excess water and solutes from the blood into the kidney ultrafiltrate while retaining larger plasma molecules.

In consequence, excess water and solutes are filtered into the urinary space and subsequently pass into the system of renal tubules as kidney ultrafiltrate. The bigger molecules, turned back at the glomerular filtration barrier, eventually re-enter the bloodstream. It is important to mention that the slit diaphragms are closely connected to the foot processes of podocytes and the podocyte actin cytoskeleton.

Since slit diaphragms are tiny spaces – even smaller than podocyte foot processes – they can only be seen with high magnification under the electron microscope.

Actin Cytoskeleton
A Cell's Backbone

The actin cytoskeleton of a cell can be seen as what the bone-based skeleton is for the human body: a structure serving static and dynamic functions, providing structural integrity and the ability to adapt to changes in the environment by changing shape and moving.

The cytoskeleton is mainly composed by a complex structural system of fibers, sometimes also called stress fibers. These fibers are assembled in a coordinated fashion from small protein subunits, with the protein actin being one of the key components. In the podocyte, the cytoskeleton responds to the unique demands of the glomerular filtration barrier by doing such things as maintaining kidney function under a number of various conditions or adapting to blood pressure.

A well-developed actin cytoskeleton ideally supports the defined shape of podocytes and their foot processes. The latter contain a dense network of stress fibers that are connected to the slit diaphragm. In contrast, podocyte injury and foot process effacement is accompanied by physical changes of the actin cytoskeleton and a disruption of the slit diaphragm site.

Foot Process Effacement
Consequence of Podocyte Injury

Proteinuria, the presence of protein in the urine, is a hallmark of glomerular disease and results from an increased permeability of the glomerular filtration barrier. In many forms of glomerular diseases, proteinuria is correlated with injury of podocytes. In these cases, the examination of kidney biopsy specimens under the electron microscope reveals the loss of normal podocyte foot process structure, resulting in a flattened podocyte phenotype, where foot processes form a monolayer lacking functional slit diaphragms.

This condition is referred to as foot process effacement and goes hand in hand with physical changes in the podocyte actin cytoskeleton. Foot process effacement itself is a reversible process , and even in normal kidneys one may find areas of partial foot process effacement. However, if the underlying cause for podocyte injury and foot process effacement persists and the early structural changes of podocytes are not reversed, severe and progressive glomerular damage is likely to develop.

For example, podocyte injury can eventually lead to the detachment of podocytes from the glomerular blood vessels. Since the highly specialized podocytes cannot be replaced by the body, the damage and loss of single podocytes leads to podocyte depletion over time, which is a major determinant in the development of glomerulosclerosis and chronic kidney failure.

Nephrotic Syndrome
A Set of Symptoms - Not a Disease Itself

Nephrotic syndrome is a condition marked by these symptoms: 1. very high levels of protein in the urine (proteinuria), 2. low levels of protein in the blood, 3. swelling, especially around the eyes, feet, and hands, and 4. high cholesterol.

The nephrotic syndrome is a set of symptoms, not a disease in itself. It can occur with many diseases, so prevention relies on controlling the diseases that cause it, such as FSGS. Treatment of the nephrotic syndrome focuses on identifying and treating the underlying cause, if possible, and reducing high cholesterol, blood pressure, and protein in the urine through diet, medication, or both.

The nephrotic syndrome may go away once the underlying cause, if known, is treated. If the cause is not known, the condition is referred to as idiopathic Nephrotic Syndrome. When these cases do not respond to treatment, the kidneys may gradually lose their ability to filter wastes and excess water from the blood. The final outcome may be End-Stage Renal Disease (ESRD).

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Focal Segmental Glomerulosclerosis (FSGS)
When Kidney Filters Become Hardened or Scarred

The most heard-of sclerotic disease is probably atherosclerosis, a condition that hardens and thickens the arteries of affected individuals. In general, the term sclerosis refers to a condition that involves hardening or scarring of any kind of tissue.

The kidney may be affected by such alterations since many glomerular diseases involve inflammation and subsequent scarring of the glomeruli, a condition called glomerulosclerosis. FSGS (Focal and Segmental Glomerulosclerosis) is a prominent example. Focal means that the scarring occurs only in some glomeruli (and not all of them), and segmental means that only parts of the affected glomerulus (not the entire glomerulus) actually show the scarring.

In many cases, early changes in podocyte morphology such as foot process effacement represent the first stage in the development of glomerulosclerosis.

