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Nephrotic Syndrome

  1. What is nephrotic syndrome?
  2. Symptoms & Complications
  3. Causes
  4. Diagnosis
  5. Treatment
  6. FAQ

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 typically develop as a result of another condition or underlying medical problem.

There can be various underlying conditions or problems, all of which require specific treatment. It can occur among adults and children, but is more common among children, especially children aged between 18 months and four years.[1] In children under 8 years old, 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
  • Edema, abnormal accumulations of fluid, causing swelling of the body or parts of it

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 (drugs which are potentially damaging to the kidneys), 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 relieving edema and stopping or lessening the loss of protein in the urine. Ways to do this include following a specific diet and taking medication to lower lipid levels and manage hypertension.[3][4] 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 ddetermined 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.

Symptoms and complications of nephrotic syndrome

Symptoms of nephrotic syndrome include:[1][5][6]

  • 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 or other high blood lipid values
  • Hypertension; high blood pressure
  • Hypoalbuminemia and albuminuria, 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 nephrotic syndrome

In a healthy kidney, small groupings of capillaries, known as glomeruli, filter the blood. The glomerulus and nearby tube for the removal of byproducts, known as a tubule, together make up a structure called a nephron.[7]

In the nephron, the glomerulus filters the blood. Substances needed by the body, such as potassium, protein and phosphorus, return to the blood, while unwanted products pass through a membrane into the tubule. These unwanted products pass from the tubule to the ureter, to the bladder and are eventually passed out of the body in the urine. If the tubule, glomerulus, or both, become damaged or infected, this filtration system may become unbalanced. Waste products may build up in the body, and necessary substances such as proteins and minerals may be lost, instead of being reabsorbed.[7]

In glomerular disorders, such as some of those that lead to nephrotic syndrome, the membrane between the glomerulus and the tubule may lose its ability to prevent protein molecules and red blood cells from passing out into the tubule, for various reasons.[8]

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 subsequently lost, causing blood protein levels to fall.[2] Nephrotic range proteinuria is defined as 3 to 3.5 or more grams of protein lost in urine over a twenty-four hour period.[5] This is almost eight times the amount of protein a healthy glomerulus would allow through.

This has various 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.

Edema , ascites and pleural effusion

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 starting in the face, around the eyes, or in the legs and ankles, but may lead to generalized swelling of the entire body, too. [9][10] It can also lead to fluid build up around the lungs.[11] This is known as pleural effusion, and if this happens, the affected person may experience difficulty breathing and breathlessness. If this is the case a doctor should be consulted urgently. If fluid builds up inside the belly this is called ascites and may be uncomfortable. Ascites can lead to an increased abdominal circumference and a feeling of heaviness and discomfort in the stomach area or the entire belly.

While edema is generally not serious most of the time, it can among others cause joint and abdominal pain that are a cause of concern for people affected. If someone is not sure what causes their particular symptoms it is always advisable to see a doctor to get a proper diagnostic work-up..

Ascites

Ascites is a common complication in disorders that involve proteinuria, such as nephrotic syndrome. In ascites, fluid accumulates inside the abdominal cavity, causing the abdomen to distend.[12] Ascites caused by nephrotic syndrome is more common among children than adults.[13] Symptoms of ascites include:[12]

  • Abdominal pain
  • A swollen abdomen
  • Weight gain
  • Feeling full sooner during meals
  • Shortness of breath

Ascites has to be treated by a doctor, and anyone who develops ascites should seek medical help as soon as possible.[12] In nephrotic syndrome, treatment for ascites involves treating the underlying condition. In addition to this, some cases of ascites may need to be drained using a process called therapeutic paracentesis.

Pleural effusion

A pleural effusion is the buildup of an unusually large amount of fluid around the lungs between the layers of the pleura, the thin membrane that lines the inside of the chest cavity, and the surface of the lungs.[14] Symptoms of a pleural effusion include:[15]

  • A dry cough
  • Shortness of breath
  • Chest pain
  • Difficulty breathing properly or worsening of shortness of breath while sitting or lying down

The treatment of pleural effusion depends on the degree of discomfort it is causing, whether it is obstructing breathing and what is causing it. Treating pleural effusion caused by nephrotic syndrome involves treating the underlying condition, but can also involve draining the fluid in a procedure called thoracentesis.[15][16]

If you are concerned that you or someone you know is experiencing ascites or pleural effusion because of nephrotic syndrome, you can do a free symptom assessment using the Ada app at any time.

