Nephrotic syndrome

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Overview

 * Not to be confused with nephritic syndrome

Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein (at least 3 grams per day) 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 underlying cause, such rash associated with SLE, or neuropathy with diabetes.
 * Examination should also exclude other causes of gross edema- especially the cardiovascular and hepatic system.

Maltese cross
The classic Maltese cross pattern is evident in fatty casts with polarized microscopy because of the birefringence of the lipid. Maltese crosses are due to cholesterol, which is increased in nephrotic syndrome.

Investigations
The following are baseline, essential investigations
 * Urine sample shows proteinuria. It is also examined for active casts; which is more a feature of active nephritis.
 * Hypoalbuminemia: albumin levels in blood < 30g/L
 * 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 (not usually done in children)
 * 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 rebsorbed 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 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.

They are usually described by the underlying cause.

Secondary causes by histologic pattern
Membranous nephropathy (MN)
 * Hepatitis B
 * Sjogren's syndrome
 * Systemic lupus erythematosus (SLE)
 * Diabetes mellitus
 * Sarcoidosis
 * Syphilis
 * Drugs
 * Malignancy (cancer)

Focal segmental glomerulosclerosis (FSGS)
 * Human immunodeficiency virus (HIV)
 * Diabetes mellitus
 * Obesity
 * Kidney loss

Minimal change disease (MCD)
 * Drugs
 * Malignancy, especially Hodgkin's lymphoma

GN with Nephrotic Syndrome

 * Captopril
 * Cancer
 * Diabetes Mellitus
 * Drugs
 * Hepatitis B
 * Hodgkin's Lymphoma
 * Mixed Connective Tissue Disease
 * Penicillamine
 * Streptococcal throat infection
 * Systemic Lupus Erythematosus
 * Thyroiditis

Acute Glomerulonenephritis

 * Berger's Disease
 * Goodpasture's Syndrome
 * Henoch-Schonlein Syndrome
 * Streptococcal Infection
 * Shunt infections
 * Subacute Endocarditis
 * Systemic Lupus Erythematosus
 * Wegener's Granulomatosis

Secondary

 * Alport's Syndrome
 * Amyloidosis
 * Congenital Nephrotic Syndrome
 * Dermatomyositis
 * Diabetes Mellitus
 * Drugs
 * Endocarditis
 * Fabry's Disease
 * Goodpasture's Syndrome
 * Henoch-Schonlein purpura
 * Hepatitis A,B,C
 * HIV
 * Infectious Mononeucliosis
 * Lipoatrophy
 * Lymphomas
 * Malaria
 * Multiple Myeloma
 * Orthostatic Proteinuria
 * Polyarteritis Nodosa
 * Rheumatoid arthritis
 * Sarcoidosis
 * Sickle Cell Anemia
 * Sjogren's Syndrome
 * Streptococcal Infection
 * Syphillis
 * Systemic Lupus Erythematosus
 * Toxoplasmosis
 * Vasculitis

Miscellaneous

 * Chronic interstitial nephritis
 * Graft vs. Host Disease
 * Hypothyroidism
 * Pre-eclampsia
 * Renal vein thrombosis
 * Severe Obesity
 * Thyroiditis

Differential diagnosis of gross edema
When someone presents with generalised 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: dilated veins over umbilicus (caput medusae), scratch marks, 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.

Treatment
Treatment includes:

A) 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.

B) Specific treatment of underlying cause
Immunosupression for the glomerulonephritides (steroids, 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 negetive 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

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

C) Dietary recommendations
Limit high protein animal foods to 1 oz per meal (prefferably lean cuts of meat, fish, and poultry)

Limit high phosphorous foods such as cheese, cooked dried beans and peas, nut butters, soy, tofu, and yogurt, including cokes and colas.

Limit high potassium vegetables and fruits such as artichokes, avocado, bamboo shoots, beets, brussels sprouts, chard, greens (such as beet and collards), kohlrabi, okra, parsnips, potatoes, pumpkin, rutabagas, spinach, sweet potatoes, tomatoes, tomato juice, tomato sauce, wax beens, winter squash, yams. Fruits include, apricots, bananas, dates, honey dew, nectarines, orange juice, oranges, prune juice.

Avoid saturated fats and eat unsaturated fats in moderation.

Eat low-fat desserts only.

Monitor fluid intake which includes all fluids and foods that are liquid at room temperature.

Complications
Renal vein thrombosis: In nephrotic syndrome there is an excessive urinary protein loss which is in turn associated with decreased antithrombin III. This leads to a relative rise in the activity of Factor II and Factor X and in increased tendency to thrombosis. Renal vein thrombosis is a manifestation of this hypercoagulable state. It is unclear why the renal vein is susceptible to thrombosis in patients with nephrotic syndrome.

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 (the patient is intravascularly deplete]]. Decreased blood flow to the kidneys causes pre renal azotemia. Thus it is therapeutic challenge to reduce the total body fluid overload while maintaining ciculalatory euvolemia.

Pulmonary edema: again due to fluid leak associated with the low protein content of the serum, there can be non cardiogenic pulmonary edema causing hypoxia and dyspnea.

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

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).