Patient Information: the Nephrotic Syndrome

Patient information: The nephrotic syndrome

Burton D Rose, MD Harvard Medical School

UpToDate performs a continuous review of over 330 journals and other resources. Updates are added as important new information is published. The literature review for version 12.2 is current through April 2004; this topic was last changed on January 18, 2002. The next version of UpToDate (12.3) will be released in October 2004.

These materials are for your general information and are not a substitute for medical advice. You should contact your physician or other healthcare provider with any questions about your health, treatment, or care. Do not contact UpToDate or the physician authors of these materials.

The term nephrotic syndrome refers to a distinct constellation of clinical and laboratory features of kidney (renal) disease. This syndrome may occur in association with a wide variety of primary kidney diseases as well as systemic diseases, such as diabetes mellitus.

Nephrotic syndrome is specifically defined by the presence of:

 Heavy proteinuria (high levels of protein in the urine)  Hypoalbuminemia (low levels of the protein albumin in the blood)  Peripheral edema (swelling of the legs and ankles due to the abnormal collection of fluids in the tissues)

Hyperlipidemia (high blood cholesterol levels) is also common and thrombotic disease (diseases involving the formation of blood clots in different areas of the body, such as the veins and arteries) can occur.

PATHOGENESIS — Nephrotic syndrome results from damage to the glomeruli, the structures in the kidneys that play a role in filtering blood. This damage permits proteins in the blood to leak into the urine, causing proteinuria. (See "Patient information: Protein in the urine (proteinuria)"). Due to alterations in normal self-regulatory mechanisms, hypoalbuminemia and edema eventually result.

DIAGNOSIS — The diagnosis of nephrotic syndrome is made from a number of tests, including analysis of the urine, blood tests, and a renal (kidney) biopsy. In most cases, a renal biopsy is required to establish the diagnosis. (See "Patient information: Renal biopsy").

Urine tests — Examination of a patient's urine can reveal abnormal amounts of protein in the urine (proteinuria). Protein excretion is generally measured with a 24-hour urine collection. A normal value of protein in the urine is less than 150 mg/day. Patients excreting more than 3 g/day are considered to have heavy proteinuria that is in the range of nephrotic syndrome.

Blood tests — A number of blood tests are often obtained in the evaluation of patients who have nephrotic syndrome. The results of some tests can uncover the underlying cause of the nephrotic syndrome, precluding the need for renal biopsy.

Renal biopsy — Renal biopsy is the standard procedure for determining the cause of heavy proteinuria. Close inspection of tissue obtained will reveal the specific disorder.

CAUSES — Heavy proteinuria and the nephrotic syndrome may occur in association with a wide variety of primary and systemic diseases. Minimal change disease is the predominant cause in children. In adults, approximately 30 percent have a systemic disease such as diabetes mellitus or systemic lupus erythematosus; the remaining cases are usually due to primary kidney disorders such as minimal change disease, focal glomerulosclerosis, and membranous nephropathy.

Minimal change disease — Minimal change disease (also called nil disease or lipoid nephrosis) is a primary kidney disease that accounts for 90 percent of cases of the nephrotic syndrome in children under the age of 10, and more than 50 percent of cases in older children. It can occur in adults as a primary condition, in association with the use of nonsteroidal antiinflammatory drugs (NSAIDs), or as an associated effect of malignancy, most often Hodgkin's disease.

The terms minimal change and nil disease reflect the observation that the findings with light microscopy on kidney tissue are either normal or reveal only a very mild abnormality of the glomeruli. Although the cause of primary disease is unknown, it is thought to result from an abnormal immune process.

Focal glomerulosclerosis — Focal glomerulosclerosis (FGS) is the most common cause of the nephrotic syndrome in adults, accounting for 35 percent of all cases and over 50 percent of cases among blacks. FGS can present as a primary syndrome (primary FGS) or may be associated with other conditions (secondary FGS).

FGS is characterized on renal biopsy by the presence in some but not all glomeruli (hence the name focal) of collapse and scarring. The cause of primary disease is unknown, although a few cases appear to result from a genetic defect.

There is a subtype of FGS called collapsing FGS, which most often occurs in blacks. This disorder was first described in HIV-infected patients, but can occur in those without HIV infection.

Membranous nephropathy — Membranous nephropathy is the second most common cause of primary nephrotic syndrome in adults. It is most frequently unrelated to other diseases, although it can be associated with hepatitis B infection, autoimmune diseases, thyroid disease, and the use of certain drugs. An underlying malignancy has been thought to be responsible for some cases of membranous nephropathy in adults, most often a solid tumor. In almost all such patients, the existence of the malignancy is already known by the time that proteinuria is discovered or there are signs suggestive of a possible malignancy such as weight loss or blood in the stool.

Diabetes mellitus — Kidney disease in patients with diabetes mellitus is a common problem that is most likely to occur in those who have poor blood glucose control or hypertension. It is also more common among blacks, Mexicans, and Pima Indians. The risk of kidney disease is roughly equivalent in both type 1 and type 2 diabetes. The earliest clinical manifestation is microalbuminuria (which is defined as persistent urine protein values between 30 and 300 mg/day), a stage at which the kidneys may appear to be relatively normal. Over time, many patients with this early sign develop progressive kidney dysfunction, including nephrotic syndrome.

Systemic lupus erythematosus — Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect the multiple organs of the body, including the kidney. Distinct immunologic abnormalities, especially the production of a number of antibodies directed against body proteins, are another prominent feature of the disease.

Patients with SLE may develop nephrotic syndrome, which is commonly due to a similar pathogenic mechanism as that observed with membranous nephropathy.

