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Overview

Nephrotic syndrome (NS) is a condition that is often caused by any of a group of diseases that damage the kidneys’ filtering system, the glomeruli. The structure of the glomeruli prevents most protein from getting filtered through into the urine. Normally, a person loses less than 150 mg of protein in the urine in a 24-hour period. Nephrotic-range proteinuria, the urination of more than 3.5 grams of protein during a 24-hour period, or 25 times the normal amount, is the primary indicator of NS.

Incidence and Prevalence
About two in every 10,000 people experience nephrotic syndrome. Nephrotic syndrome prevalence is difficult to establish in adults because the condition is usually a result of an underlying disease. In children, it is diagnosed in more boys than girls, usually between 2 and 3 years of age.

Signs and Symptoms

In addition to proteinuria, there are three main symptoms of nephrotic syndrome associated with protein leaking into the urine:

• Hypoalbuminemia (low level of albumin in the blood)
• Edema (swelling)
• Hypercholesterolemia (high level of cholesterol in the blood)

Hypoalbuminemia is a low level of albumin (a protein) in the blood due to proteinuria. Low albumin in the blood causes fluid to move from the blood into the tissue, causing swelling. The kidney perceives the decrease of fluid in the blood and aggressively retains as much fluid and salt as it can. This contributes to the body’s fluid-overload state.

Nephrotic-related swelling makes tissue puffy, soft, and impressionable to the touch. Edema is most common in the legs and feet, especially after standing all day. It can cause feelings of tightness in the extremities and may affect mobility. In later stages, swelling may occur in the abdomen (ascites), hands, and around the eyes in the morning (called periorbital edema). In later stages, the whole body may swell (anasarca). Some people gain weight after fluid builds up in their bodies for a long time.

Hypercholestrolemia, high blood cholesterol, is common in nephrotic syndrome). In addition to albumin, other important enzymes involved in cholesterol metabolism slip through the glomeruli, which contribute to high blood cholesterol.

Complications
Nephrotic syndrome is associated with renal failure. The disease that causes NS can damage the glomeruli and can interfere with their ability to clean the blood. The edema that is present in the legs may also be occurring in the kidney tissue itself and can interfere with the kidneys’ ability to clean the blood. Renal failure can either be gradual (CRF) or acute (ARF).

A hypercoaguable state, in which the blood abnormally overclots, is also seen in some patients with NS. This means that they are at risk for developing a blood clot in the legs or in the renal veins that transport blood from the kidney. Some patients take blood thinners to prevent this complication.

Causes

There are a number of different disorders that can cause NS. Diabetes and, to a lesser extent, hypertension can cause diffuse damage to the glomeruli and can ultimately lead to NS.

The following diseases can cause specific damage to the glomeruli and often result in the development of heavy proteinuria and in many instances NS:

• Amyloidosis (the stiffening and subsequent malfunction of the kidney due to fibrous protein deposit in the tissue)
• Congential nephrosis
• Focal segmental glomerular sclerosis (FSGS) (creates scar tissue in the glomerulus, damaging its protein-repellant membrane)
• Glomerulonephritis (GN)
  • Diffuse mesangial proliferative GN (affecting the messangium)
  • Membranous (damages the protein-repellant membrane)
  • Postinfectious (occurs after an infection)
• IgA nephropathy (Berger’s disease) (deposit of specific immunoglobulin A causing an inflammatory reaction and leading to glomerulonephritis)
• Minimal change disease (Nil’s disease)
• Pre-eclampsia (rarely associated with NS, more often associated with heavy proteinuria)

Many of these diseases tend to occur more often in certain age groups:

• Less than 1yr old
  • Congenital nephrosis
• Less than 15 years old
  • Min change
  • FSGS
  • Other
• Age 15 to 40
  • Min change
  • FSGS
  • Other
• Over age 40
  • Membranous GN
  • Diabetic nephropathy
• Over 60
  • Amyloidosis may account for up to 20% of cases

Diagnosis

In addition to a physical examination and the assessment of family health history, the following three tests are used to make a diagnosis:

• Blood analysis
• Urinalysis
• Kidney biopsy

Blood analysis often shows high cholesterol levels and low albumin. BUN and creatinine may or may not be elevated. If bun and creatinine are elevated the patient has renal failure and the prognosis is worse.