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][17][18]

  • 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][19][20]

  • Diabetic nephropathy, which results from long-term high levels of blood glucose
  • Preeclampsia, a pregnancy complication
  • 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, which may then in some cases lead to nephrotic syndrome. Nephrotoxic drugs that can cause kidney damage in children include:[21]

  • 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 and it is always advisable to talk to your doctor if you are worried about medication side effects.

Other drugs that can be nephrotoxic include:[22]

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

In cases where a certain drug may be causing nephrotic syndrome, stopping using the drug usually improves the symptoms and relieves the syndrome.

Nephrotic syndrome in adults

Glomerulonephritis is the most common cause for nephrotic syndrome. The two most common subtypes of glomerulonephritis are focal segmental glomerulosclerosis (FSGN) and membranous glomerulonephritis, also known as MGN or membranous nephropathy. FSGN is the most common form of glomerulonephritis among people of African or African-American ancestry, while MGN is the most common among people with European ancestry.

There are many other causes for nephrotic syndrome, the most common being diabetes and systemic lupus erythematosus.[9] Glomerulonephritis can also be the result of a streptococcal infection. 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.[23]

The various types of glomerulonephritis are characterized by change or damage to the structures of the glomerulus, for example as a result of attack by the body’s own immune system, infection or exposure to toxins. It can lead to nephrotic syndrome, but also to another different syndrome called nephritic syndrome. In most cases of nephrotic syndrome, the underlying condition affects the membrane between the tubule and the glomerulus, which causes the loss of protein into the urine.

The causes of the inflammation of the glomeruli that characterises focal segmental glomerulonephritis (FSGN) are not well-understood, but it is suspected that viral infection or exposure to toxins may be at least part of the problem. In most cases of membranous nephropathy, the cause for the damage to the glomerular membranes can be considered a result of an autoimmune attack on the glomeruli, leading to the person affected producing antibodies against their own glomerular membrane.[24] This is called primary MGN. Secondary MGN can be caused by certain painkillers, known as NSAIDs, Hepatitis B and C, systemic lupus erythematosus, or other conditions, particularly other infections, but rarely also secondary due to tumors.

Nephrotic syndrome in children

Although nephrotic syndrome can affect people of any age, it often affects children between the ages of eighteen months and five years. Below the age of 8, more boys than girls are affected. While most cases of nephrotic syndrome in children can be treated and managed quite well (see the ‘Treatment’ section of this resource), some cases or underlying conditions causing nephrotic syndrome are congenital and more difficult to manage. However, the most common form of nephrotic syndrome among children, minimal change disease, is not congenital.

Minimal change disease

Minimal change disease is the cause of up to 90% of cases of nephrotic syndrome among children older than one year.[25] Although adults can have minimal change disease, it is very rare among adults. Most cases of minimal change disease respond very well to treatment with steroids (see the ‘Treatment’ section of this resource).

If you are concerned that your child, or a child you care for, may have one of these kidney problems, you can do a free symptom assessment with the Ada app at any time.

Congenital nephrotic syndrome

Congenital nephrotic syndrome is, generally, a very rare form of nephrotic syndrome that affects children from infancy; symptoms often appear in the child’s first three months of life.[26] Congenital nephrotic syndrome often does not respond well to treatment, and it is possible for the condition to become quite severe and for kidney failure to develop before the age of ten.

End-stage renal disease may develop before puberty, although treatment can postpone this.[26] Congenital nephrotic syndrome is hereditary and is sometimes known as familial nephrotic syndrome.

