Management of Nephrotic Syndrome in Children

Nephrotic syndrome is a common disease in children. Minimalchange disease remains the most frequent cause, but a careful evaluation to exclude other renal conditions is important, particularly to distinguish between isolated nephrotic syndrome and nephrotic syndrome with nephritis. Corticosteroids and sodium restriction form the mainstay of therapy. Although most patients with isolated nephrotic syndrome recover quickly without major sequelae, the physician must remain alert for signs and symptoms of serious complications. Detailed patient and family education, along with close follow-up and support, will help ensure the best outcomes.

Robert S. Gillespie, MD, MPHPediatric Nephrologist

Driscoll Children's Hospital

Assistant Professor of Pediatrics

College Station, Tex

PRACTICE POINTS

• The classic triad of proteinuria, hypoproteinemia, and edema defines the nephrotic syndrome.
• A urinalysis with microscopic examination is the single most useful diagnostic test.
• Counsel parents and patients to expect several relapses during the childhood years.

Nephrotic syndrome is one of the more common renal disorders encountered in children in the primary care setting. Most patients have a favorable response to treatment, which can lead to the misconception that it is a minor, benign illness. In reality, the care of children with nephrotic syndrome requires diligence, patience, and long-term follow-up.

This review will focus exclusively on children with high-grade proteinuria but no hematuria. Management of adults with nephrotic syndrome differs in many respects.

Clinical Features

Children of any age can develop nephrotic syndrome, but typically patients are between the ages of 18 months and 8 years. Boys appear to be affected more frequently than girls. Nephrotic syndrome describes a constellation of findings, not a specific disease process. The classic triad of proteinuria, hypoproteinemia, and edema defines the syndrome. Other features, such as hypercholesterolemia, hypertension, or hyponatremia, are often present but are not essential for diagnosis.

The vast majority of children with clinical findings of nephrotic syndrome have a histologic diagnosis of minimal-change disease, so named because these children have normal or near-normal biopsy findings on light microscopy. Electron microscopy shows characteristic changes in the glomerular podocyte foot processes and slit diaphragm. The cause of this disease and the exact relationship between the histopathologic and clinical findings remain unclear. Decades of experience have shown that in children with typical presentations, one can usually presume this diagnosis and begin treatment accordingly. Although a reasonable and evidence-based practice, this can lead to a misconception that nephrotic syndrome and minimal-change disease are synonymous. Nephrotic syndrome is a clinical finding associated with many renal diseases, just as a cardiac murmur is a clinical finding associated with many different types of heart disease.

A basic physical examination and urinalysis can help differentiate patients into 1 of 5 clinical groupings (Table 1).

Etiology

Minimal-change disease accounts for the majority of uncomplicated nephrotic syndrome cases in children. A small percentage of patients has focal segmental glomerulosclerosis (FSGS), and a much smaller percentage has a variety of other diseases. Recent data have indicated an increased incidence of FSGS, although the reasons are unknown.¹

Diagnosis

Physical examination

Physical examination should include careful documentation of edema in all parts of the body, not just in the lower extremities. Edema can shift, depending on the position of the body. A supine patient may have marked ascites but no lower-extremity edema; an ambulatory patient may show more prominent leg edema. When evaluating a patient suspected of nephrotic syndrome, always examine for genital edema, an especially uncomfortable condition. The presence of rash, purpura, petechiae, or arthritis suggests a multisystem disease with renal involvement rather than isolated nephrotic syndrome.

Renal biopsy

Although nephrologists routinely perform renal biopsies in adults with new-onset nephrotic syndrome, the overwhelming prevalence of minimal-change disease and the prognostic value of a therapeutic trial of corticosteroids make biopsy unnecessary in most children with nephrotic syndrome. Patients with evidence of nephritis or other atypical or "red flag" clinical features (Table 2) or those who do not respond to therapy may, however, require renal biopsy.

In practice, response to corticosteroid therapy is usually more significant than the histologic diagnosis in terms of management and outcome. Patients who improve with corticosteroid therapy have a more favorable prognosis, whereas those who do not remain at a much greater risk for progressive renal disease, regardless of histologic findings. Renal biopsy is also subject to sampling error; since only a few glomeruli are collected, a biopsy specimen may not include any diseased glomeruli in a patient with FSGS, creating a false impression of minimal-change disease.