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End-Stage Renal Disease (ESRD)
Total Kidney Failure

Total kidney failure, sometimes called end-stage renal disease (ESRD), indicates permanent loss of kidney function. Depending on the form of glomerular disease, renal function may be lost in a matter of days or weeks or may deteriorate slowly and gradually over the course of decades.

To stay alive, a patient with total kidney failure must go on dialysis, or receive a new kidney through transplantation. With the help of dialysis or transplantation, many people continue to lead full, productive lives after reaching total kidney failure.

Proteinuria Large Amounts of Protein in the Urine

Many glomerular diseases damage the glomeruli, letting protein leak into the urine as the glomerular filtration barrier malfunctions. This condition is called proteinuria. In general, conditions referred to as “-urias” indicate that something is lost in the urine, thus protein loss is consequently called protein-uria.

Very high levels of protein in the urine are referred to as “nephrotic-range” proteinuria. The loss of certain proteins in the urine can result in a decrease in their levels in the blood. The loss of the protein albumin in the urine, for example, is a condition referred to as albuminuria.

To determine whether someone suffers from proteinuria or albuminuria, doctors usually measure the concentration of total protein, or the concentration of albumin, respectively, in the urine of this patient. Sometimes it is possible to detect proteinuria by the presence of foam in the urine upon discharge. Kidney diseases presenting with proteinuria are also referred to as proteinuric diseases.

Albuminuria
Loss of Protein Albumin in the Urine

In normal blood, the protein albumin acts like a sponge, drawing extra fluid from the body into the bloodstream, where it remains until the kidney eventually removes it. When kidney filters malfunction, albumin may leak, that is, pass through the glomerular filtration barrier, and be discharged into the urine.

Loss of albumin in the urine may result in lower than normal levels in the blood. When albumin leaks into the urine, the blood loses its capacity to absorb extra fluid from the body. Fluid can accumulate outside the circulatory system in the face, hands, feet, or ankles and cause a characteristic form of swelling referred to as edema.

Hematuria
Blood in the Urine

Hematuria is yet another “-uria” condition describing that something is lost in the urine as the glomerular filtration barrier gets leaky. In this case, it is red blood cells that are lost in the urine. Hematuria is a frequent finding in patients with kidney disease, in particular in some forms of glomerular disease.

To determine whether someone suffers from hematuria, doctors usually measure the number of red blood cells in the urine of this patient. Sometimes it is even possible to conclude for the presence of hematuria by solely looking on the appearance of the urine as blood may cause the urine to be pink or cola-colored.

Idiopathic Disease
Diseases Occur Without a Known Cause

When a disease occurs without a known cause, one commonly refers to it as an idiopathic disease. Known causes for kidney disease are for example primary disorders such as HIV-infection or diabetes. In these disorders, kidney disease can appear as a secondary disorder (HIV-nephropathy, or diabetic nephropathy, respectively).

Also, there are a number of systemic diseases that can affect multiple parts of the body including the kidney. One prominent example thereof is systemic Lupus erythematodesa (SLE).

Finally, known causes of kidney disease can be of genetic origin such as the Congenital Syndrome of the Finnish type, caused by mutations in the protein nephrin, which is a key element of the glomerular filtration barrier in the slit diaphragm.

Systemic Disease
Affecting Multiple Parts of the Body

When a disease affects not just an isolated body part or organ, but through several different mechanisms touches multiple parts of the body, it is termed a systemic disease, one that involves the entire system. An example of a systemic disease that can affect the kidney is Fabry Disease.

Fabry Disease is caused by genetic defects in the gene coding for the protein alpha-galactosidase and it can cause problems in many parts of the body, including the kidney. An example of a non-systemic disease is the Congential Nephrotic Syndrome of the Finnish Type (CNF), caused by mutation in the protein nephrin. Mutations in this protein lead to problems only at the slit diaphragm, making CNF a disease isolated to kidney glomeruli.

While the resulting disruption of the kidney filter leads to adverse effects throughout the whole body, this is still considered a non-systemic disease because its source is found within the glomerulus.

Genome
The Entirerety of the Genetic Code

Every protein is a living organism and is “manufactured” according to a specific blue-print. The information about how to make a certain protein is encoded by a gene. In simplified terms, there is one gene for every protein that exists in a human being. The entirety of all genes in an organism is referred to as the genome of this organism.

