Nephrotic syndrome

Nephrosis

Last reviewed: September 20, 2011.

Nephrotic syndrome is a group of symptoms that include protein in the urine, low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.

Causes, incidence, and risk factors

Symptoms

Cancer

Diseases such as diabetes, systemic lupus erythematosus, multiple myeloma, and amyloidosis

Genetic disorders

Immune disorders

Infections (such as strep throat, hepatitis, or mononucleosis)

Use of certain drugs

It can occur with kidney disorders such as:

Focal and segmental glomerulosclerosis Glomerulonephritis

Mesangiocapillary glomerulonephritis

Nephrotic syndrome can affect all age groups. In children, it is most common between ages 2 and 6. This disorder occurs slightly more often in males than females.

Swelling (edema) is the most common symptom. It may occur:

In the face and around the eyes (facial swelling)

In the arms and legs, especially in the feet and ankles

In the belly area (swollen abdomen)

Other symptoms include:

Foamy appearance of the urine

Poor appetite Weight gain (unintentional) from fluid retention

Signs and tests

Urinalysis Fats are often also present in the urine. Blood cholesterol and triglyceride levels may be high. A kidney biopsy may be needed to find the cause of the disorder. Tests to rule out various causes may include the following:

Albumin blood test Blood chemistry tests such as basic metabolic panel or comprehensive metabolic panel Blood urea nitrogen (BUN) Creatinine - blood test Creatinine clearance - urine test

Antinuclear antibody Cryoglobulins Complement levels Glucose tolerance test Hepatitis B and C antibodies


Treatment
Treatments:

HIV test

Rheumatoid factor Serum protein electrophoresis (SPEP)

Syphilis serology

Urine protein electrophoresis (UPEP)

This disease may also change the results of the following tests:

Vitamin D level

Serum iron Urinary casts

The goals of treatment are to relieve symptoms, prevent complications, and delay kidney damage. To control nephrotic syndrome, you must treat the disorder that is causing it. You may need treatment for life.

Keep blood pressure at or below 130/80 mmHg to delay kidney damage. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are the medicines most often used. ACE inhibitors may also help decrease the amount of protein lost in the urine.

You may take corticosteroids and other drugs that suppress or quiet the immune system.

Treat high cholesterol to reduce the risk of heart and blood vessel problems. A low-fat, low-cholesterol diet is usually not very helpful for people with nephrotic syndrome. Medications to reduce cholesterol and triglycerides (usually statins) may be needed.

A low-salt diet may help with swelling in the hands and legs. Water pills (diuretics) may also help with this problem.

Low-protein diets may be helpful. Your health care provider may suggest eating a moderate-protein diet (1 gram of protein per kilogram of body weight per day).

You may need vitamin D supplements if nephrotic syndrome is long-term and not responding to treatment.

Blood thinners may be needed to treat or prevent blood clots.

Expectations (prognosis)
The outcome varies. The condition may be acute and short-term or chronic and not respond to treatment. The complications that occur can also affect the outcome. Some people may eventually need dialysis and a kidney transplant.

Complications

Acute kidney failure Atherosclerosis and related heart diseases Chronic kidney disease Fluid overload, congestive heart failure, pulmonary edema Infections, including pneumococcal pneumonia

Malnutrition

Renal vein thrombosis

Calling your health care provider

You have symptoms of nephrotic syndrome

Nephrotic syndrome does not go away

New symptoms develop, including:

Cough Decreased urine output Discomfort with urination Fever Severe headache

Sores on the skin

Go to the emergency room or call the local emergency number (such as 911) if you have convulsions.

Prevention
Treating conditions that can cause nephrotic syndrome may help prevent the syndrome.

References
1. 2. Appel GB. Glomerular disorders and nephrotic syndromes. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 122. Nachman PH, Jennette JC, Falk RJ. Primary glomerular disease. In: Brenner BM, ed. Brenner and Rector's the Kidney. 8th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 30.