Laboratory testing

A urinalysis with microscopic examination is the single most useful diagnostic test. In a patient with nephrotic syndrome, it would show an elevated protein level without other abnormalities. A small amount of blood (<5 red blood cells per high-power field) in the urine is normal, but high-grade hematuria, red blood cell casts, or white blood cells should raise suspicion for nephritis or another serious renal disease. In a patient with obvious nephrotic syndrome, quantifying urinary protein with a urine protein:creatinine ratio or 24-hour urine protein rarely adds clinically useful information.

Serum albumin concentration will be low?often very low (<1.5 g/dL or below the laboratory's threshold of detection). Hypoalbuminemia invariably reduces total serum calcium because of a loss of the albumin-bound fraction. However, the ionized portion of the total calcium may remain normal or near-normal; the ionized calcium atoms are more clinically significant than the albumin-bound portion, because only the ionized calcium is available to cells. A simple formula for calculating the corrected total calcium value is: 4 minus the serum albumin (in g/dL) plus total serum calcium (in mg/dL). For example, if total calcium is 6 mg/dL, and serum albumin is 1 g/dL, then 4 -1 = 3. Adding 3 to the total calcium of 6 mg/dL yields a corrected serum calcium value of 9 mg/dL. Obtain an ionized calcium level if true hypocalcemia is a concern.

Small elevations in blood urea nitrogen (BUN) and creatinine often reflect the intravascular volume depletion typical of nephrotic syndrome and may not be clinically important. Large elevations in BUN and creatinine, hyperkalemia, and/or acidosis suggest renal insufficiency and should markedly increase the index of suspicion for other diseases.

Cholesterol levels are typically elevated because of a loss of the serum lipoproteins responsible for lipid metabolism. However, serum lipid values are of little use in the initial management, since lipidlowering therapy is seldom indicated in this setting, and the abnormalities will resolve with remission of the nephrotic syndrome.

Serologic tests, such as antinuclear antibodies, complement C3 and C4, antistreptolysin O, anti-DNase B, or Streptozyme, should be reserved for patients with findings suggestive of nephritis, which is beyond the scope of this article. In these settings, a brief phone consultation with a nephrologist may be helpful for selecting the initial laboratory evaluation. These tests are not indicated in a patient with uncomplicated nephrotic syndrome without evidence of nephritis.

Imaging studies

Imaging studies provide little useful information in uncomplicated nephrotic syndrome and are unnecessary in most cases. Renal ultrasound will be normal, because the pathologic changes of nephrotic syndrome occur at a microscopic level. Small pleural effusions are common but seldom affect respiratory function. Imaging studies should be ordered only if clinical findings suggest a significant concern, such as respiratory impairment or congestive heart failure.

Treatment

The following treatment guidelines apply only to patients with clinical features suggestive of minimal-change disease. Patients believed to have other renal diseases should undergo additional diagnostic workup, usually including renal biopsy, and may require alternative management. The treatment algorithm (Figure) summarizes the approach to the child with minimal-change disease.

The majority of children can be managed as outpatients, but some do require hospitalization (Table 3).

Steroids

The oral corticosteroids prednisone (eg, Deltasone, Meticorten, Orasone) and prednisolone (Table 4) form the mainstay of treatment for minimal-change disease.² The specific treatment protocol varies widely among centers; a widely used evidence-based protocol (Table 5) is derived from a German study.³

Many experts recommend performing a purified protein derivative test for tuberculosis before initiating corticosteroid therapy. Lengthening the initial course of treatment appears to increase the interval between relapses.⁴ Steroid nonresponsiveness is defined as no improvement after 6 to 8 weeks of fulldose prednisone, but in practice, a lack of significant improvement after 3 to 4 weeks warrants concern and early referral to a nephrologist.

Potential adverse effects of prednisone therapy, in addition to obesity, include acne, hirsutism, striae, emotional lability, hyperactivity, and loss of bone mineral content. Patient and family education and follow-up can help minimize adverse effects, most of which improve or resolve with the discontinuance of prednisone.

Nonsteroidal agents

Nonsteroidal agents also shown to be effective in minimal-change disease include oral cyclophosphamide (Cytoxan), cyclosporine (Gengraf, Neoral, Sandimmune), and levamisole (Ergamisol).⁵ Promising but less well-studied therapies include mycophenolate (CellCept, Myfortic),⁶ tacrolimus (Prograf),⁷ and intravenous (IV) cyclophosphamide (Cytoxan, Neosar).⁸ All these nonsteroidal agents constitute second-line therapy and are reserved for patients who do not respond to steroids, who require excessive courses of steroids, or who experience significant steroid toxicity. They should be prescribed only under the guidance of a nephrologist who is experienced in their use.

