Recognizing and treating the nephrotic syndrome:
Avoid unnecessary delays

By Ronald J. Hogg, MD, Ronald J. Portman, MD, Dawn Milliner, MD, Kevin V. Lemley, MD, PhD, Allison Eddy, MD, and Julie Ingelfinger, MD

Prompt screening for proteinuria can bring this uncommon condition to light in children who present with periorbital edema. Close consultation with a pediatric nephrologist offers the best hope for minimizing complications.

In recent years, nephrologists have recognized that persistent proteinuria may be associated with, and even cause, progressive renal disease.^1-3 Figure 1 shows some of the important mechanisms in this process. Although many discrete glomerular lesions have been described in patients with proteinuria, it has been proposed that the common denominator in such patients is loss of the charge and size-selective barrier to protein filtration that normally exists in the glomeruli. The most severe levels of proteinuria lead to a constellation of clinical features that constitutes the nephrotic syndrome (NS). Proteinuria may also be a risk factor for cardiovascular disease in some patients.^4,5

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

The classic definition of NS is proteinuria that is severe enough to cause hypoalbuminemia and edema. Hypercholesterolemia often accompanies these features. The prevalence of childhood NS in the United States is low—approximately two to three cases per 100,000 children—so pediatricians and family physicians generally encounter very few patients with NS in their practices. Because NS is so rare, early consultation with a pediatric nephrologist is advisable, especially since both the disease and its treatment can have very serious, even life-threatening complications. Managing children with NS should be a collaboration between the primary care physician and the specialist. With optimal care, the prognosis for most children with NS is excellent, since children with treatment-responsive NS rarely go into renal failure.

The recommendations offered here for evaluating and treating proteinuria and NS in children were developed following a 1998 National Kidney Foundation conference, "Proteinuria, Albuminuria, Risk, Assessment, Detection and Elimination (PARADE)," in Nashville, TN.⁶ They are based, where ever possible, on controlled studies in children, although clinical trials in children have not been done to evaluate some of the treatments described. In such instances, the recommendations represent consensus opinions of the authors.

Identifying proteinuria

Obviously, detecting proteinuria is of foremost importance in making a diagnosis of NS (Table 1).The method most often used in the physician's office is the urinary dipstick, which primarily detects albumin, leaving low-molecular-weight proteins undetected. A color reaction between urinary albumin and tetrabromphenol blue produces various green hues depending on the concentration of albumin in the sample, for example: trace (about 15 mg/dL); 1+ (about 30 mg/dL); 2+ (about 100 mg/dL); 3+ (about 300 mg/dL), and 4+ (2,000 mg/dL or greater). Since the urinary dipstick method measures the concentration of urine protein, false-negative results may occur with a very dilute urine specimen. Conversely, false-positive results may occur with very alkaline or concentrated specimens or in the presence of contaminating antiseptics or radiographic contrast material—following an intravenous pyelogram, for example.

TABLE 1
Methods of testing for proteinuria

A 24-hour urine collection usually is employed to measure urinary protein excretion accurately in adults. In children, however, accurately timed urine collections are difficult to obtain and the results are often spurious. Recently, therefore, pediatric nephrologists have used the protein-to-creatinine (Pr/Cr) ratio of an untimed ("spot") urine specimen (preferably a first morning specimen, since urine protein concentrations can vary significantly during the day) to provide a semiquantitative estimate of protein excretion in children.^7,8 The urine Pr/Cr ratio (mg/mg) obtained in this way reflects 24-hour urine protein excretion quite accurately and has virtually eliminated 24-hour urine protein measurements for evaluating proteinuria in young children.

Another measurement that has assumed increasing importance in assessing patients with a variety of renal diseases, such as diabetic nephropathy, is the determination of microalbuminuria. Many laboratories now offer convenient and sensitive assays for low-to-moderate amounts of albuminuria (reported as mg albumin/g creatinine). For very high urinary albumin concentrations (greater than 5,000 mg/L), however, the test may give erroneous results. It should be noted that "microalbuminuria" is really a misnomer. The test measures "ordinary" albumin, but its high sensitivity and ability to detect very small quantities of albumin led to the term microalbuminuria.

The normal daily rate of protein excretion in the urine is less than 100 mg/m² of body surface area in both boys and girls. This is approximately equivalent to a urine Pr/Cr ratio of less than 0.2 in children and adolescents and less than 0.5 in infants. Protein excretion is usually low because the filtration of large serum proteins, such as albumin and immunoglobulins, across the glomeruli is restricted, and smaller proteins that are able to pass through the glomerular filter are largely absorbed by the proximal tubules. Excess urinary protein losses may result from either increased glomerular permeability to the passage of serum proteins or decreased reabsorption of smaller proteins by the tubules.

