Nephrotic Syndrome

What is nephrotic syndrome?

Nephrotic syndrome is not a single disease - it is a syndrome. A syndrome is a set of symptoms and signs that tend to occur together and which can be caused by one or more different diseases. Nephrotic syndrome can be caused by many different diseases, some more serious than others.

Cross-section diagram of the urinary tract

The main feature of nephrotic syndrome is that the kidneys leak a lot of protein. Normally, urine contains virtually no protein. In nephrotic syndrome the urine contains large amounts of protein. Filters in the kidneys (the glomeruli) become 'leaky' and protein, instead of remaining in the blood, leaks out into the urine. Protein in the urine is called proteinuria.

The other key features of nephrotic syndrome are:

• A low level of protein in the blood as a result of protein loss in the urine. Although there is a drop in many of the proteins normally found in the bloodstream, the main protein that leaks from the blood into the urine is called albumin. A low blood level of albumin is a main feature of nephrotic syndrome.
• Fluid retention (oedema). This is a consequence of the low level of albumin in the bloodstream. Fluid becomes trapped in body tissues. Parts of the body, particularly the feet and ankles, appear puffy and swollen.
• A high blood level of cholesterol and other fats (lipids). This is due to the change in the balance of various protein levels in the blood due to protein leakage.
• Normal kidney function, at least initially. This means that the 'waste clearing' function of the kidneys is not affected - at least not at first. However, some of the conditions that cause nephrotic syndrome can progress to cause kidney disease.

Other typical symptoms and signs of nephrotic syndrome are discussed later.

What are the causes of nephrotic syndrome?

Various diseases can affect the glomeruli and cause nephrotic syndrome. The following gives a brief description of the main ones:

Minimal change disease

'Minimal change' means there is virtually no change detectable in the glomeruli if a sample of kidney is looked at under a microscope. Although the glomeruli appear normal, there seems to be some minor change in the glomeruli that allows leakage of protein.

The cause of minimal change disease is not clear. It probably has something to do with a slight change in the immune system, or perhaps a reaction of parts of the immune system to some unidentified factor.

Minimal change disease causes about 9 in 10 cases of nephrotic syndrome in children under the age of 5 years. It causes about 1 in 5 cases of nephrotic syndrome in adults. It usually responds well to treatment with steroid medication taken by mouth and does not cause kidney failure in most cases.

Membranous nephropathy

This is sometimes called membranous nephritis or membranous glomerulonephritis. It is a common cause of nephrotic syndrome in adults. It is an uncommon cause in children.

In this condition there is some thickening of the membrane in the glomeruli (the 'filter' of the glomeruli) which makes the glomeruli 'leaky' to protein. The thickening can be seen under a microscope if a sample of kidney is taken for testing.

In many cases, the cause or reason for this change to occur in the glomeruli is not known. However, there are various conditions that can cause membranous nephropathy to develop. For example, an abnormal reaction of the immune system to some infections or medicines can cause this disease.

Focal segmental glomerulosclerosis (FSGS)

This is a condition where small scars (sclerosis) develop on some glomeruli. The cause is unknown in most cases. However, a reaction of the immune system to something, or to various different things, is thought to be the cause. FSGS accounts for up to 1 in 10 cases of nephrotic syndrome in children but a higher percentage of cases in adults.

Congenital nephrotic syndrome

This is a rare cause of nephrotic syndrome which affects children. 'Congenital' means it is present from birth. It is genetic (inherited due to a faulty gene) in most cases. Babies with this form of nephrotic syndrome usually develop symptoms within the first three months of life. It is usually hard to treat and most children eventually require dialysis (diversion of blood, often to a machine, to remove waste products) or a kidney transplant (replacement of a faulty kidney with a healthy one).

Other disorders of the glomeruli

There are various other uncommon kidney disorders, which primarily affect the glomeruli, that can result in nephrotic syndrome. For example, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, fibrillary glomerulosclerosis, diffuse mesangial sclerosis, IgM mesangial nephropathy.

The cause of some of these conditions is not clear. However, some are probably caused by reactions of the immune system that cause damage to the glomeruli or nearby cells.

Other general conditions

A complication of some other more generalised conditions can cause damage to glomeruli, resulting in nephrotic syndrome. For example, nephrotic syndrome is a possible complication of diabetes, systemic lupus erythematosus (SLE), rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, various infections, some cancers and amyloidosis. It can also occur as a side-effect of certain medicines and as a consequence of various poisons or toxins.

What are the symptoms of nephrotic syndrome?