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 more specific tests.[27]

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 now often replaced by a more convenient single-sample test.[11]

A common urine test performed by medical professionals is a test on a single urine sample, which is often gathered first thing upon waking.[28] 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.[5] Urine samples will also be checked for lipids and cell casts, which are microscopic structures that may be produced by the kidneys if nephrotic syndrome or other disorders are present.[1]

Also depending on the result of the urine test, different blood tests will be carried out to help in determining what the underlying cause of the nephrotic syndrome might be. Blood tests for underlying causes may include:[1]

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

While these tests can usually identify many causes, a kidney biopsy may additionally be needed to diagnose and clearly confirm the underlying cause and help in finding the best treatment option.[5]

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.[6]

Treatment of nephrotic syndrome

Treatment of nephrotic syndrome usually involves a combination of supportive treatment intended to reduce symptoms such as proteinuria, edema, hypertension and hyperlipidemia, and treatment of the underlying cause.[2] Steps should also be taken to prevent possible complications.[27]

While some cases of nephrotic syndrome clear up whether or not treatment is administered, it is generally not advisable to wait and see, and medical advice should be sought without delay.[6] Prognosis in cases of nephrotic syndrome is generally good, but this greatly depends on the underlying cause and how effectively it is treated.

Treatment may include:[1][2][5]

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

ACEs and ARBs lower blood pressure, which reduces the pressure inside the glomeruli. They thereby also prevent protein loss in the urine. Increasing protein consumption in the diet does not alleviate protein loss and is generally not advised. Blood-thinning medications should generally 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 and are advised to get yearly flu shots.[5]

In children, nephrotic syndrome is often treated with corticosteroids such as prednisone or prednisolone.[29]

Complications of nephrotic syndrome

Nephrotic syndrome can cause complications due to the way it may unbalance bodily systems. Complications can include:[1][5][11][30][31]

  • Hypothyroidism
  • Protein undernutrition, in children
  • High cholesterol (hyperlipidemia or hypercholesterolemia, due to changes in blood composition resulting from protein loss
  • Coronary artery disease, in adults
  • Blood clots (hypercoagulability), which occur because of abnormal protein levels in the blood
  • Thrombosis in the lungs, limbs, kidney vessels or brain
  • Anemia, due to a mechanism yet not fully understood, iron no longer being adequately transported in the blood
  • Acute kidney injury, sudden, temporary loss of kidney function
  • Hematuria, blood in the urine
  • Severe azotemia, high levels of nitrogen compounds in the blood
  • Infections, such as cellulitis, a skin infection, pneumonia, meningitis and spontaneous bacterial peritonitis, which may be more likely than in healthy people, due to a loss of immunoglobulins.

Good to know: Immunoglobulins are proteins that form part of the immune system and help to fight disease and infections. If they are increasingly lost, the body is at increased risk of infections.

Hypercoagulability and hyperlipidemia are not merely complications, but also classic features of nephrotic syndrome. Both states are the result of increased protein loss and the following protein synthesis. As albumin is lost in the urine, as part of the nephrotic syndrome, the liver is trying to compensate by producing more. Because protein synthesis is rather unspecific and not all proteins are being lost in the urine, the levels of some proteins in the blood, e.g. lipoproteins, actually rise. Simplified, increased lipoprotein levels lead to rising fat levels in the blood.

Good to know: Hypoalbuminemia (low albumin in the blood) can sometimes also manifest as white bands in the nails, known as Muerkhe’s Lines.[27]

Nephrotic syndrome FAQs

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 enzymes known as cyclooxygenases, which reduce 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 irritation or even stomach ulcers.

The list of medications classified as NSAIDs includes:[32]

  • Ibuprofen
  • Aspirin, depending on the dose; lower doses used for instance long-term, after a heart attack, may not be anti-inflammatory but just modulate the blood clotting
  • Naproxen
  • Indomethacin
  • Diclofenac
  • Celecoxib
  • Ketoprofen
  • Oxaprozin
  • Piroxicam

Many over-the-counter NSAIDs come packaged with a warning not to use them continuously for more than a few days without consulting a primary care physician. If your pain does not respond well to NSAIDs or worsens substantially at any time, seek further medical advice. If you have pain that is not responding to treatment, you can try to get an idea of what may be causing the pain by doing a symptom assessment using the Ada app for free at any time.

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.[33]. Younger adults are seldom affected.[34] In most cases, the situation improves when use of the drug is discontinued.[35] However, in rare cases, chronic renal insufficiency may occur.