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

[edit]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

Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic-range proteinuria is 3 grams per day or more. On a single spot urine collection, it is 2 g of protein per gram of urine creatinine. There are many specific causes of nephrotic syndrome. These include kidney diseases such as minimal-change nephropathy, focal glomerulosclerosis, and membranous nephropathy. Nephrotic syndrome can also result from systemic diseases that affect other organs in addition to the kidneys, such as diabetes, amyloidosis, and lupus erythematosus. Nephrotic syndrome may affect adults and children, of both sexes and of any race. It may occur in typical form, or in association with nephritic syndrome. The latter connotes glomerular inflammation, with hematuria and impaired kidney function.

Classification
Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary, being a renal manifestation of a systemic general illness. In all cases, injury to glomeruli is an essential feature. Primary causes of nephrotic syndrome include the following, in approximate order of frequency:

Minimal-change nephropathy Focal glomerulosclerosis Membranous nephropathy Hereditary nephropathies Secondary causes include the following, again in order of approximate frequency: Diabetes mellitus Lupus erythematosus Amyloidosis and paraproteinemias Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] ) Preeclampsia Nephrotic-range proteinuria may occur in other kidney diseases, such as IgA nephropathy. In that common glomerular disease, one third of patients may have nephrotic-range proteinuria.[1] Nephrotic syndrome may occur in persons with sickle cell disease and evolve to renal failure. Membranous nephropathy may complicate bone marrow transplantation, in association with graft versus host disease. Kidney diseases that affect tubules and interstitium, such as interstitial nephritis, will not cause nephrotic syndrome. The above causes of nephrotic syndrome are largely those for adults, and this article will concentrate primarily on adult nephrotic syndrome. However, nephrotic syndrome in infancy and childhood is an important entity. For discussion of this topic, see the Medscape Reference article Pediatric Nephrotic Syndrome. From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive, steroid resistant, steroid dependent, or frequently relapsing. Corticosteroids (prednisone), cyclophosphamide, and cyclosporine are used to induce remission in nephrotic syndrome. Diuretics are used to reduce edema. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are administered to reduce proteinuria. (See Treatment and Medication.)

Pathophysiology
In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier. [2] Controversy exists regarding the sieving of albumin across the glomerular permeability barrier. On the basis of studies in experimental animals, it has been proposed that there is ongoing albumin passage into the urine, in many grams per day, with equivalent substantial tubular uptake of albumin, the result being that the urine has 80 mg per day or less of daily albumin.[3] However, studies of humans with tubular transport defects suggest that the glomerular urinary space albumin concentration is 3.5 mg/L.[4] With this concentration, and a normal daily glomerular filtration rate (GFR) of 150 liters, one would expect no more than 525 mg per day of albumin in the final urine. Amounts above that level point to glomerular disease. The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which envelops the capillaries with cellular extensions called foot processes. In between the foot processes are the filtration slits. These 3 structuresthe fenestrated endothelium, glomerular basement membrane, and glomerular epithelium are the glomerular filtration barrier. A schematic drawing of the glomerular barrier is provided in the image below.

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Filtration of plasma water and solutes is extracellular and occurs through the endothelial fenestrae and filtration slits. The importance of the podocytes and the filtration slits is shown by genetic diseases. Thus, in congenital nephrotic syndrome of the Finnish type, the gene for nephrin, a protein of the filtration slit, is mutated, leading to nephrotic syndrome in infancy . Similarly, podocin, a protein of the podocytes, may be abnormal in a number of children with steroid-resistant focal glomerulosclerosis. The glomerular structural changes that may cause proteinuria are damage to the endothelial surface, the glomerular basement membrane, or the podocytes. One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take place. Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative charge, and it is proposed that loss of glomerular membrane negative charges could be important in causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not involve changes in glomerular net charge but rather a generalized defect in permeability. This construct does not permit clear-cut separation of causes of proteinuria, except in minimal-change nephropathy, in which proteinuria is selective.