Fluid retention (oedema) is a main symptom

Fluid retention occurs when fluid leaks out of blood vessels into the body tissues. This causes swelling and puffiness. The swelling is usually painless but the swollen tissues may feel tight. With children, the face is often affected first and the face becomes puffy. With adults, the ankles often become swollen at first (as gravity helps fluid to pool in the lower legs). As fluid retention becomes worse, the calves and then the thighs may become swollen.

In severe cases, the fluid retention can become extensive. Fluid may accumulate in the lower back, the arms, in the tummy (abdominal) cavity (where it is called ascites), genitals, or in the chest between the lungs and the chest wall (pleural effusion). Ascites can cause tummy pain and discomfort due to swelling of the abdomen. Pleural effusions may cause chest pain and breathlessness.

The main reason why fluid leaks out from the blood vessels and into the body's tissues with nephrotic syndrome is because of a low level of protein in the blood. As protein is lost from the body in the urine, the body makes more protein in the liver which passes into the bloodstream.

However, the amount made by the liver cannot keep up with the amount lost by the leaky kidneys and so the blood level of protein goes down. If the blood level of protein is low, then fluid tends to leak out of the blood vessels into the body tissues. Protein and other chemicals in the blood create an osmotic pressure which tends to pull fluid into the blood vessels. If the concentration of protein reduces, the osmotic pressure reduces and fluid leaks out.

Note: nephrotic syndrome is just one cause of fluid retention. There are other causes of fluid retention. For example, heart failure is the most common cause of fluid retention, especially in older people.

Other symptoms

The following symptoms may also develop due to nephrotic syndrome:

• Urine that looks frothy.
• Tiredness and a poor appetite.
• Diarrhoea and/or being sick (vomiting) - especially in children.
• If the nephrotic syndrome persists for a long time then wasting of the muscles may develop and the nails may look like they have white bands on them (called Muehrcke's lines).
• Depending on the cause of the nephrotic syndrome, there may also be other symptoms. For example, if nephrotic syndrome has arisen as a complication of rheumatoid arthritis there may be a range of other symptoms caused by the arthritis. Some conditions of the kidney can cause high blood pressure (hypertension) and/or chronic kidney disease.

Tests of kidney function

Doctors can assess how well (or poorly) the kidneys are working with blood and urine tests.

'U&Es' is the abbreviation medical professionals use for urea and electrolytes. These are a group of blood tests to measure the levels of salts (such as sodium and potassium) in the blood, as well as the urea and creatinine levels, which show the kidney function as they are waste products.

The eGFR is a term doctors use. It stands for estimated glomerular filtration rate and is another measure of kidney function. The levels of protein and albumin (a type of protein) can also be measured with blood tests.

Urine can be tested for blood and protein with a 'dipstick' in clinic, or an exact measurement can be calculated by the laboratory. Other chemicals in urine can be measured and the urine is often examined under the microscope to see if it contains any abnormal cells or sediment.

Sometimes doctors refer to CKD. This stands for chronic kidney disease, which itself is a general term and can be caused by many different diseases or processes. The term 'chronic' mean the illness is persistent or long-lasting, and does not relate to how severe it is.

What are the possible complications of nephrotic syndrome?

Possible complications from nephrotic syndrome itself

Complications can be caused by nephrotic syndrome itself due to the loss of normal proteins from the blood. These include:

• An increased risk of developing infections. This is because antibodies can be lost in the urine. Antibodies are proteins that help to defend the body from infection. Any signs of infection (sore throat, high temperature (fever), etc) should be taken seriously and reported promptly to a doctor.
• An increased risk of developing blood clots in the blood vessels (thrombosis). For example, a deep vein thrombosis (DVT) in a leg. This can cause pain, swelling and other complications. The reason for this is because there can be a change in the balance of proteins in the blood that protect against blood clots forming.
• A high cholesterol level. If this persists long-term it is a risk factor for developing heart disease.
• Increased risk of vitamin D deficiency which may lead to bone problems. This is due to loss of vitamin D-binding protein from the bloodstream.
• Anaemia. This is due to loss of proteins that help to carry iron around in the bloodstream. Iron is needed to make red blood cells and to prevent anaemia.
• Acute kidney injury. This may rarely occur from the nephrotic syndrome itself, or more commonly due to complications such as infections, or as an unintended result of treatment.

Depending on the duration and severity of the nephrotic syndrome, treatment may be advised to help prevent or reduce the risk of these possible complications.