Not surprisingly, different species have different genomes, e.g. the genome of a cat considerably differs from a dog’s genome. Within a species, the genomes of two different individuals are usually very similar (most humans have 2 eyes), but there are always little differences between each individual (some humans have blue eyes, others have brown eyes) – the only exceptions are identical twins or multiples.

Every gene is represented by a specific sequence. Notably, all cells of an individual always contain identical copies of the whole genome of this individual. That means that the sequences for every single gene can be found in every single cell.

DNA -Desoxyribo-Nucleic Acid Contains the Genetic Code

is a chemical structure that contains the genetic blue-print for the biological development and function of all cellular life forms and some viruses. The entirety of the genetic information that is represented by the is referred to as genome.

is a polymer, basically a long chain that is composed of subunits called nucleotides. There are four different nucleotides that are usually designated by the letters A, T, C, and G. It is the sequence of these four subunits in the chain that represents the genetic information, organized in genes. In simplified terms, each gene contains the information on how to make a certain protein.

One may ask how only four subunits can encode the entire information required for an organism. However, when looking on the number of possible combinations that may occur in the sequence, it quickly becomes clear that the system works: even if a -fragment were only five nucleotides long, one would already deal with 5 (4)=625 possible combinations. In the real world, -fragments are oftentimes several thousand nucleotides long, generating by far enough data storage potential for the genetic code. In fact, only a tiny proportion of the genome contains useful information, the rest is though to be junk – evolutionary relics no longer required.

Protein
Essential for Life

Proteins are relatively large molecules composed of a set of 20 different subunits called amino acids. The amino acids are arranged in a linear chain and joined by so-called peptide bonds. The function of a protein is determined by the sequence in which the amino acids appear in the chain. The length of a protein sequence varies, and proteins can be composed of several hundred amino acids. The unique sequence of amino acids in a protein is encoded by a gene. It is estimated that in the human body there are around 30,000 to 40,000 different active genes and therefore a similar number of proteins.

Like other biological macromolecules such as polysaccharides, lipids, or nucleic acids, proteins are essential parts of all living organisms and participate in every process within cells. Many proteins are enzymes that catalyze biochemical reactions, and are vital to metabolism. Other proteins have structural or mechanical functions, such as the proteins in the actin cytoskeleton. Proteins are also important in cell signaling, immune responses, cell adhesion, and the cell cycle.

Protein is also a necessary component in our diet, since animals cannot synthesise all the amino acids and must obtain essential amino acids from food. Through the process of digestion, animals break down ingested protein into free amino acids that can be used for protein synthesis.

The name protein comes from the Greek word “prota”, meaning “of primary importance”. Proteins were first described and named in 1838. However, their central role in living organisms was not fully appreciated until 1926, when it was shown that the enzyme urease was a protein. Only 32 years later, the first protein structure was solved, namely that of myoglobin in 1958 – a discovery acknowledged with the Nobel Prize in Chemistry.

Kidney Biopsy
Obtaining Small Pieces of Kidney Tissue for Microscopic Examination

If blood tests indicate impaired kidney function, doctors may recommend ultrasound or an x-ray to see whether the shape of size of the kidneys is abnormal. These tests are called renal imaging. But since glomerular diseases cause problems at the cellular level, doctors will probably also recommend a kidney biopsy.

This is a procedure in which a needle is used to extract small pieces of kidney tissue for examination with different types of microscopes, each of which shows a different aspect of the tissue. A biopsy may be helpful in confirming glomerular disease and identifying the cause.

Diuretic
"Water Pill"

A diuretic is a substance that elevates the rate of urine excretion, a process referred to as “diuresis”. Diuretics can be either something found in nature or chemically engineered drugs.

Among the naturally occurring diuretics are cranberry juice, alcohol and caffeine (after all, everyone knows that drinking coffee prompts a bathroom visit). Among the chemically engineered diuretics, sometimes also referred to as “water pills”, are drugs such as furosemide, hydrochlorothiazide, and spironolactone.

While these drugs mediate their effects through various molecular mechanisms, most of them interfere with the process of reabsorption of primary urine in the tubules. Their common outcome is that the kidneys produce more urine. This is what doctors use as a therapy to treat heart failure, liver problems, high blood pressure, and certain kidney diseases. In many of these diseases, patients suffer from edema caused by excess water and sodium in the body.

When a diuretic is applied, and in consequence more urine is excreted, excess water and sodium from the edema moves back into the bloodstream to replace the volume that has been excreted as urine, thereby effectively reducing the edema.