Dietary restriction

Dietary education is critical. Sodium restriction significantly reduces water retention and edema. Corticosteroids stimulate a voracious appetite, and education on low-fat foods and healthy snacks can help reduce the potential for fatty weight gain during treatment. Dietary protein restriction has no role in the management of nephrotic syndrome and will not reduce proteinuria.

Other options

Diuretics, primarily furosemide (Lasix) and/or metolazone (Mykrox, Zaroxolyn), can be of great value in patients with severe edema. Patients taking diuretics require careful follow-up as well as laboratory monitoring.

IV albumin infusions followed by furosemide yield only transient improvement in edema. The albumin leaves through the urine almost as quickly as it infuses. In addition, IV albumin can exit the pulmonary capillaries and create or exacerbate pulmonary edema. Therefore, albumin and furosemide infusions should be reserved for rare special situations, in consultation with a physician experienced in the management of this condition. Inducing remission of the primary disease remains the most important long-term strategy for managing edema.

Educate the parents

Always counsel parents and patients to seek medical attention if the child develops abdominal pain or fever, or appears ill. Complications related to nephrotic syndrome can be severe and even life-threatening, so the physician must evaluate the ill-appearing nephrotic child very carefully for the presence of serious conditions.

Also teach parents to test their child's urine for protein at home using dipsticks. They should check the urine once a day (recording the results on a calendar), using the first-morning specimen, until the child is in remission. Write a prescription for urine albumin dipsticks and emphasize the importance of using the correct type of dipsticks. Our group has seen an alarming number of families who erroneously believed their child's nephrotic syndrome was in remission, because they were using glucose or ketone dipsticks. Ask the family to bring the dipsticks to their next appointment to verify that they are suitable. If any uncertainty remains as to the accuracy of home testing, ask the family to bring a urine sample to test in the office or laboratory.

Complications

Nephrotic syndrome, even from minimal-change disease, is not a benign condition. Loss of plasma proteins creates a complex derangement of the coagulation regulatory process. As a result, nephrotic patients are at very high risk for thromboembolic events, including pulmonary embolism and sagittal sinus thrombosis.⁹ Avoidance of central venous lines and arm boards (which promote venous stasis) helps reduce the risk of thrombotic events. The role of prophylactic anticoagulant therapy is poorly defined. Current evidence does not support routine use, but in the absence of clear guidelines, some nephrologists use low-molecularweight heparin in selected, very high-risk patients.

Streptococcus pneumoniae

Similarly, loss of immunologic proteins places nephrotic patients at risk for infectious complications, particularly spontaneous bacterial peritonitis, most frequently caused by . Nephrotic patients with abdominal pain require very careful evaluation for peritonitis.

Red

Book

Patients with significant exposure to the varicella virus who have no history of varicella vaccination or disease may require varicella-zoster immunoglobulin. The American Academy of Pediatrics (AAP) provides additional guidance on the management of children exposed to varicella.¹⁰

Follow-up and Long-term Issues

Patients in remission do not require sodium restriction, although continuing a diet that avoids excessive sodium will ease the transition to a strict low-sodium diet during future relapses. Counsel parents and patients to expect several relapses during the childhood years. Relapses often occur during an acute infectious illness, such as an upper respiratory infection or otitis media. Most relapses represent the normal course of the disease and not a failure on the part of the parents or the physician.

Patients with prolonged courses or multiple relapses may receive unusually large cumulative amounts of prednisone. This can cause linear growth failure, despite marked weight gain or obesity. Persistent nephrosis in poorly controlled patients also results in loss of essential serum growth factors. Therefore, documentation of height, weight, and blood pressure at each visit is extremely important, because this information cannot be recovered later if it is not recorded.

Continue counseling on healthy dietary choices and nutritional follow-up at each visit. Refer patients with growth or weight concerns to a nephrologist who can determine whether nonsteroidal alternative therapies can be used. The role of exogenous growth hormone in patients with nephrotic syndrome without renal failure remains undefined and is not a standard therapy.

Immunization

Red Book

The AAP recommends postponing livevirus vaccination for 1 month after discontinuing high-dose corticosteroids (generally defined as 2 mg/kg per day or 20 mg/day for more than 14 days).¹⁰ Under the current US immunization schedule, this only affects the measles-mumps-rubella, varicella, and intranasal influenza vaccines.

