Nephrotic syndrome
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Not to be confused with nephritic syndrome

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

Presentation

It is characterised by proteinuria (>3.5g/day), hypoalbuminemia, hyperlipidemia and edema. A few other characteristics are:

• The most common sign is excess fluid in the body. This may take several forms:
  • Puffiness around the eyes, characteristically in the morning.
  • Edema over the legs which is pitting (i.e. leaves a little pit when the fluid is pressed out, which resolves over a few seconds).
  • Fluid in the pleural cavity causing pleural effusion.
  • Fluid in the peritoneal cavity causing ascites.
• Hypertension (rarely)
• Some patients may notice foamy urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as hematuria or oliguria are uncommon, and 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.

Investigations

The following are baseline, essential investigations

• Urine sample shows proteinuria (>3.5 per 1.73 m² per 24 hour). It is also examined for urinary casts; which is more a feature of active nephritis.
• Comprehensive metabolic panel (CMP) shows Hypoalbuminemia: albumin level ≤2.5g/dL (normal=3.5-5g/dL).
• High levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly elevated VLDL
• 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)

Pathogenesis

The glomeruli of the kidneys are the parts that normally filter the blood. They consist of capillaries that are fenestrated (leaky, due to little holes called fenestrae or windows) and that allow fluid, salts, and other small solutes to flow through, but normally not proteins.

In nephrotic syndrome, the glomeruli become damaged due to inflammation and hyalinisation so that small proteins, such as albumins immunoglobulins and anti-thrombin can pass through the kidneys into urine.

Albumin is the major protein in the blood which maintains colloid osmotic pressure—this prevents leakage of blood from vessels into tissue. However, experiments show that the edema formation in nephrotic syndrome is more so due to microvascular damage and intense salt and water retention by the damaged kidneys (due to increased angiotensin secretion). The mechanism is very complex and still not fully understood.

In response to leakage of albumin, the liver begins to make more of all its proteins, and levels of large proteins (such as alpha 2-macroglobulin and lipoproteins) increase. The excess lipoproteins end up in the urine filtrate, which is then reabsorbed by the tubular cells, which end up shedding and forming oval fat bodies or fatty casts.

Classification and 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.

Etiologic classification

A broad classification of nephrotic syndrome based on etiology:

Histologic classification

Nephrotic syndrome is often classified histologically:

Primary causes

Primary causes of nephrotic syndrome are usually described by the histology, i.e. minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN).

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

Secondary causes

Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though may exhibit some differences suggesting a secondary cause, such as inclusion bodies.

They are usually described by the underlying cause.

Secondary causes by histologic pattern

Membranous nephropathy (MN)^[1]

• Hepatitis B
• Sjogren's syndrome
• Systemic lupus erythematosus (SLE)
• Diabetes mellitus
• Sarcoidosis
• Syphilis
• Drugs
• Malignancy (cancer)

Focal segmental glomerulosclerosis (FSGS)^[1]

• Hypertensive Nephrosclerosis
• Human immunodeficiency virus (HIV)
• Diabetes mellitus
• Obesity
• Kidney loss

Minimal change disease (MCD)^[1]

• Drugs
• Malignancy, especially Hodgkin's lymphoma

Differential diagnosis of gross edema

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: alcoholic, IV drug user, some hereditary causes.
   Stigmata 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 seeds the lungs or abdomen it causes effusions and fluid accumulation due to obstruction of lymphatics and veins as well as serous exudation.

Diagnosis

Diagnosis is based on blood and urine tests and sometimes imaging of the kidneys, a biopsy of the kidneys, or both.

Treatment^{citation needed}

Treatment includes:

General measures (supportive)

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

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

• Prevent and treat any complications [see below]

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

Specific treatment of underlying cause

Immunosupression for the glomerulonephritides (steroids,^[2] cyclosporin)

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

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

Frequent Relapses treated by:cyclophosphamide or nitrogen mustard or cyclosporin or levamisole.

Achieving stricter blood glucose control if 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.

Dietary recommendations^{citation needed}

Reduce sodium intake to 1000-2000 milligrams 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. There is 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.

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.)

• Infection: due to leakage of immunoglobulins, encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumonia 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. Thyroxine is reduced due to decreased thyroid binding globulin.

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

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).

References

• Brenner, Barry M. (editor) (2004). Brenner & Rector's The Kidney, seventh edition. W.B. Saunders Company. ISBN 0-7216-0164-2. 

External links

• Nutrition Care Manual from the American Dietetic Association
• Information from the NephCure Foundation
• 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