Nephrotic syndrome

Nephrotic syndrome
Classification and external resources
Histopathological image of diabetic glomerulosclerosis with nephrotic syndrome. H&E stain.
ICD-10	N04
ICD-9	581.9
DiseasesDB	8905
MedlinePlus	000490
eMedicine	med/1612 ped/1564
MeSH	D009404

Not to be confused with nephritic syndrome.

Nephrotic syndrome is a triad of proteinuria, hypoalbuminemia and edema. It is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein (proteinuria at least 3.5 grams per day per 1.73m² body surface area) from the blood into the urine.

Kidneys affected by nephrotic syndrome have small pores in the podocytes, large enough to permit proteinuria (and subsequently hypoalbuminemia,<25g/L, because some of the protein albumin has gone from the blood to the urine) but not large enough to allow cells through (hence no hematuria). By contrast, in nephritic syndrome RBCs pass through the pores, causing hematuria.

Signs and symptoms

It is characterized by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia, and edema (which is generalized and also known as anasarca or dropsy) that begins in the face. Lipiduria (lipids in urine) can also occur, but is not essential for the diagnosis of nephrotic syndrome. Hyponatremia also occurs with a low fractional sodium excretion.

Hyperlipidemia is caused by two factors:

• Hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of lipoproteins.
• Lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein breakdown. Cofactors, such as Apolipoprotein C2 may also be lost by increased filtration of proteins.

A few other characteristics seen in nephrotic syndrome are:

• The most common sign is excess fluid in the body due to the serum hypoalbuminemia. Lower serum oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention aggravate the edema. This may take several forms:
  • Puffiness around the eyes, characteristically in the morning.
  • Pitting edema over the legs.
  • Fluid in the pleural cavity causing pleural effusion. More commonly associated with excess fluid is pulmonary edema.
  • Fluid in the peritoneal cavity causing ascites.
  • Generalized edema throughout the body known as anasarca.
• Most of the patients are normotensive but hypertension (rarely) may also occur.
• Anemia (iron resistant microcytic hypochromic type) maybe present due to transferrin loss.
• Dyspnea may be present due to pleural effusion or due to diaphragmatic compression with ascites.
• Erythrocyte sedimentation rate is increased due to increased fibrinogen & other plasma contents.
• Some patients may notice foamy or frothy urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as hematuria or oliguria are uncommon, though these are seen commonly in nephritic syndrome.
• May have features of the underlying cause, such as the rash associated with systemic lupus erythematosus, or the neuropathy associated with diabetes.
• Examination should also exclude other causes of gross edema—especially the cardiovascular and hepatic system.
• Muehrcke's nails; white lines (leukonychia) that extend all the way across the nail and lie parallel to the lunula

Causes

Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney, called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.

Primary

Primary causes of nephrotic syndrome are usually described by the histology, i.e. minimal change disease (MCD)-like minimal change nephropathy which is the most common cause of nephrotic syndrome in children, and focal segmental glomerulosclerosis, which is the most common cause of nephrotic syndrome in adults.

They are considered to be "diagnoses of exclusion", i.e. they are diagnosed only after secondary causes have been excluded.

Secondary

Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though may exhibit some difference suggesting a secondary cause, such as inclusion bodies. They are usually described by the underlying cause.

Secondary causes by histologic pattern:

Membranous nephropathy (MN):

• Hepatitis B
• Sjögren's syndrome
• Systemic lupus erythematosus (SLE)
• Diabetes mellitus
• Sarcoidosis
• Drugs (such as corticosteroids, gold, intravenous heroin)
• Malignancy (cancer)
• Bacterial infections, e.g. leprosy & syphilis
• Protozoal infections, e.g. malaria

Focal segmental glomerulosclerosis (FSGS)

• Hypertensive nephrosclerosis
• HIV^{[citation needed]}
• Obesity^{[citation needed]}
• Kidney loss

Minimal change disease (MCD)

• Drugs, especially NSAIDs in the elderly
• Malignancy, especially Hodgkin's lymphoma
• Allergy
• Bee sting

Membranoproliferative Glomerulonephritis

• Hepatitis C

Diagnosis

The gold standard in diagnosis of nephrotic syndrome is 24 hour urine protein measurement. Aiding in diagnosis are blood tests and sometimes imaging of the kidneys (for structure and presence of two kidneys), and/or a biopsy of the kidneys.

The following are baseline, essential investigations:

• 24 hour bedside urinary total protein estimation.

Urine sample shows proteinuria (>3.5 g per 1.73 m² per 24 hours). It is also examined for urinary casts, which are more a feature of active nephritis.

