Nephrotic Syndrome

What is nephrotic syndrome?

Nephrotic syndrome is a collection of signs and symptoms which indicate that there is a problem with the kidneys. It is a syndrome rather than a disease. A syndrome is a group of symptoms that often occur together and develop as a result of another condition.

There can be various underlying conditions or problems, all of which require specific treatment. It can occur among adults and children, but is most common among children aged between 18 months and four years.[1] In children, boys are more commonly affected than girls.

While the prognosis is usually quite good, nephrotic syndrome can become severe and even potentially life-threatening, if left untreated. The degree of severity depends on the underlying cause.

The major symptoms of nephrotic syndrome include:

  • The excretion of abnormally large amounts of protein, especially albumin, in the urine, known as proteinuria generally and albuminuria specifically.
  • Reduced levels of protein in the blood.
  • Consequent edema, abnormal accumulations of fluid.

Hypertension (high blood pressure) and thrombotic events (blood clots) may also be present, as might hyperlipidemia, a high level of lipids in the blood.

Causes of nephrotic syndrome include kidney damage from nephrotoxic drugs, systemic disorders such as diabetes or lupus, or diseases affecting the kidneys directly, such as glomerulonephritis.[2] In children, most cases of nephrotic syndrome are caused by minimal change disease (MCD).

Treating nephrotic syndrome usually involves managing hypertension and hyperlipidemia, as well as alleviating edema and arresting the loss of protein in the urine. This can be done with diet and antihypertensive medications. If the nephrotic syndrome is caused by minimal change disease, steroids may be used as part of treatment.[2]

How is nephrotic syndrome different to nephritic syndrome?

Nephritic syndrome is an inflammatory kidney disorder that is sometimes confused with nephrotic syndrome during initial diagnosis. However, there are several clear differences that are differentiated during laboratory testing. While nephritic syndrome is characterised by inflammation and hematuria (blood in urine), nephrotic syndrome is mostly characterised by proteinuria.

Of the two, nephrotic syndrome is often the more serious, depending on the underlying cause. In both cases, medical assistance should be sought out as quickly as possible.

Causes of nephrotic syndrome

Nephrotic syndrome is not a disease in itself, but rather a sign that something else is wrong in the body. Underlying conditions that can cause nephrotic syndrome can be primary, originating in the kidneys, or secondary, originating elsewhere in the body. Primary causes include:[1][3][4]

  • Minimal change disease, which can cause proteinuria, mostly found among children
  • Focal segmental glomerulosclerosis, which causes scarring of the glomeruli
  • Membranous nephropathy, which occurs when the glomeruli become thickened and damaged

Secondary causes include:[1][5][6]

  • Diabetic nephropathy, which results from long-term high levels of blood glucose
  • Pre-eclampsia
  • Amyloidosis, a bone-marrow disorder that causes malformed protein chains, mostly found among older adults
  • HIV-associated nephropathy

Some drugs may lead to kidney damage, causing glomerulonephritis, which may then lead to nephrotic syndrome. Nephrotoxic drugs that can cause kidney damage in children include:[7]

  • Cyclosporine
  • Aminoglycoside antibiotics
  • Cisplatin
  • Amphotericin B
  • Beta-lactam antibiotics
  • Indomethacin

It should be noted that the circumstances in which these drugs can become nephrotoxic vary from case to case.

Other drugs that can be nephrotoxic include:[8]

  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Radiocontrast media
  • Antirheumatic drugs
  • Anticancer drugs

In cases where drugs are implicated in nephrotic syndrome, symptoms usually improve once the drug concerned is discontinued.

Symptoms and complications of nephrotic syndrome

Symptoms of nephrotic syndrome include:[1][9][10]

  • Appetite loss
  • Malaise, a general feeling of unwellness
  • Frothy urine due to proteinuria
  • Edema (accumulated fluid under the skin, which may appear as weight gain)
  • Hyperlipidemia (high cholesterol)
  • Hypertension (high blood pressure)
  • Hypoalbuminia and albuminaria, low blood levels and high urine levels of the protein albumin.