CLINICAL MANIFESTATIONS — Edema, poor nutrition, kidney failure, blood clots, and infections are the principal manifestations of the nephrotic syndrome.

Edema — Two common symptoms of edema are swelling in and around the lining of the eye socket upon waking in the morning, and swelling in the feet that is most prominent when upright.

Poor nutrition — A loss in body mass often occurs in patients with marked proteinuria, although it may be masked by concurrently increasing edema. This may be compounded by gastrointestinal symptoms of appetite loss and vomiting that are secondary to edema of the gastrointestinal tract.

Kidney failure — Some patients with the nephrotic syndrome develop a gradual decline in renal function, which is initially asymptomatic. However, different signs and symptoms may be observed with advanced renal dysfunction, including volume overload, elevated potassium concentrations, hypertension (high blood pressure), anemia (low red blood cell count), and bone disease.

Acute renal failure can also develop in some patients with the nephrotic syndrome, particularly in those who have minimal change disease. Though it is not understood why this may happen, it has been suggested that several factors, including low blood volume, swelling of kidney tissues, injury to the tubules in the kidneys due to lack of blood flow, and the use of nonsteroidal antiinflammatory drugs, may play a role.

Blood clots — As discussed in detail below, patients with the nephrotic syndrome have an increased incidence (10 to 40 percent of patients) of arterial and venous blood clots that block blood flow (thromboemboli), particularly deep vein and renal vein thrombosis.

Thrombosis of the renal vein is found disproportionately in patients with membranous nephropathy. It can present suddenly with flank pain and blood in the urine or, much more commonly, develop slowly over time and cause no symptoms.

Infection — Patients with the nephrotic syndrome are susceptible to infection. Before antibiotics became available, they were the leading cause of death decades ago in children with the nephrotic syndrome. Pneumococcal infections, especially peritonitis (an infection within the abdomen), were particularly common. It is not well understood why the body's normal defense mechanisms are impaired with the nephrotic syndrome.

TREATMENT — The first line of treatment in nephrotic syndrome is to treat the underlying disease that is causing the nephrotic syndrome. In addition, almost all patients are given an angiotensin converting enzyme (ACE) inhibitor, a commonly used antihypertensive drug that is generally well tolerated and may protect against progressive disease.

Diabetes mellitus — The optimal therapy of diabetic kidney disease continues to evolve. The best approach may be intensive combined therapy, thereby targeting the many factors underlying the disease, including elevated glucose and lipid levels, and hypertension. Aggressive antihypertensive therapy frequently slows, particularly with ACE inhibitors, and may halt disease progression.

Systemic lupus erythematosus — Lupus patients with nephrotic syndrome or signs of progressive renal insufficiency can be treated with corticosteroids and other immunosuppressive agents. Most patients respond well to such a regimen.

Minimal change disease — Patients with minimal change disease almost always respond to steroid therapy. Some patients have one or more relapses and some become steroid-dependent, in which case other therapies can be used.

Focal glomerulosclerosis — Steroid therapy is recommended for primary FGS. The success of steroid therapy strongly depends upon the initial responsiveness of the disease to treatment. Secondary FGS is treated only with ACE inhibitors. The optimal therapy of collapsing FGS is uncertain.

Membranous nephropathy — The course of membranous nephropathy is variable. Without treatment, spontaneous remission occurs in approximately 5 to 20 percent of cases, partial remission in 25 to 40 percent, and 40 percent develop a slowly progressive loss of renal function. Optimal therapy for membranous nephropathy is therefore difficult to determine, as it is uncertain if the benefits of corticosteroid and cytotoxic therapy (immunosuppressive therapy) outweigh the risks, and there is not definitive evidence that cytotoxic drugs alter the long-term course of the disease.

Given the high rate of complete or partial spontaneous remission, most patients without severe symptoms or complicated nephrotic syndrome are followed without specific immunosuppressive therapy for a prolonged period. By comparison, those with more severe disease are usually treated with immunosuppressive therapy.

Symptoms and signs of the nephrotic syndrome — In addition to treating the underlying disease or diseases, sometimes the specific symptoms of the nephrotic syndrome are targeted for treatment.

Proteinuria — In the absence of specific therapy directed against the underlying disease, efforts to lower pressure in the glomeruli and decrease the level of proteinuria may slow the rate of disease progression. This is usually achieved by the administration of an ACE inhibitor. Although protein restriction through the diet may also slow disease progression, this has not been definitively established and is not usually used in nephrotic patients because of concerns about malnutrition.

Edema — Peripheral edema and ascites (an abnormal collection of fluid in the abdomen) in most patients is due to sodium retention by the kidneys and should be treated with dietary sodium restriction and water pills (diuretics). Edema should be reversed slowly.

Elevated blood lipids — The increase in blood cholesterol that are often seen with the nephrotic syndrome reverse when the disease resolves. When the nephrotic syndrome persists, attempts are typically made to lower blood cholesterol. Dietary modification is generally of little benefit, so most patients are initially treated with a lipid lowering drug. These are usually from the class of drugs called statins. (See "Patient information: Hyperlipidemia").

Thrombotic disease — Some researchers have suggested that blood thinners should be given as a preventative measure to the patient with membranous nephropathy due to the increased incidence of blood clots that block blood flow in arteries and veins (thromboemboli). However, this is not standard practice in the usual patient. If thrombosis occurs (ie, a blood clot forms in a blood vessel), the patient is typically treated with blood thinners, such as warfarin (Coumadin), for as long as the nephrotic syndrome persists.