Physiology of Nephrotic Syndrome

Nephrotic Syndrome is not a disease. It is a condition that is characterized by damaged glomeruli in the kidney. This damage might be caused by one or more disease. These diseases can be related to the kidney as in Familial Focal Segmental Glomerulosclerosis, abbreviated FFGS or membranous nephropathy. Or it can present from relatively distantly related diseases such as heart diseases, hypertension, diabetes and lupus. The types of diseases that cause nephrotic syndrome also vary with age. Some cases can be corrected with properly prescribed medication, despite some side effects.

In more serious cases, kidney failure can occur. Regular dialysis and ultimately, transplantation may be required. Nephrotic Syndrome can cause damage to (or arise from damage to) the glomeruli, which affects it's function of filtering out waste matter and excess water that is converted into urine. Nephrotic syndrome is identified from symptoms known as proteinuria, hematuria and edema. The first is an excess of protein in the urine. This condition is paralleled by the loss of protein in the blood. The decrease of protein in the blood is called hypoproteinemia.

The second is the presence of blood, or more specifically, red blood cells or erythrocytes in the urine. The loss of glomerular function results in the non-removal of excess fluids, which are retained by the body, especially in the extremities. This retention of fluids and salts is called edema. Additionally, patients suffering from nephrotic syndrome also experience varying levels of discomfort and toxicities due to increasing levels of wastes in the blood due to inefficient filtration in the glomerular layer.

(Jennette, 2004) Background In order to gain a perspective on understanding the physiology of Nephrotic Syndrome, it is important to understand how critical properly functioning glomeruli are in the execution of normal excretion. The kidneys are bean shaped organs. They are approximately the size of a person's fist and are located in the lower dorsal portion of the body. The function of kidneys is to remove waste from the body in liquid form. This means that the kidneys contain a complex set of filtration devices.

Studies and extrapolations show that more than 350 liters of blood flows through the kidneys in a 24-hour period. About two liters of waste material and any excess water is then removed from the body and excreted as urine. To perform their function, the kidneys receive blood through arteries that branch (on entering the kidneys) into clusters of smaller blood vessels. These clusters are called glomeruli (s. glomerulus). The process of urine creation starts at the glomeruli. Each glomerulus is attached (or ends into) to a tubule.

The tubule serves as a collection for the waste and excess water. The nephron, an important part of this process, comprises each glomerulus-tubule unit. There are more than a million such nephrons in a normal human kidney. This explains how complex the process of excretion is. The actual filtration takes place at a membrane called the glomerular membrane. This membrane separates the blood vessel -- glomerulus and the tubule. On the other side, the tubules aggregate to form larger tubes, which further aggregate into the ureters.

The ureters then carry the urine into the bladder for excretion. (Kassirer, 1971) Causes of Nephrotic Syndrome (EdREN, 2004) The causes of nephrotic syndrome, as mentioned in the Introduction, are varied and range from disease localized around the kidneys or diseases that affect the entire body and are far removed from the kidneys. Symptoms and effects of nephrotic syndrome can also be due to external factors. These are infections -- bacterial and viral. They can also be due to allergic and toxic reactions due to certain drugs.

The immediate non-symptomatic affects on the glomeruli physiologically are inflammation and scarring. Occasionally, symptoms of nephrotic syndrome are idiopathic. This term means that they are not associated with any diseases. In considering the different reasons how glomerular damage occurs, occasionally it is the body's immune system turning against itself. These are cases of autoimmune diseases. When an antigen -- a bacterium, virus or other foreign body -- attacks the body, the body produces an antibody that acts as a foil to destroy the antigen.

The first step in the mechanism of immunity is the formation of an antibody-antigen complex. In autoimmune diseases, due to a perceived attack on the body, whose mechanism is not completely understood, the body produces antibodies called autoantibodies. These antibodies can be systemic or they might attack specific parts of the body. Systemic Lupus erythematosus (SLE), commonly known as lupus attacks the skin, joints and, on occasion, the kidneys. It causes painful inflammations. This is an autoimmune disease.

If the kidneys are infected, it is because the body deposits autoantibodies into the glormeruli. This causes inflammation of the glomeruli. Since more women are afflicted by lupus, researchers believe that there is a causative factor with the sex gene for females. Others believe that a virus triggers it. Goodpasture's syndrome is another autoimmune disorder where autoantibodies attack the kidneys and the lungs. Coughing up blood is how patients of Goodpasture's syndrome first present the condition, however the damage on the kidneys is progressive, permanent and not immediately evident.

This illness also affects the glomeruli. As does the consequences of IgA nephropathy. In this case, the immunoglobulin A deposits in the glomeruli. Immunoglobulins are antibody proteins responsible for immunity functions throughout the body. Basically, the molecular structure if Igs consists of four proteins chains, two each of which are identical. Two chains are heavy and two are light. They are connected through sulfide linkages. IgA depositions cause inflammation and eventual kidney scarring. This disease takes several years to develop and is not often found in children.