Proteinuria and edema are the two most distinctive symptoms of nephrotic disorder.

Proteinuria

In a healthy kidney, small groupings of capillaries, known as glomeruli, filter the blood. The glomerulus and nearby waste tube, known as a tubule, together make up a structure called a nephron.[11]

In the nephron, the glomerulus filters the blood. Substances needed by the body, such as potassium, protein and phosphorus, return to the blood, while waste products pass through a membrane into the tubule. Waste products pass from the tubule to the ureter, and are eventually eliminated in the urine. If the tubule, glomerulus, or both, become damaged or infected, this filtration system becomes unbalanced. Waste products may build up in the body, and necessary substances such as proteins and minerals may be lost.[11]

In glomerular disorders, such as those that lead to nephrotic syndrome, the membrane between the glomerulus and the tubule loses its ability to prevent protein molecules and red blood cells from passing out into the tubule.[12]

Healthy glomeruli allow less than 400mg of protein into urine per day. In nephrotic syndrome, three grams or more of protein pass into the urine and are lost through excretion, causing blood protein levels to fall.[2] Nephrotic range proteinuria is defined as 3.5 or more grams of protein lost in urine over a twenty-four hour period.[9] This is roughly twenty times the amount of protein a healthy glomerulus would allow through.

This has various cascading effects on the body, as the protein loss causes low levels of blood protein. Because blood protein is vital to the absorption and elimination of extra fluid from the body’s tissues, low levels of protein result in a buildup of fluids in the tissues, known as edema.

Glomerulonephritis is the most common cause for nephrotic syndrome. One specific subtype of glomerulonephritis, membranous glomerulonephritis (MGN), is the most common cause for nephrotic syndrome in adults.

Specifically, glomerulonephritis is damage to the glomerulus, often the result of attack by the body’s own immune system. It can also be the result of a streptococcal Infection or other underlying conditions. While some cases of glomerulonephritis clear up on their own, others may take longer. In cases where the glomerulonephritis becomes chronic, long-term damage to the kidneys may occur.[13]

In MGN, also know as membranous nephropathy, the small membrane between the tubule and the glomerulus is especially affected which causes the loss of protein. In most cases, no cause for this damage can be found, but it is suggested that it is a result of an autoimmune attack on the glomeruli. This is called primary MGN. Secondary MGN can be caused by NSAIDs, Hepatitis B, systemic lupus erythematosus, cancer or others.

Edema

In nephrotic syndrome, the lack of protein leads to a buildup of fluid made up of sodium and water in the tissues. It is usually found in the lower legs, but can build up around the lungs.[14] This is known as pleural effusion, and if this happens, the affected person may experience breathlessness. If fluid builds up in the abdominal cavity (ascites), it may be uncomfortable. Ascites, in particular, can lead to an increased abdominal circumference and a feeling of heaviness and discomfort. Most of the time, however, edema is generally not serious, although it can cause joint and abdominal pain.

Complications of nephrotic syndrome

Nephrotic syndrome can cause complications due to the way it unbalances bodily systems. Complications can include:[1][9][14][15]

  • Blood clots (hypercoagulability), which occur because of abnormal protein levels in the blood
  • Coronary artery disease (in adults)
  • Thrombosis in the lungs, limbs or brain
  • High cholesterol (hyperlipidemia or hypercholesterolemia), due to changes in blood composition resulting from protein loss
  • Acute kidney injury (sudden, temporary loss of kidney function)
  • Anemia, due to iron no longer being adequately transported in the blood
  • Infections, such as cellulitis, pneumonia, meningitis and spontaneous bacterial peritonitis, which result from loss of immunoglobulins. Medications used to treat these infections can themselves be nephrotoxic.
  • Hypothyroidism
  • Protein undernutrition (in children)
  • Hematuria (blood in the urine)
  • Severe azotemia, high levels of nitrogen compounds in the blood

Hypercoagulability and hyperlipidemia are the result of abnormal protein synthesis. As albumin is lost in the urine, the liver compensates by producing more. But because protein synthesis is nonspecific, and not all proteins are being lost in the urine, the levels of some proteins actually rise in the blood.