• Comprehensive metabolic panel (CMP) shows hypoalbuminemia: albumin level ≤2.5 g/dL (normal=3.5-5 g/dL).
• Lipid profile.

High levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly elevated VLDL is typical.

• Electrolytes, urea and creatinine (EUCs): to evaluate renal function.

Further investigations are indicated if the cause is not clear:

• Biopsy of kidney.
• Auto-immune markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis).
• Ultrasound of the whole abdomen.

Classification

A broad classification of nephrotic syndrome based on underlying cause:

Nephrotic syndrome

Primary

Secondary

Nephrotic syndrome is often classified histologically:

Nephrotic syndrome

MCD

FSGS

MN

MPGN

Differential diagnosis

When someone presents with generalized edema, the following causes should be excluded:

1. Heart failure: The patient is older, with a history of heart disease. Jugular venous pressure is elevated on examination, might hear heart murmurs. An echocardiogram is the gold standard investigation.
2. Liver failure: History suggestive of hepatitis/ cirrhosis: alcoholism, IV drug use, some hereditary causes.
   Signs of liver disease are seen: jaundice (yellow skin and eyes), dilated veins over umbilicus (caput medusae), scratch marks (due to widespread itching, known as pruritus), enlarged spleen, spider angiomata, encephalopathy, bruising, nodular liver.
3. Acute fluid overload in someone with kidney failure: These people are known to have kidney failure, and have either drunk too much or missed their dialysis.
4. Metastatic cancer: when cancer spreads to the lungs or abdomen it causes effusions and fluid accumulation due to obstruction of lymphatics and veins, as well as serous exudation.

Treatment

Treatment includes:

Supportive

• Monitoring and maintaining euvolemia (the correct amount of fluid in the body):
  • Monitoring urine output, BP regularly.
  • Fluid restrict to 1 L.
  • Diuretics (IV furosemide).

• Monitoring kidney function:
  • do EUCs daily and calculating GFR.

• Treat hyperlipidemia to prevent further atherosclerosis.

• Prevent and treat any complications [see below]

• Albumin infusions are generally not used because their effect lasts only transiently.

Prophylactic anticoagulation may be appropriate in some circumstances.

Specific

• Immunosuppression for the glomerulonephritides (corticosteroids, ciclosporin).

• Standard ISKDC regime for first episode: prednisolone -60 mg/m²/day in 3 divided doses for 4 weeks followed by 40 mg/m²/day in a single dose on every alternate day for 4 weeks.

• Relapses by prednisolone 2 mg/kg/day till urine becomes negative for protein. Then, 1.5 mg/kg/day for 4 weeks.

• Frequent relapses treated by: cyclophosphamide or nitrogen mustard or ciclosporin or levamisole.

• Achieving better blood glucose level control if the patient is diabetic.

• Blood pressure control. ACE inhibitors are the drug of choice. Independent of their blood pressure lowering effect, they have been shown to decrease protein loss.

Diet

Reduce sodium intake to 1000–2000 mg daily. Foods high in sodium include salt used in cooking and at the table, seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods, fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to calories per serving. Sodium should be less than or equal to calories per serving.

Eat a moderate amount of high protein animal food: 3-5 oz per meal (preferably lean cuts of meat, fish, and poultry)

Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and nuts. Eat low-fat desserts.

Increase intake of fruits and vegetables. No potassium or phosphorus restriction necessary.

Monitor fluid intake, which includes all fluids and foods that are liquid at room temperature. Fluid management in nephrotic syndrome is tenuous, especially during an acute flare.Treatment for nephrotic syndrome depends on the cause and the age of the person who has the condition. Medicines, changes in diet, and care for other conditions, such as diabetes or high blood pressure, are all possible treatments for this syndrome. These treatments may reverse, slow, or prevent further kidney damage.

Most children who have nephrotic syndrome do well with treatment and have a normal life expectancy.

Doctors define complete recovery as living without symptoms or treatment for more than 2 years.

Initial treatment

Treatment of nephrotic syndrome depends on the cause of the disease and may include:

• Corticosteroids, such as prednisone or prednisolone, to reduce swelling.
• Diuretics to reduce fluid buildup in the body (edema) and to help with reducing sodium, potassium, and water. Fluid reduction should occur slowly to avoid further kidney damage and low blood pressure.
• Medicines, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), to reduce the amount of protein lost in the urine, lower blood pressure, and slow the progress of the disease.
• In rare cases, salt-free albumin given through a vein (IV). Albumin helps remove extra fluid from the tissues.