As opposed to lupus, IgA nephropathy affects men more than it does women. Glomerular diseases and the associated nephrotic syndrome can also be inherited in a small number of patients. This condition is known as Alport syndrome. It is inherited. Men pass it down to their daughters. Women can pass it to their sons or daughters. This condition usually ends up in end stage renal failure by the age of 40. Interestingly, Alport syndrome is often associated with sight and hearing impairment.

Congenital Nephrotic Syndrome can be found in babies of Finnish descent (overwhelmingly) but also in other nationalities and races. This disease is characterized by low birth weight and enlarged placenta. The weight gain within 24 hours followed by swelling (due to edemas) is abnormal. The baby is dangerously ill and immediate steps have to be taken to preserve its life. Infections or over stimulation of the immune system may also have damaging effects on the renal glomeruli. The condition acute post-streptococcal glomerulonephritis (PSGN) is caused indirectly.

In the case of strepthroat or in the rare skin condition impetigo, the streptococcus bacterial infection stimulates the immune system to such an extent that the antibodies to combat the disease will deposit in the glomeruli. Edema, hematuria and oliguria (reduced urination) along with hypertension and elevated levels of creatinine and urea nitrogen in the blood are used to characterize PSGN. PSGN is most common among young children. It is also prevalent in male children. PSGN if left untreated eventually results in ESRD.

Bacterial cardiac infections such as endocarditis can also result in kidney lesions associated with damaged glomeruli. Chronic renal failure and ESRD can occur from endocarditis. Mechanistically, it is not known whether there is bacterial infection in the kidneys similar to that of the heart of whether it is the result of an overstimulated immune response. HIV also causes damage to the renal glomeruli. Once again, this is an autoimmune condition. Renal failure is observed in a statistically significant number of patients even when HIV has not escalated to AIDS.

Sclerosis or scaring also results in glomerular damage. This gives rise to the ill effects of nephrotic syndrome. Glomerularsclerosis is a condition caused by lesions and scars in the glomeruli. These might be brought about in two different ways. Research on this is speculative at best. One way is by means of growth factors. The glomerular cells create these themselves. Growth factors are stimulants necessary in the life cycles of all cells. In some cases, overproduction of growth factors leads to sclerosis.

It is also possible, that growth factors -- abnormal -- are introduced into the glomeruli through blood transport from remote regions of the body. One of the biggest drawbacks of the glucose imbalances in diabetes mellitus is association with sometimes-fatal renal failure. This is despite the inherent diabetic problems associated with the rapidly (and dangerously) varying glucose levels in the blood -- that can render a diabetic comatose. Diabetes causes scars and lesions in the kidneys.

There is reason to believe that elevated levels of glucose increase the speed of the flow of the blood. This increased force creates a strain on the glomerular layer of a nephron, interfering with the function of filtration. Naturally, moderating diets and increasing physical activity have a salubrious effect on the blood pressure. Angiotensin converting enzymes (ACE) and angiotensin receptor blockers in medications are used to slow down the blood flow, thus protecting the glomeruli and the waste filters.

Focal segmental glomerulosclerosis (FSGS) is the scarring of the glomeruli in random scattered patterns or in specific areas. Biopsies, which are typically suggested to determine diseased kidneys, are difficult as a diagnostic tool in the case of FSGS. Repeated biopsies become necessary in the hope of retrieving scarred renal tissue, since it is non-uniformly dispersed. This is one condition that is idiopathic in nature. There is no known associated disease (or causes as described above) for FSGS. Nephrotic syndrome is diagnosed through proteinuria.

While diabetic nephropathy is the commonest cause of Nephrotic Syndrome, membranous glomerulopathy (nephropathy) is the second highest cause of nephrotic syndrome. As in FSGS, more than seventy five percent of patients that present MG have no associate causes. The rest show MG from diabetes, lupus, immune deficiency disease and cancer. MG is said to have been caused by the deposition of immunglobulin G. And C3 in the glomeruli. MG is progressive. Approximately 20 to 40% of the cases end in ESRD. Most show remission.

Or, even in case of progression of disease do not see renal failure. A significant proportion of the patients recover even without treatment. How to treat a patient, and how aggressively to do so is often a matter of debate. Steroids, ACEs and ARBs are varyingly used to treat membranous glomerulopathy. Minimum change disease (MCD) is glomerular disease that afflicts children more than it does adults. In MCD, a biopsy of a diseased portion of tissue does not a significant change from normal tissue.

In some cases, small amounts of lipids (fats) may be present. But no scarring is observed. The origins of MCD are indeterminate. It is idiopathic in nature. Steroids are not often prescribed for MCD. A changed diet often helps. Also, ARBs ACEs and other anti-inflammatory drugs also help. (EdREN, 2004) Amyloidosis, which is the stiffening of kidneys due to excess protein deposits often affects the elderly. Effects of Nephrotic Syndrome Let's consider the ill effects of nephrotic syndrome. These effects were alluded to in the first paragraph of this work.

