Nephrotic syndrome is a condition where the 'filters' in the kidney become 'leaky' and large amounts of protein leak from your blood into your urine. The main symptom is fluid retention (oedema) which is mainly due to the low protein level in the blood. Various diseases can cause nephrotic syndrome, some more serious than others. Treatment and outcome (prognosis) vary, depending on the cause. The common cause in children (minimal change disease) usually responds very well to treatment.
Understanding kidneys and urine
To understand nephrotic syndrome, we first need to understand how the kidneys work.
The kidneys clear waste materials from the body and maintain a normal balance of fluids and chemicals in the body.
The two kidneys lie to the sides of the upper tummy (abdomen), behind the intestines and on either side of the spine. The kidneys are higher up in the body than people imagine - from behind they are actually partially protected by the lowest ribs. The kidneys move slightly with change in your body position and with movement of the diaphragm with breathing.
Each kidney is about the size of a large orange but bean-shaped.
'Renal' is a descriptive medical word, meaning 'related to the kidney'. For example, a renal physician is a doctor who looks after people with kidney (renal) diseases (so-called 'renal medicine').
A large renal artery takes blood to each kidney. The artery divides into many tiny blood vessels (capillaries) throughout the kidney. In the outer part of the kidneys tiny blood vessels cluster together to form structures called glomeruli.
Each glomerulus (the singular form of glomeruli) is like a filter. The structure of the glomerulus allows waste products and some water and salt to pass from the blood into a tiny channel called a tubule, while keeping blood cells and protein in the bloodstream. Each glomerulus and tubule is called a nephron. There are about one million nephrons in each kidney.
As the waste products, water and salts pass along the tubule there is a complex adjustment of the content. For example, some water and salts may be absorbed back into the bloodstream, depending on the current level of water and salt in your blood. Tiny blood vessels next to each tubule enable this 'fine tuning' of the transfer of water and salts between the tubules and the blood.
The liquid that remains at the end of each tubule is called urine. This drains into larger channels (collecting ducts) which drain into the inner part of the kidney (the renal pelvis). From the renal pelvis the urine passes down a tube called a ureter which goes from each kidney to the bladder. Urine is stored in the bladder until it is passed out through another tube, called the urethra, when we go to the toilet. The 'cleaned' (filtered) blood from each kidney collects into a large renal vein which takes the blood back towards the heart. The kidneys, ureters, bladder and urethra are, together, called the urinary tract.
Doctors can assess how well (or poorly) your kidneys are working by testing your blood and your urine.
'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 you might hear your 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 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.
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. What happens is that 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, and other complex factors not fully understood.
- 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 the 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 can result in nephrotic syndrome. The following gives a brief description of the main ones:
Minimal change disease
The name 'minimal change' comes from the fact that there is virtually no change detectable in the glomeruli if a sample of kidney is looked at under the microscope. Although the glomeruli look normal under the microscope, 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 and does not cause kidney failure in most cases.
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 result in membranous nephropathy developing. 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.
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 specific parts of 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 of the affected tissues. 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 distension. 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, in time 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 exert 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 that may develop due to nephrotic syndrome include:
- Urine that looks frothy.
- Tiredness, lethargy and a poor appetite.
- Diarrhoea and/or being sick (vomiting) - especially in children.
- If the nephrotic syndrome persists for a long time then you may develop wasting of your muscles and your nails may look like they have white bands on them (called Muehrcke's lines).
- Depending on the cause of the nephrotic syndrome, you may also have other symptoms. For example, if you have nephrotic syndrome as a complication of rheumatoid arthritis you may have 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.
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 you can lose antibodies 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. You need iron 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, you may be advised to take treatment to help prevent or reduce the risk of these possible complications.
Possible complications from the cause of the nephrotic syndrome
You may also have various complications 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 for long periods.
Do I need any tests for nephrotic syndrome?
To confirm nephrotic syndrome
A simple 'dipstick' test of your 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. You are likely to be asked to give an early morning urine sample. Previously, you might have been asked to collect all the urine that you passed over 24 hours, but this no longer routinely done and is not necessary. A low blood level of albumin combined with a lot of protein found in the urine usually confirms that you have nephrotic syndrome.
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. (There are some exceptions to this general rule.)
To check on the function of the kidneys
Blood tests can check on the function of the kidneys. The U&Es and eGFR (mentioned earlier in 'Understanding kidneys and urine') show how well the kidneys are clearing waste products from the bloodstream.
How is nephrotic syndrome treated?
Treatment of fluid retention (oedema)
'Water tablets' (diuretics) help to clear the body of fluid retention. 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, you pass out more urine. The excess fluid in the body's tissues then passes back into the bloodstream to keep the blood volume up to normal. Your doctor may also advise you to limit the amount of salt in your diet to try to limit fluid retention. One way of trying to measure whether you are retaining fluid (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 you develop high blood pressure then treatment is usually advised to bring your 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. These medicines might not be suitable for everyone but your doctor can advise you whether you need to take them. In very rare circumstances they can make your kidney function worse (if you have an undiagnosed problem called renal artery stenosis).
Treatment of the underlying cause
As mentioned, there are many causes of nephrotic syndrome. The treatment depends on the underlying cause. Some causes are more serious than others; some causes can be treated more easily than others.
For example, treatment for minimal change disease usually works well to stop the leak of protein from the kidneys. The usual treatment for minimal change disease is a course of steroid medication. . In some cases, this is a one-off treatment and the disease does not return. In some 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. Your doctor will advise on the treatment options for each situation.
What is the outlook (prognosis)?
The outlook depends on the cause. For example, 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. Your doctor will be able to give an outlook for your particular condition.
Further reading and references
Kodner C; Diagnosis and Management of Nephrotic Syndrome in Adults. Am Fam Physician. 2016 Mar 1593(6):479-85.
Pasini A, Benetti E, Conti G, et al; The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I - Diagnosis and treatment of the first episode and the first relapse. Ital J Pediatr. 2017 Apr 2143(1):41. doi: 10.1186/s13052-017-0356-x.
Hahn D, Samuel SM, Willis NS, et al; Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2020 Aug 31(8):CD001533. doi: 10.1002/14651858.CD001533.pub6.
Nishi S, Ubara Y, Utsunomiya Y, et al; Evidence-based clinical practice guidelines for nephrotic syndrome 2014. Clin Exp Nephrol. 2016 Jun20(3):342-70. doi: 10.1007/s10157-015-1216-x.
Canetta PA, Radhakrishnan J; The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome. Front Pediatr. 2015 Sep 253:78. doi: 10.3389/fped.2015.00078. eCollection 2015.
Hodson EM, Wong SC, Willis NS, et al; Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2016 Oct 1110:CD003594.