First treatments can last from 6 to 15 weeks, often longer in adults. Depending on how severe your symptoms are or whether they return, ongoing treatment may be needed for months to years, or even for the rest of your life.

Ongoing treatment

Ongoing treatment for nephrotic syndrome and complications of the disease include:

• Daily or alternate-day prednisone, if nephrotic syndrome returns.
• Cyclophosphamide, cyclosporine, or mycophenolate mofetil, when treatment with corticosteroids is not successful.
• Steps to lower blood pressure, including medicine, a healthier diet, and exercise. Untreated high blood pressure increases your risk for stroke or heart attack. For more information, see the topics high blood pressure, coronary artery disease, and stroke.
• Changes in diet to replace nutrients lost through the urine, reduce fluid buildup in the body, and reduce the risk of complications. Some doctors prescribe a diet that limits protein, salt (sodium), and fats but is high in carbohydrates. The amount of protein allowed may vary, depending on your condition.
• Anticoagulants, such as warfarin (Coumadin) or heparin, to treat blood clots if they form.
• Early treatment of infections with antibiotics.
• Vaccinations with a pneumococcal vaccine, chickenpox (varicella) vaccine, and a yearly flu shot. Vaccination is not recommended until nephrotic syndrome has responded to treatment with corticosteroids.
• Calcium and vitamin D supplements to protect your bones and help prevent osteoporosis during long-term corticosteroid treatment (for example, prednisone).

You may need emotional support during treatment for nephrotic syndrome. If you or your child has nephrotic syndrome and you are having a hard time handling treatment or the severity of your child's condition, it may help to talk with a doctor or seek counseling.

Treatment if the condition worsens

Sometimes treatment for nephrotic syndrome is unsuccessful. If this occurs, you may develop chronic kidney disease. Your doctor may recommend that you begin hemodialysis, peritoneal dialysis, or consider a kidney transplant. For more information, see the topic chronic kidney disease.

Clinical trials are ongoing to test more effective medicines for the treatment of steroid-resistant (relapsing) nephrotic syndrome. If treatment has not successfully controlled your nephrotic syndrome, ask your doctor about clinical trials. To take part in a clinical trial, you may need to travel to a large treatment center.

WebMD Medical Reference from Healthwise Last Updated: May 17, 2011 This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information. © 1995-2012 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.

Complications

• Venous thrombosis: due to leak of anti-thrombin 3, which helps prevent thrombosis. This often occurs in the renal veins. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin 3 which is lost in the proteinuria so it will be ineffective.) Hypercoagulopathy due to extravasation of fluid from the blood vessels (edema) is also a risk for venous thrombosis.

• Infection: due to leakage of immunoglobulins, encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae can cause infection.

• Acute renal failure is due to hypovolemia. Despite the excess of fluid in the tissues, there is less fluid in the vasculature. Decreased blood flow to the kidneys causes them to shutdown. Thus it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia.

• Pulmonary edema: again due to fluid leak, sometimes it leaks into lungs causing hypoxia and dyspnoea.

• Growth retardation: does not occur in MCNS.It occurs in cases of relapses or resistance to therapy. Causes of growth retardation are protein deficiency from the loss of protein in urine, anorexia (reduced protein intake), and steroid therapy (catabolism).

• Vitamin D deficiency can occur. Vitamin D binding protein is lost.

• Hypothyroidism can occur. Thyroxine is reduced due to decreased thyroid binding globulin.

• Microcytic hypochromic anemia is typical. It is iron-therapy resistant.

• Hypocalcemia can occur as a result of nephrotic syndrome. It may be significant enough to cause tetany. Hypocalcemia may be relative; calcium levels should be adjusted based on the albumin level and ionized calcium should be checked.

• Cushing's Syndrome

Prognosis

The prognosis depends on the cause of nephrotic syndrome. It is usually good in children, because minimal change disease responds very well to steroids and does not cause chronic renal failure. However other causes such as focal segmental glomerulosclerosis frequently lead to end stage renal disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood pressure control and kidney function (GFR).

See also

• Lipiduria

External links

• Nephrotic Syndrome Research A team of kidney doctors and scientists from Beth Israel Deaconess Medical Center / Harvard Medical School working to learn more about the cause of Nephrotic Syndrome in children and adults, with an emphasis on the genetic basis of this disease.
• Childhood Nephrotic Syndrome - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH
• Adult Nephrotic Syndrome - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH

Kidcomm.org A resource for parents of children with nephrotic syndrome since 2007