Nonlive vaccines may be given to patients with active nephrotic syndrome and to those who are receiving high-dose immunosuppression. The main theoretical concerns about giving nonlive vaccines to such children are that optimal seroconversion may not occur or that the antigenic stimulus might trigger a relapse of nephrotic syndrome. Practices vary among centers, and very little evidence exists supporting or refuting these concerns.^11,12 Ideally, patients would receive all vaccines while in remission and off steroids. In the real world, this can lead to disturbing immunization delays.

The pediatric community in general emphasizes vaccination whenever possible, dismissing minor or unproven excuses for deferring immunizations. In the absence of definitive guidelines on this complex topic, evaluate nephrotic patients on an individual basis to determine the best time to immunize each patient (Table 6).

Most experts recommend that patients with nephrotic syndrome receive the 23-serotype pneumococcal polysaccharide vaccine (Pneumovax), primarily to protect against peritonitis. This vaccine is complementary to the newer 7-valent pneumococcal conjugate vaccine (Prevnar), which is now included in the routine childhood immunization schedule. The 7 serotypes in Prevnar are included in Pneumovax, but the former is believed to possess more immunogenicity. Nephrotic patients should receive both vaccines to ensure optimal protection.

Patients with nephrotic syndrome should also be immunized against influenza. As a result of immune suppression from the disease and its treatment, they are at risk for more complicated influenza illness. In addition, acute viral infections can trigger relapses of nephrotic syndrome.

Conclusion

Nephrotic syndrome is not a disease but is a set of signs and symptoms, which include high urinary protein levels, low serum protein levels, and edema. The most common condition diagnosed in children with nephrotic syndrome is minimal-change disease. The cause of this condition is unknown. Treatment consists of corticosteroid therapy, usually prednisone, and dietary sodium restriction. Relapse can occur spontaneously or more typically after a viral illness.

SELF-ASSESSMENT TEST

1. Which triad defines nephrotic syndrome?

• Proteinuria, hypoproteinemia, and hyponatremia
• Proteinuria, hypoproteinemia, and edema

2. Which of these urinalysis findings is most suggestive of nephrotic syndrome?

• Low-grade proteinuria with hematuria
• High-grade proteinuria with hematuria

3. All these features suggest serious renal disease in a child with nephrotic syndrome, except:

• Red blood cell casts in urine
• Rash

4. All these medications may be used to induce or maintain remission in steroid-resistant minimal-change disease or in patients with steroid toxicity, except:

• Oral cyclophosphamide
• Oral levamisole

5. Which of these statements about the management of minimal-change disease is NOT true?

• Children in remission should be maintained on a strict sodium-restricted diet
• Urine albumin dipsticks should be used for home testing

(Answers at end of reference list)

Pediatr

Nephrol

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Pediatrics

2. Hogg RJ, Portman RJ, Milliner D, et al. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). . 2000;105:1242-1249.

Lancet

3. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. . 1988;1:380-383.

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4. Lande MB, Gullion C, Hogg RJ, et al. Long versus standard initial steroid therapy for children with the nephrotic syndrome. A report from the Southwest Pediatric Nephrology Study Group. . 2003;18:342-346.

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5. Abeyagunawardena AS, Dillon MJ, Rees L, et al. The use of steroidsparing agents in steroid-sensitive nephrotic syndrome. 2003;18:919-924.

Pediatr Nephrol

6. Barletta GB, Smoyer WE, Bunchman TE, et al. Use of mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome. . 2003;18:833-837.

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7. Loeffler K, Gowrishankar M, Yiu V. Tacrolimus therapy in pediatric patients with treatment-resistant nephrotic syndrome. 2004;19:281-287.

Pediatr Nephrol.

8. Bajpai A, Bagga A, Hari P, et al. Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome. 2003;18:351-356.

Pediatr Nephrol

9. Citak A, Emre S, Sairin A, et al. Hemostatic problems and thromboembolic complications in nephrotic children. . 2000;14:138-142.

Red Book: 2003 Report of the Committee on Infectious

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10. Pickering LK, ed. Elk Grove Village, Ill: American Academy of Pediatrics;2003:74-75.

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11. Steele RW. Current status of vaccines and immune globulins for children with renal disease. 1994;8:7-10.

Pediatr

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12. Schnaper HW. Immunization practices in childhood nephrotic syndrome: a survey of North American pediatric nephrologists. 1994;8:4-6.

Answers:

1. D; 2. C; 3. A; 4. A; 5. B

Patient education handouts are available at:

• www.geocities.com/pedirob/
• http://cnserver0.nkf.med.ualberta.ca/nephkids/childhoodns .htm