Pathogenesis of edema
An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water throughout the body and thus the development of edema. Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. The oncotic pressure is mainly determined by the protein content. The flux of water across the capillary wall can be expressed by the following formula: Qw = K ([Pc - Pi] - [pp - pi] In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is capillary hydrostatic pressure, and Pi is the interstitial fluid hydrostatic pressure, while pp is the plasma oncotic pressure, and pi is the interstitial fluid oncotic pressure. With a high enough capillary hydrostatic pressure or a low enough intravascular oncotic pressure, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In patients with nephrotic syndrome, this causes a reduction in plasma volume, with a secondary increase of sodium and water retention by the kidneys. An alternative hypothesis is that a condition of renal sodium retention occurs because of the proteinuria, but this is not related to intravascular volume or to serum protein concentration. The evidence supporting this so-called overfill hypothesis includes the facts that (1) sodium retention is observed even before the serum albumin level starts falling and (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome. This could occur if intraluminal protein directly stimulated renal epithelial sodium reabsorption. [5] A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome.[6] This would then lead to increased tissue oncotic pressure and fluid retention in the peripheral tissues.

Metabolic consequences of proteinuria

Infection Hyperlipidemia and atherosclerosis Hypocalcemia and bone abnormalities Hypercoagulability Hypovolemia Acute renal failure may indicate an underlying glomerulonephritis but is more often precipitated by hypovolemia or sepsis. Edema of the kidneys that causes a pressure-mediated reduction in the GFR has also been hypothesized. Hypertension related to fluid retention and reduced kidney function may occur. Failure to thrive may develop in patients with chronic edema, including ascites and pleural effusion. Failure to thrive may be caused by anorexia, hypoproteinemia, increased protein catabolism, or frequent infectious complications. Edema of the gut may cause defective absorption, leading to chronic malnutrition. Infection Infection is a major concern in nephrotic syndrome; patients have an increased susceptibility to infection with Streptococcus pneumoniae,Haemophilus influenzae, Escherichia coli, and other gram-negative organisms. Varicella infection is also common. The most common infectious complications are bacterial sepsis, cellulitis, pneumonia, and peritonitis. Proposed explanations include the following:

Urinary immunoglobulin losses Edema fluid acting as a culture medium Protein deficiency Decreased bactericidal activity of the leukocytes Immunosuppressive therapy Decreased perfusion of the spleen caused by hypovolemia Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria Hyperlipidemia and atherosclerosis Hyperlipidemia may be considered a typical feature of the nephrotic syndrome, rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of lipoproteins.[7] In addition, reduced plasma levels of lipoprotein lipase results in diminution of lipid catabolism. Some of the elevated serum lipoproteins are filtered at the glomerulus, leading to lipiduria and the classical findings of oval fat bodies and fatty casts in the urine sediment.

Atherosclerotic vascular disease appears to occur in greater frequency in persons with nephrotic syndrome than in healthy persons of the same age. Curry and Roberts showed that the frequency and extent of coronary artery disease stenoses were greater in patients with nephrotic syndrome than in nonnephrotic control subjects. [8] When their study was published, in 1977, lipid-lowering treatments were less widely used than they are today. Accordingly, the average highest serum total cholesterol in this series was over 400 mg/dL. That is in the range of serum cholesterol seen in familial hypercholesterolemia, a disease that predisposes individuals to myocardial infarction. Hypocalcemia Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia, it is usually caused by a low serum albumin level. Nonetheless, low bone density and abnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin Dbinding proteins, with consequent hypovitaminosis D and, as a result, reduced intestinal calcium absorption.[9] Tessitore et al reported that when the GFR was normal, persons with the nephrotic syndrome had no consistent calcium or bony abnormalities.[10] Yet in that same study, when the GFR was reduced, bone mineralization defects were found by biopsy. A later study found osteomalacia on bone biopsy in over half of adults who had longstanding nephrotic syndrome but whose GFR was preserved.[9] A further complication derives from therapies, especially prednisone use. Low bone mass may be found in relation to cumulative steroid dose.[11] This subject remains controversial; as reported by Leonard et al, intermittent corticosteroid treatment of childhood steroid-sensitive nephrotic syndrome does not appear to be associated with bone mineral deficits.[12] It is possible that long duration of either the nephrotic syndrome or treatments for it are the important risk factors for bone disease in these patients. Hypercoagulability Venous thrombosis and pulmonary embolism are well-known complications of the nephrotic syndrome. Hypercoagulability in these cases appears to derive from urinary loss of anticoagulant proteins, such as antithrombin III and plasminogen, along with the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X. A study by Mahmoodi et al of almost 300 patients with nephrotic syndrome confirmed that venous thromboembolism (VTE) was almost 10 times higher in these persons than in the normal population (1% vs 0.10.2%).[13] Moreover, that risk appeared especially elevated during the first 6 months of nephrotic syndrome, being at almost 10%. This high incidence may justify the routine use of preventive anticoagulation treatment during the first 6 months of a persistent nephrotic syndrome. Mahmoodi's study also showed an increased risk of arterial thrombotic events, including coronary and cerebrovascular ones, in nephrotic syndrome. Unlike the risk of VTE, which was related to proteinuria, this arterial risk was related to usual risk factors for arterial disease, such as hypertension, diabetes, smoking, and reduced GFR. Hypovolemia Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL. Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet, delayed capillary filling, oliguria, and tachycardia. Hypotension is a late feature.