They are proteinuria, hematuria, hypoproteinemia and edema. Proteinuria, as described above is a high preponderance of protein in the urine. A person with normal kidney function loses approximately 150 mg of protein in one day. Contrast that with a person with proteinuria whose average protein excretion (through the urine) is more than three grams per day. This number can rise up to more than 25 times normal protein secretions. These proteins improperly filtered into the urine are essential to the normal functioning of the body.

Proteins are built from units called amino acids. They are essential for functions, which are varied and involuntary. Breathing, muscle control, the clotting of blood, the balance and functioning of the immune system all depend on proteins. Proteinuria is often specifically called albuminuria. That is because of the albumin, which is a relative smaller protein. It can pass through the glomerular layers easily if the latter is damaged. Larger proteins may be blocked and are not detectable unless the damage in the glomeruli is significant.

A qualitative test to test for proteinuria and nephrotic syndrome and other kidney diseases often detects the presence of albumin. In fact, microalbuminuria (detection of small amounts of albumin) is a precursor to proteinuria. (Weiner, 2004) One might suppose therefore depending on the levels of proteinuria, large amounts of albumin is lost. The function of albumin is to retain water in the blood. This water retention maintains the blood volume. It acts as a sponge does.

Edema, the secretion of salts away from the blood and tissue and retention in areas where it causes discomfort, is therefore a consequence of the loss of albumin. The blood volume decreases due to the loss of albumin. The body perceives this loss and retains more salt. In order to maintain concentrations, fluid moves into these areas to combat this excess salt. This causes fluid retention. Also, due to inefficient filtration, excess sodium is sometimes retained in the blood and consequently, so is fluid.

Edema is evident if the person afflicted, not realizing this consumes more salt than the body can excrete. Edema is the result of this intake-excretion imbalance. While swelling in the ankles can result from edemas after a person is on their feet for extensive periods, edemas can also occur around the eyes. This is observed when the patient wakes up in the morning. There are several reasons for hematuria. Some of these are as simple as bleeding due to exercise or external trauma to the kidneys.

Hematuria occurs from nephrotic syndrome. This is because the damage to the glomeruli allows the blood to filter into the tubule. This blood shows up in the urine. A urine test generally reveals blood in the urine when it is invisible to the naked eye. On the other hand, in severe cases, the urine is the color of blood or a dark brown color. Renal failure occurs due to the inefficient filtration of waste. This leads to the buildup to toxins in the blood and the tissue.

The effects are varied, as are the levels of seriousness. The symptoms of renal failure from acute nephrotic syndrome can be fatal unless dialysis or a transplant is not recoursed. Two primary waste products are creatinine and urea. Excess build up of these can lead to fatigue, weakness, loss of appetite and vomiting. Acids that are not discarded can build up leading to metabolic acidosis. Phosphate waste when accumulated causes blood phosphate to increase decreasing the level of other calcium salts, as that can be used to strengthen bones.

Thus, bone brittleness can result. The body can decrease its production of erythropoietin. This can result in anemia. The resulting edema can result in complications that include breathlessness. (Weiner, 2004) While the short-term effects are used in the diagnosis of nephrotic syndrome and its underlying causes, the condition if remained unchecked can result in acute or chronic renal problems. Eventually, end stage renal failure may occur. The previous section indicated how PSGN could result in nephrotic syndrome.

Acute renal failure will occur within a short time after the throat or skin infection in PSGN. Dialysis is often called for in these cases. Though the effects of acute renal failure are not lasting, it can devolve into Chronic Renal Failure. Acute renal failure, while it lasts, is extremely dangerous and can be life threatening. Chronic renal failure, on the other hand takes longer to manifest. Chronic renal failure leads to end stage renal failure.

It is incurable and the only way to slow down the failure is to treat the problems that may have caused it. Chronic renal failure is due to the destruction of nephron function. Nephrons once destroyed cannot be regenerated. End Stage Renal Failure means that kidney function has completely shut down. Kidney function can only be treated by a transplant or dialysis. In dialysis, there are two types. The most common is hemodialysis where the blood is circulated outside the body.

It is outside the body that the blood is divested of wastes. Dialysis has to be performed about thrice a week for three to four hours at a time. (Kidney-Failure-Symptoms, 2003) Recent Studies The previous two sections have shown that the exact mechanism for and from Nephrotic Syndrome is not known, especially in patients that present symptoms from idiopathy. This section is devoted to recent studies without a specific theme.

These studies contribute information that will enable researchers to understand the complex renal processes in nephrotic syndrome better Exactly how the filtration occurs is also a matter for debate. We know that smaller proteins such as albumin can flow through the damaged pores. Recent studies have also shown that the glomerular membrane not only acts as a size filter but also as a shape filter. In addition, the charge presented by the molecule being filtered is also an important consideration.

According to the authors, the filtration should not be considered as a static process, but dynamic depending on the type of molecule it needs to filter. Studies conducted on normal rats showed that different components.