Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.
Causes include a number of kidney diseases such as focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. It may also occur as a complication of diabetes, lupus, or amyloidosis. The underlying mechanism typically involves damage to the glomeruli of the kidney. Diagnosis is typically based on urine testing and sometimes a kidney biopsy. It differs from nephritic syndrome in that there are no red blood cells in the urine.
Treatment is directed at the underlying cause. Other efforts include managing high blood pressure, high blood cholesterol, and infection risk. A low-salt diet and limiting fluids are often recommended. About 5 per 100,000 people are affected per year. The usual underlying cause varies between children and adults.
Signs and symptoms
Nephrotic syndrome is characterized by large amounts of proteinuria (>3.5 g per 1.73 m2 body surface area per day, or > 40 mg per square meter body surface area per hour in children), hypoalbuminemia (< 3.5 g/dl), hyperlipidaemia, and edema that begins in the face. Lipiduria (lipids in urine) can also occur, but is not essential for the diagnosis of nephrotic syndrome.
A few other characteristics seen in nephrotic syndrome are: The most common sign is excess fluid in the body due to 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 is known as anasarca. Most of the people with nephrotic syndrome are normotensive but hypertension (rarely) may also occur. Anaemia (iron resistant microcytic hypochromic type) may be 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 people may notice foamy or frothy urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as haematuria or oliguria are uncommon, though these are commonly seen 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 liver systems. Muehrcke's nails; white lines (leukonychia) that extend across the nail and lie parallel to the lunula
The main signs of nephrotic syndrome are: Proteinuria of greater than 3.5 g /24 h /1.73 m2 (between 3 and 3.5 g/24 h /1.73 m2 is considered to be proteinuria in the nephrotic range) or greater than 40 mg/h/m2 in children. The ratio between urinary concentrations of albumin and creatinine can be used in the absence of a 24-hour urine test for total protein. This coefficient will be greater than 200–400 mg/mmol in nephrotic syndrome. This pronounced loss of proteins is due to an increase in glomerular permeability that allows proteins to pass into the urine instead of being retained in the blood. Under normal conditions, a 24-hour urine sample should not exceed 80 milligrams or 10 milligrams per decilitre. Hypoalbuminemia of less than 2.5 g/dL, that exceeds the liver clearance level, that is, protein synthesis in the liver is insufficient to increase the low blood protein levels. Edema is thought to be caused by two mechanisms. The first being hypoalbuminemia, which lowers the oncotic pressure within vessels, resulting in hypovolemia and subsequent activation of the renin–angiotensin system and thus retention of sodium and water (underfill hypothesis). Additionally, it is thought that urinary proteases (excreted as a result of significant proteinuria) cause a direct effect by activating the epithelial sodium channel (ENaC) on the principal cell that leads to the reabsorption of sodium and water (overfill hypothesis). Nephrotic syndrome edema initially appears in parts of the lower body (such as the legs) and the eyelids. In the advanced stages, it also extends to the pleural cavity and peritoneum (ascites) and can even develop into a generalized anasarca. Hyperlipidaemia in nephrotic syndrome is typically caused by two mechanisms. First, hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of low and very-low-density lipoproteins. There is also an increase in the liver synthesis of cholesterol. Second, 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. Thrombophilia, or hypercoagulability, is a greater predisposition for the formation of blood clots that are caused by a decrease in the levels of antithrombin III in the blood due to its loss in urine. Lipiduria or loss of lipids in the urine is indicative of glomerular pathology due to an increase in the filtration of lipoproteins.