n the preantibiotic era, infection was a major factor in the mortality rate among patients with nephrotic syndrome. [26] Treatments for nephrotic syndrome and its complications appear to have reduced the morbidity and mortality once associated with the syndrome. Currently, the prognosis for patients with primary nephrotic syndrome depends on its cause. Infants with congenital nephrotic syndrome have a dismal prognosis: survival beyond several months is possible only with dialysis and kidney transplantation. Only approximately 20% of patients with focal glomerulosclerosis undergo remission of proteinuria; an additional 10% improve but remain proteinuric. Many patients experience frequent relapses, become steroiddependent, or become steroid-resistant. End-stage renal disease develops in 25-30% of patients with focal segmental glomerulosclerosis by 5 years and in 30-40% of these patients by 10 years. The prognosis for patients with minimal-change nephropathy is very good. Most children respond to steroid therapy; still, about 50% of children have 1 or 2 relapses within 5 years and approximately 20% of them continue to relapse 10 years after diagnosis. Only 30% of children never have a relapse after the initial episode. Approximately 3% of patients who initially respond to steroids become steroid-resistant. Adults with minimal-change nephropathy have a burden of relapse similar to that of children. However, the long-term prognosis for kidney function in patients with this disease is excellent, with little risk of renal failure. Poor patient response to steroid therapy may predict a poor outcome. Children who present with hematuria and hypertension are more likely to be steroid-resistant and have a poorer prognosis than are those who do not present with these conditions. A study by Donadio et al of 140 patients with idiopathic membranous nephropathy, 89 of whom received no treatment with corticosteroids or immunosuppressive drugs and 51 of whom were treated primarily with short-term courses of prednisone alone, found that survival rates in these patients were the same as those expected for the general population.[27] The prognosis may worsen because of (1) an increased incidence of renal failure and the complications secondary to nephrotic syndrome, including thrombotic episodes and infection, or (2) treatment-related conditions, such as infectious complications of immunosuppressive treatments. In secondary nephrotic syndromes, morbidity and mortality are related to the primary disease process (eg, diabetes, lupus, amyloidosis). In diabetic nephropathy, however, the magnitude of proteinuria itself relates directly to mortality.[28] In diabetic nephropathy with nephrotic syndrome, there is usually a good response to angiotensin blockade, with reduction of proteinuria to low, sub-nephrotic levels. True remission is uncommon, however. Cardiovascular morbidity and mortality increase as kidney function declines, and some patients will eventually need dialysis or a kidney transplant. In primary amyloidosis, prognosis is not good, even with intensive chemotherapy. In secondary amyloidosis, remission of the underlying cause, such as rheumatoid arthritis, is followed by remission of the amyloidosis and its associated nephrotic syndrome.