Good to know: Hypoalbuminemia (low albumin) can also manifest as white bands in the nails, known as Muerkhe’s Lines.[16]

Diagnosis of nephrotic syndrome

Nephrotic syndrome is initially diagnosed using urine testing, as well as a physical examination. Visible edema is considered a sign that kidney function might be disturbed, but urine tests for protein generally, and albumin in particular, are considered specific tests.[16]

Albumin levels can be determined by a dipstick test, but a larger urine sample is needed if diagnosis if to be confirmed. Formerly, a twenty-four hour collection of the affected person’s urine would be tested for albumin, but this is considered less efficient than a single-sample test, and is being phased out.[14]

The most common urine test performed by medical professionals is a test on a single urine sample gathered first thing upon waking. This test measures albumin and creatinine in ratio. A ratio of 30mg of albumin to one gram of creatinine signals that there is a problem.[9] Urine samples will also be checked for cell casts and lipids.[1]

Depending on the result of the urine test, blood tests will be carried out to determine what the underlying cause of the nephrotic syndrome might be. While these tests can usually isolate secondary causes, a kidney biopsy may also be needed to diagnose primary causes.[9]

Blood tests for underlying causes may include:[1]

  • HbA1c to determine whether diabetes is present.
  • Hepatitis B and C tests
  • Rheumatoid factor
  • HIV antibody tests
  • Serologic syphilis tests

In children, treatment with steroids is often begun without waiting for biopsy results. This is because nephrotic syndrome is usually the result of minimal change disease. Biopsy may be likewise unnecessary in the case of adults with diabetes, given that diabetic nephropathy is a very common underlying cause.[10]

Treatment of nephrotic syndrome

Treatment of nephrotic syndrome usually involves a combination of supportive treatment intended to alleviate symptoms such as proteinuria, hypertension and hyperlipidemia, and treatment of the underlying cause.[2] Steps should also be taken to prevent possible complications. Treatment is broadly the same, whatever the underlying cause.[16]

While some cases of nephrotic syndrome go into remission whether or not treatment is administered, it is generally not advisable to wait and see, and medical advice should be sought without delay.[10] Prognosis in cases of nephrotic syndrome is generally good, but this depends on the underlying cause and how effectively it is treated.

Treatment may include:[2][1][9]

  • Angiotensin-converting-enzyme (ACE) inhibitors
  • Angiotensin receptor blockers (ARB)
  • Salt/sodium restriction in the diet
  • Diuretics to reduce blood pressure and edema
  • Statins to lower cholesterol

ACEs and ARBs lower blood pressure, which reduces the pressure inside the glomeruli. They also prevent protein loss in the urine. Increasing protein consumption in the diet does not alleviate protein loss and is not advised. Blood-thinning medications should only be prescribed if the affected person has had a blood clot already. If possible, people with nephrotic syndrome should be vaccinated against pneumococcal disease.[9]

Nephrotic syndrome FAQs

Q: What is the link between non-steroidal anti-inflammatory drugs (NSAIDs) and nephrotic syndrome?
A: In recent years, doctors have seen an increase in the number of cases of kidney injury and nephrotic syndrome resulting from long-term use of NSAIDs. It is most often found in adults, usually in more senior people, but is also possible among children.[17]. Younger adults are seldom affected.[18] In most cases, the situation improves when use of the drug is discontinued.[19] However, in rare cases, chronic renal insufficiency may occur.

It is likely that NSAIDs, which reduce blood-flow to the kidneys, can, in some instances, change the permeability of the membrane that separates the glomerulus from the tubule in the nephron, leading to nephrotic syndrome.[19] NSAIDs can also cause lesions in the kidneys, leading to a problem known as acute interstitial nephritis (AIN).[20]

Q: What are NSAIDs?
A: NSAIDs are a class of medications that are commonly sold over the- counter and reduce pain and inflammation. For this reason, they are often used to relieve headaches, fever and pain from mild injuries. NSAIDs work by blocking the actions of an enzyme known as cyclooxygenase, which reduces prostaglandins in the body. Prostaglandins promote inflammation, pain and fever. Thus, if they are blocked, those symptoms are reduced. However, because prostaglandins also protect the stomach, long-term use of NSAIDs can also cause stomach ulcers.