Possible complications from the cause of the nephrotic syndrome

Various complications can arise from the underlying condition which has caused the nephrotic syndrome. For example:

• One of the most common complications of kidney disorders is high blood pressure (hypertension).
• Some kidney disorders lead to chronic kidney disease.
• Some disorders (for example, diabetes, rheumatoid arthritis, etc) that cause nephrotic syndrome can have various other symptoms and complications.

Possible complications from treatment

Often, the treatment of nephrotic syndrome requires a course of steroid medicines or other medicines to suppress the immune system (see below). Some people develop side-effects and complications from these treatments, especially if the treatment requires high doses, or is needed for long periods.

Do I need any tests for nephrotic syndrome?

To confirm nephrotic syndrome

A simple 'dipstick' test of the urine can confirm that it contains a lot of protein. Protein in the urine is not always due to nephrotic syndrome but is often a cause of underlying kidney disease. There are exceptions, such as protein in the urine caused by a urinary tract infection, exercise, or dehydration. The amount of protein lost can be measured by more detailed urine and blood tests.

An early morning urine sample is usually requested. A low blood level of albumin combined with a lot of protein found in the urine usually confirms that nephrotic syndrome is present.

Blood tests are also performed to check the function of the kidneys.

To find the cause of the nephrotic syndrome

A range of blood tests may be done to try to identify the cause of the nephrotic syndrome. A kidney biopsy may also be done. A kidney biopsy is a procedure which involves taking a small sample of tissue from a kidney. The sample is looked at under a microscope, or tested in other ways.

This is often the most important test to clarify the cause of the nephrotic syndrome in adults. However, in children a biopsy is usually only done in specific situations. This is because most cases in young children are due to minimal change disease. A trial of treatment is usually advised first and a biopsy done only if treatment does not work, although there are some exceptions to this general rule.

How is nephrotic syndrome treated?

Treatment of fluid retention (oedema)

'Water tablets' (diuretics) help to clear the body of excess fluid. Diuretics work by acting on the cells in the kidney tubules to make them pass out more water rather than reabsorbing water back into the bloodstream, so more urine is passed out. The excess fluid in the body's tissues then passes back into the bloodstream to keep the blood volume up to normal.

Limiting the amount of salt in the diet may also be advised to try to limit fluid retention. One way of trying to measure whether fluid is being retained (or to see if the diuretics are helping) is to weigh yourself regularly.

Treatment of high blood pressure (hypertension)

Many people with kidney disorders have high blood pressure. This is because the kidney makes chemicals involved in the control of blood pressure. If high blood pressure develops then treatment is usually advised to bring the blood pressure down. A medicine called an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-II receptor antagonist (AIIRA) - sometimes called an angiotensin receptor blocker (ARB) - is commonly used for this.

These medicines seem to have a protective effect on the kidneys and can reduce the amount of protein leaking. However, these medicines might not be suitable for everyone.

Treatment of the underlying cause

The exact treatment offered will depend on the underlying cause. For example, a course of steroid medication usually works well to stop the leak of protein from the kidneys in minimal change disease. In some cases, this is a one-off treatment and the disease does not return. In other cases of minimal change disease, the disease comes back (recurs) from time to time which needs repeated courses of steroid medication.

Steroids or other medicines called immunosuppressants may be used to reduce inflammation and abnormal immune responses in various diseases that cause nephrotic syndrome. In a small number of cases, steroids or immunosuppressant medications do not work or they stop working after a period of time. Dialysis or a kidney transplant may be required. The treatment options available for each situation are usually discussed on a case-by-case basis.

Can nephrotic syndrome be cured?

There is no cure for nephrotic syndrome at present. The treatments described above are used to prevent the damage to the kidneys from getting worse and to manage symptoms.

Depending on the underlying cause, a course of steroid medication, or other therapy, may cause remission. Remission means that the signs and symptoms of the condition have gone, but there is still a chance it could return in the future. Remission is different from the term cure, which means that the condition will never occur again. However some people may recover from their first episode and never have another relapse. 25 - 30% of children with minimal change disease go into complete remission after the first episode. So they are considered to be 'cured' once they have been relapse-free for several years.

What is the outlook (prognosis)?

The outlook depends on the cause. As mentioned, the most common cause of nephrotic syndrome in children (minimal change disease) usually responds well to treatment and generally has a good outlook. The outlook is less good with some other conditions. Those affected by nephrotic syndrome can discuss the outlook for their particular cause with their doctor.

Cross-section diagram of the urinary tract

The kidneys clear waste materials from the body and maintain a normal balance of fluids and chemicals in the body.