It is likely that NSAIDs, which may reduce blood-flow to the kidneys, can sometimes affect the membrane that separates the glomerulus from the tubule in the nephron.These changes can contribute to, or sometimes even cause, the development of nephrotic syndrome.[35] NSAIDs can also cause other lesions in the kidneys, leading to a problem known as acute interstitial nephritis (AIN).[36]

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 liquid waste products. Many people who need dialysis only need it temporarily. However, depending on the cause of the renal insufficiency or failure, some people may need dialysis for the foreseeable future, until a kidney transplant becomes available, or for the rest of their lives. As nephrotic syndrome is a sign of a greater underlying problem, whether someone will need dialysis very much depends on the underlying condition.[2]

People with diabetic nephropathy, chronic glomerulonephritis, polycystic kidney disease, or other chronic kidney disease, have a risk of developing kidney failure as a complication and therefore may possibly need long-term dialysis.[37] Those with acute kidney failure may only need dialysis for the short-term.

Q: Is nephrotic syndrome hereditary?
A: Some cases of nephrotic syndrome are hereditary or may run in the family. In particular, some types of nephrotic syndrome in children have been linked to several genes.[38]

Q: Can babies be affected by nephrotic syndrome?
A: Unfortunately, some forms of nephrotic syndrome can, although very rarely, affect babies. When it affects babies, this may have various causes. Congenital infections, such as congenital toxoplasmosis for instance, may rarely lead to secondary nephrotic syndrome that is not hereditary. Congenital nephrotic syndrome on the other hand, has hereditary links and may often begin very early in infancy. It is, however a very rare genetic kidney condition which is only slightly more often found in families of Finnish or Mennonite ancestry.[36][9][39]

Q: Can autoimmune conditions such as systemic lupus erythematosus cause nephrotic syndrome?
A: Yes, nephrotic syndrome seems to be more likely to occur in people with autoimmune conditions than in the general population. These conditions may for instance include some chronic connective tissue disorders, e.g. systemic scleroderma, or systemic lupus erythematosus.[40] Lupus nephritis, which may then lead to nephrotic syndrome, often affects people who have severe systemic lupus erythematosus. Systemic lupus erythematosus can cause both nephritic syndrome and nephrotic syndrome.[41][42] Severe systemic lupus erythematosus commonly affects the kidneys and may cause the sort of changes – proteinuria and edema especially – that are known as nephrotic syndrome. Lupus causes glomeruli to become inflamed, which can affect how effectively the kidneys remove unwanted byproducts from the blood.[43]

Q: What sort of diet should people with nephrotic syndrome follow?
A: There is no evidence that diet can cause nephrotic syndrome or that adjusting one’s diet can prevent nephrotic syndrome.[5] Some dietary changes may be useful and supportive in the management of nephrotic syndrome, however. A person affected by nephrotic syndrome, or the caregiver of a child with nephrotic syndrome, should always discuss their diet with their nephrologist before making any specific changes.

However, generally it can be said that, with nephrotic syndrome, regulating salt and fluid intake is important, and some dietary changes can help to manage this, e.g., by drinking water or lower fat milk rather than soda and avoiding salty foods.[44] Dietary changes may possibly involve restricting salt, cholesterol and fat, eating more vegetables and fruits, and choosing lean meats. No specific changes should be made without first getting a professional medical opinion, and protein and overall fluid intake should only be restricted in case of a nephrologist specifically advising someone to do so.[45]

Q: What is End-Stage Renal Disease (ESRD)?
A: End-stage renal disease (ESRD) is also known as kidney failure, a state in which the kidneys cannot function well enough to prevent the buildup of toxic levels of substances in the blood.In a person with healthy kidneys, these would normally be eliminated by the kidneys. People with ESRD very often need dialysis or a kidney transplant. ESRD is the final stage of chronic renal failure, which is nowadays commonly known as chronic kidney disease.[46]

Q: What is the difference between a syndrome and a disease?
A: Although many people use the terms interchangeably, a syndrome and a disease are medically not the same. A disease or condition is usually defined as the body’s response to external or internal factors, such as a virus, bacteria or a faulty immune-system reaction. A syndrome is a group of symptoms or signs that may suggest the presence of a particular disease or disorder. The term syndrome may also be used as an umbrella term summing up the presence of multiple conditions or diseases. In the case of metabolic syndrome, for example, to give the diagnosis, at least 3 out of 5 conditions must present out of a cluster of increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.[47]


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