The list of medications classified as NSAIDs includes:[21]

  • Ibuprofen
  • Aspirin
  • Diclofenac
  • Celecoxib
  • Ketoprofen
  • Naproxen
  • Indomethacin
  • Oxaprozin
  • Piroxicam

Many over-the-counter NSAIDs come packaged with a warning not to use them continuously for more than ten days without consulting a primary care physician. If your pain does not respond well to NSAIDs, seek further medical advice.

Q: If I have nephrotic syndrome, will I need to have dialysis?
A: Dialysis is typically only necessary for people whose kidney function has fallen too low for the body to adequately eliminate its own waste products. Many people who need dialysis only need it temporarily. However, depending on the cause of the renal failure, some people may need dialysis for the foreseeable future, until a kidney transplant becomes possible, or for the rest of their lives. As nephrotic syndrome is a sign of a greater underlying problem, whether you will need dialysis depends on the underlying condition.[2]

People with diabetic nephropathy, chronic kidney disease, chronic glomerulonephritis or polycystic kidney disease may all develop kidney failure and need long-term dialysis.[22] Those with acute kidney failure may only need dialysis for the short-term.


  1. MSD Manuals. “Overview of Nephrotic Syndrome” January 2018. Accessed 5 April 2018.

  2. Kidney Care UK. “Nephrotic Syndrome”. Accessed 5 April 2018.

  3. National Kidney Foundation. “Focal Segmental Glomerulosclerosis (FSGS)”. Accessed 9 April 2018.

  4. UNC Kidney Centre. “Membranous Nephropathy”. Accessed 9 April 2018.

  5. Amyloidosis Foundation. “AL Amyloidosis”. Accessed 9 April 2018.

  6. Kidney and Urology Foundation of America. “Nephrotic Syndrome in Adults”. Accessed 9 April 2018.

  7. Journal of Paediatric Nephrology. “Nephrotoxic drugs.”. October 1988. Accessed 9 April 2018.

  8. Japanese Journal of Clinical Medicine. “Drug induced nephrotic syndrome”. October 2004. Accessed 9 April 2018.

  9. National Institute of Diabetes and Digestive and Kidney Diseases. “Nephrotic Syndrome in adults”. February 2014. Accessed 9 April 2018.

  10. Edinburgh Royal Infirmary Renal Unit. “More info on nephrotic syndrome” April 2010. Accessed 5 April 2018.

  11. Kidneyhealthcare.com. “The Nephron - Structure and Function of the Nephron”. Accessed 5 April 2018.

  12. National Institute of Diabetes and Digestive and Kidney Diseases. “Glomerular Diseases”. Accessed 4 April 2018.

  13. Patient.info. “Glomerulonephritis”. 21 May 2018. Accessed 20 April 2018.

  14. National Kidney Federation. “Nephrotic Syndrome (Adults)”. 1999. Accessed 9 April 2018.

  15. Nephrotic Syndrome Trust. “What is Nephrotic Syndrome?”. Accessed 5 April 2018.

  16. RenalMed. “Nephrotic Syndrome”. Accessed 9 April 2018.

  17. NEJM Journal Watch. “Nephrotic syndrome from NSAIDS.” May 18 1990. Accessed 17 April 2018.

  18. Pharmaceuticals (Basel). “Nonsteroidal Anti-Inflammatory Drugs and the Kidney”. July 2010. Accessed 17 April 2018.

  19. Seminars in Nephrology. “Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs.”. May 1995. Accessed 17 April 2018.

  20. UpToDate. “Clinical manifestations and diagnosis of acute interstitial nephritis”. Accessed 17 April 2018.

  21. MedicineNet.com. “Nonsteroidal Anti-inflammatory Drugs (NSAIDs)”. Accessed 17 April 2018.

  22. DaVita. “What is dialysis and when do I start?”. Accessed 17 April 2018.