Complications Nephrotic syndrome can be associated with a series of complications that can affect an individual's health and quality of life: Thromboembolic disorders: particularly those caused by a decrease in blood antithrombin III levels due to leakage. Antithrombin III counteracts the action of thrombin. Thrombosis usually occurs in the kidney veins, although it can also occur in arteries. 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. Infections: The increased susceptibility of people with nephrotic syndrome to infections can be a result of the leakage of immunoglobulins from the blood, the loss of proteins in general, and the presence of oedematous fluid (which acts as a breeding ground for infections). The most common infection is peritonitis, followed by lung, skin, and urinary infections, meningoencephalitis, and in the most serious cases septicaemia. The most notable of the causative organisms are Streptococcus pneumoniae and Haemophilus influenzae. Spontaneous bacterial peritonitis can develop where there is ascites present. This is a frequent development in children but is very rarely found in adults. Acute kidney failure due to hypovolemia: the loss of vascular fluid into the tissues (edema) produces a decreased blood supply to the kidneys, which causes a loss of kidney function. Thus, it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia. Pulmonary edema: the loss of proteins from blood plasma and the consequent fall in oncotic pressure causes an abnormal accumulation of liquid in the lungs, causing hypoxia and dyspnoea. Hypothyroidism: deficiency of the thyroglobulin transport protein thyroxin (a glycoprotein that is rich in iodine and is found in the thyroid gland) due to decreased thyroid-binding globulin. Vitamin D deficiency can occur. Vitamin D binding protein is lost. Hypocalcaemia: lack of 25-hydroxycholecalciferol (the way that vitamin D is stored in the body). As vitamin D regulates the amount of calcium present in the blood, a decrease in its concentration will lead to a decrease in blood calcium levels. It may be significant enough to cause tetany. Hypocalcaemia may be relative; calcium levels should be adjusted based on the albumin level, and ionized calcium levels should be checked. Microcytic hypochromic anaemia: iron deficiency caused by the loss of ferritin (compound used to store iron in the body). It is iron-therapy resistant. Protein malnutrition: this occurs when the amount of protein that is lost in the urine is greater than that ingested, which leads to a negative nitrogen balance. Growth retardation: This can occur in cases of relapse 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). Cushing's syndrome
Causes
Nephrotic syndrome has many causes and may either be the result of a glomerular disease that can be either limited to the kidney, called primary nephrotic syndrome (primary glomerulonephrosis), or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.
Primary glomerulonephrosis Primary causes of nephrotic syndrome are usually described by their histology: Minimal change disease (MCD): is the most common cause of nephrotic syndrome in children. It owes its name to the fact that the nephrons appear normal when viewed with an optical microscope as the lesions are only visible using an electron microscope. Another symptom is pronounced proteinuria. Focal segmental glomerulosclerosis (FSGS): is the most common cause of nephrotic syndrome in adults. It is characterized by the appearance of tissue scarring in the glomeruli. The term focal is used as some of the glomeruli have scars, while others appear intact; the term segmental refers to the fact that only part of the glomerulus is damaged. Membranous glomerulonephritis (MGN): The inflammation of the glomerular membrane causes increased leaking in the kidney. It is not clear why this condition develops in most people, although an auto-immune mechanism is suspected. Membranoproliferative glomerulonephritis (MPGN): is the inflammation of the glomeruli along with the deposit of antibodies in their membranes, which makes filtration difficult. Rapidly progressive glomerulonephritis (RPGN): (Usually presents as a nephrotic syndrome) A person's glomeruli are present in a crescent moon shape. It is characterized clinically by a rapid decrease in the glomerular filtration rate (GFR) by at least 50% over a short period, usually from a few days to 3 months.
They are considered to be "diagnoses of exclusion", i.e., they are diagnosed only after secondary causes have been excluded.
Secondary glomerulonephrosis
Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though they may exhibit some differences suggesting a secondary cause, such as inclusion bodies. They are usually described by the underlying cause, such as: Diabetic nephropathy: is a complication that occurs in some diabetics. Excess blood sugar accumulates in the kidneys, causing them to become inflamed and unable to carry out their normal function. This leads to the leakage of proteins into the urine. Systemic lupus erythematosus: this autoimmune disease can affect several organs, among them the kidney, due to the deposit of immunocomplexes that are typical of this disease. The disease can also cause lupus nephritis. Sarcoidosis: This disease does not usually affect the kidney, but on occasions, the accumulation of inflammatory granulomas (collection of immune cells) in the glomeruli can lead to nephrotic syndrome. Syphilis: kidney damage can occur during the secondary stage of this disease (between 2 and 8 weeks from onset). Hepatitis B: certain antigens present during hepatitis can accumulate in the kidneys and damage them.