Evaluation of the urine by a simple urine dipstick in the office can give preliminary information on the amount of protein in the urine. However, this test is a qualitative test. In order to determine the actual amount of protein in the urine, a 24-hour quantitative test must be done, which indicates levels of protein and creatinine in the urine. Often, a comparison of protein to creatinine based on a single sample is used to determine 24-hour protein loss. This is helpful for quicker results or when the patient cannot collect urine over 24 hours.

A closed kidney biopsy may be used to determine the underlying cause and extent of disease with the exception of the following cases.

1.       Children with NS most often have minimal change disease and respond well to a short course of steroids. A biopsy should only be considered if they do not show a favorable response to the steroids within 6-8 weeks.

2.       Adult patients with a history of diabetes who have tested negative to other disorders such as myeloma, infections, and collagen vascular diseases. It is presumed the cause of the proteinuria is diabetic nephropathy and a kidney biopsy is not necessary. If the duration of diabetes has been short or the severity of the NS is profound, a kidney biopsy is considered.

3.       Elderly patients, patients who are not expected to live long, or those for whom immunosuppressive drug therapy is not advisable are typically not candidates for a biopsy.

Treatment

Nonspecific treatment of nephrotic syndrome is aimed at complications like hypertension. Specific treatment addresses underlying causes, which are determined by kidney biopsy.

Nonspecific Treatment
Controlling hypertension is essential in reducing proteinuria. This is accomplished with angiotensin converting enzyme (ACE-1) inhibitors. ACE-1 inhibitors are the preferred blood pressure lowering medication because they provided added protection to the kidneys. These drugs interfere with the production of angiotensin II (AII), a chemical (vasoactive) produced in the body. AII causes vascular constriction, which increases blood pressure, including pressure in the glomeruli. This causes scarring of the kidney and exacerbates proteinuria, which accelerates the loss of renal function. ACE-1 inhibitors encourage circulation, lower blood pressure in the body, and decrease pressure in the glomeruli. This decreases protein spillage and helps to delay progressive scarring of the glomeruli.

Patients with hypertension benefit from ACE-1 inhibitors, as aggressive blood pressure control is key to protecting the kidneys and the cardiovascular system. The goal is to lower the systolic blood pressure below 130 and the diastolic below 80.

ACE-1inhibitors cause a dry cough in approximately 8% of patients who take them.

ACE-1 inhibitors are given in the highest dose tolerable to ensure kidney protection. If a patient develops a cough, a new class of drugs may be used, known as angiotensin receptor blockers (ARB). ARBs work by blocking angiotensin receptors, which blocks the effects of angiotensin after it is produced. They offer the same kidney protection as ACE-1 inhibitors without causing cough. If tolerable, ARBs may be combined with an ACE-1 inhibitor for added benefit.

Treating hypercholesterolemia (high cholesterol) typically involves medication and proper diet.

It is generally considered healthy to eat one gram of protein daily for every kilogram of body weight; physicians usually help their patients define a diet that is appropriate for kidney health.

Specific Treatment
Specific treatment is given for the following underlying causes of nephrotic syndrome:

• Diabetes
• Glomerular disease
• Minimal change disease
• Renal failure

Treating minimal change disease in children usually involves the use of diuretics to reduce edema and a corticosteroid called prednisone (Liquid Pred®), which usually resolves proteinuria in a couple of weeks. Corticosteroids heal the ongoing damage at the level of the glomerular basement membrane (i.e., they patch the holes that are allowing the proteins to leak through).

About 30% of children treated with prednisone have no recurrence of disease, roughly 20% relapse after several months, and the remaining 50% relapse a short time after discontinuing the medication.

Prognosis
The outcome of NS varies and is largely dependent on the underlying cause. Some patients may have a spontaneous recovery not requiring any specific therapy, while others worsen despite aggressive, specific therapy.

Complications that can arise during treatment include atherosclerosis "hardening of the arteries" and adverse reaction to medications such as steroids. Some severe side effects that can occur with the use of steroids include osteoporosis, cataract development, increased risk of infection, and diabetes.

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