Dialysis
Filtering the Blood When the Kidneys Have Stopped Working

Dialysis is a type of renal replacement therapy that is used to provide an artificial replacement for lost kidney function due to End-Stage Renal Disease (ESRD). Dialysis is a life-support treatment and is not a treatment of kidney disease. It may be used for very sick patients who have suddenly lost their kidney function (acute renal failure) or for quite stable patients who have permanently lost their kidney function (ESRD). When healthy, the kidneys remove waste products from the blood and also remove excess fluid in the form of urine during the process of kidney ultrafiltration. Dialysis therefore has to duplicate both of these functions, waste removal and fluid removal.

In all types of dialysis, blood passes on one side of a semipermeable membrane and a dialysis fluid is passed on the other side. A semipermeable membrane allows the flow of filtrate only in one direction, in case of dialysis this is the flow of blood solutes into the dialysis fluid. By altering the composition of the dialysis fluid, doctors can control the dialysis process, regulating what solutes will cross the semipermeable membrane and how much excess water is extracted.

There are two main types of dialysis: hemodialysis and peritoneal dialysis. In hemodialysis, the patient's blood is passed through an external system of tubing (a dialysis circuit) via a machine to an artificial semipermeable membrane (dialyzer) which has dialysis fluid running on one side of the membrane. By means of contact with the membrane, the blood is cleansed and then returned via the circuit back to the body. This dialysis process is very efficient, allowing the treatment to be undertaken intermittently, usually three times a week for 4 hours each, but often fairly large volumes of fluid must be removed in a session, which can sometimes be demanding on the patient.

In peritoneal dialysis, a special solution is run through a tube into the peritoneal cavity, the abdominal body cavity around the intestine, where the patient’s peritoneal membrane acts as a semipermeable membrane. That means that the dialysis process essentially takes place inside the patient’s body and is therefore more natural. The fluid is left in the peritoneal cavity for a period of time to absorb waste products, and then is removed through the tube. This is usually repeated a number of times during the day, usually every 4-6 hours. Alternatively, peritoneal dialysis can be performed overnight in a single dialysis session. Peritoneal dialysis is less efficient than hemodialysis and must therefore be carried out on a daily basis. However, the advantage is that the ultrafiltration process is slower and gentler.

Pathogenesis
Disease Development Mechanism

Derived from the greek words „pathos“ for disease and „genesis“ for development, the term pathogensis describes the mechanism by which a certain factor or process causes a disease.  In most diseases, the pathogenesis involves multiple processes at the same time, which together represent the cause for the disease.

A well-known example for a form of pathogensis is inflammation, involving a complex biological response of several tissues to harmful stimuli such as bacterial infection or contact with irritant substances.  In idiopathic diseases, the pathogenesis is unknown.

Proteomics
Studying Proteins on the Grand Scale
The entirety of proteins existing in an organism, or, on a smaller scale, the entirety of proteins found in a particular cell type, are referred to as the proteome of this organism or cell type respectively.  For example, recent studies suggest that there are around 1,700 different proteins in a mouse kidney.  The entirety of these 1,700 different proteins could therefore be referred to as the proteome of a mouse kidney.

Proteomic studies include the large-scale analysis of a proteome using high-throughput technology, analyzing a vast number of samples at the same time with automated approaches involving cutting-edge instruments and robotics systems.  In this context, subcellular fractionation studies and mass spectrometry-based protein sequencing are among the important experimental tools to explore a proteome.

Hemoglobin
A Pick-Up for Oxygen

Hemoglobin is one of the most important proteins in vertebrates and other animals.  In mammals, it makes up about 97 percent of a red blood cell’s dry contents (not including water).  Its main function is to transport oxygen from the lungs to the rest of the body, including the muscles where the oxygen is needed for the production of energy.  To perform this task, a hemoglobin protein has a unique molecular structure containing iron atoms, which serve as the sites for oxygen binding.

Decrease of hemoglobin, with or without an absolute decrease of red blood cells, leads to a condition referred to as anemia.  Anemia has many different causes, although iron deficiency is the most common cause in the Western world.  In another hemoglobin-related disease called hemolysis, which is characterized by accelerated breakdown of red blood cells,  circulating hemoglobin can cause renal failure.

The measurement of hemoglobin levels is amongst the most commonly performed blood tests, usually as part of a full blood count or complete blood count.  If the total hemoglobin concentration in the blood falls below a set point,  the patient is considered anemic.