Despite the limited protein excretion rate under normal circumstances, the prevalence of proteinuria in normal children is between 5% and 15% in large-scale screening studies when only a single urine specimen has been tested. The finding of persistent proteinuria on repeat urine testing in such studies is much less common. In one study of almost 9,000 school-age children, for example, proteinuria was detected on a single urine specimen in 10.7% of the subjects but persisted in only 0.1% when four consecutive urine specimens were tested.⁹

Most children who have proteinuria that does not persist on repeated testing may be considered to have transient proteinuria, a condition that is most often associated with fever, stress, dehydration, or exercise. Transient proteinuria does not indicate underlying renal disease.

Orthostatic proteinuria, defined as protein excretion that is abnormally high only when the subject is upright, usually persists when the test is conducted on repeat urines while the patient is upright. This type of proteinuria occurs most commonly in school-aged children and often results in ambulatory urine Pr/Cr ratios of 0.5 to 1.0 and 24-hour protein excretion of up to 1 g/m²/day. Long-term follow-up studies have documented that orthostatic proteinuria is benign in almost all individuals, although rare cases of glomerulosclerosis have been identified later in life in patients who were initially found to have proteinuria with an orthostatic component.^10,11 While orthostatic proteinuria may be transient, many affected individuals continue to demonstrate the "defect" well into adult life. We recommend that repeat testing be done on an annual basis after the condition is diagnosed. Provided that orthostatic proteinuria does not become "fixed" (also present on overnight urine specimens), patients with this condition will not develop significant glomerular lesions and do not require specific treatment.

It is worth noting that even proteinuria caused by renal disease may show an orthostatic pattern, being greater during activity than on a first morning specimen. Persistent proteinuria that is present in first morning urine specimens as well as ambulatory specimens is abnormal and should be investigated.

Evaluating the child with proteinuria

The first step in evaluating a child with persistent dipstick proteinuria (1+ or higher) is to obtain a complete urinalysis and a first morning "spot" urine specimen to determine the urine Pr/Cr ratio.¹² The child should be instructed to void before going to sleep at night and to remain lying down until just before the specimen is obtained in the morning.

If the urinalysis is normal and the urine Pr/Cr ratio on the first morning urine sample is less than 0.2, a diagnosis of orthostatic proteinuria may be made and no additional studies are necessary. Some pediatric nephrologists repeat this determination on more than one set of a.m./p.m. specimens before making a diagnosis of orthostatic proteinuria.

If the urinalysis shows other abnormalities, or the first morning urine Pr/Cr ratio is greater than 0.2, the additional studies shown in Figure 2 should be considered. If any of them are abnormal, consultation with a pediatric nephrologist is recommended.

Clinical features of childhood NS

Table 2 summarizes the major clinical features and possible complications of NS.

TABLE 2
Clinical features and possible complications of childhood NS

Initial: Periorbital in early morning, disappearing after patient is ambulatory

Severe: Ascites, pleural effusions, scrotal or vulvar edema, skin breakdown (occasionally)

Hyponatremia

Low total serum calcium but usually normal ionized calcium

Varicella-zoster infections

Pneumococcal infections

Primary peritonitis (caused by Pneumococcus or other organisms)

Serum cholesterol 300–500 mg/dL or higher (often resolves with successful treatment of NS)

Venous thrombosis more common than arterial thrombosis

Edema is usually the first clinical feature that brings a child with NS to the attention of a primary care physician. Initially, the edema is often restricted to one or both periorbital areas and is seen only in the early morning—it disappears after the patient has been ambulatory. This gravity-dependent movement of fluid often results in misdiagnosis of an allergic disorder until the edema becomes more generalized and persistent or a urinalysis is obtained. Unfortunately, a urinalysis often is not done when a child with NS is first evaluated. Severe edema may lead to ascites, pleural effusions, scrotal or vulvar edema, and occasionally skin breakdown.

Electrolyte disturbances. Although NS is usually associated with an increase in total body sodium, hyponatremia is a common finding. It usually results from water retention in excess of salt retention. In some patients with NS, hyponatremia may be caused in part by very high lipid levels. This so-called pseudohyponatremia depends on the laboratory methodology by which the serum sodium is measured. When the laboratory technology excludes the lipid phase, pseudohyponatremia does not contribute to the reported sodium levels.

Total serum calcium in a patient with NS is often low, but the ionized calcium level is usually normal. This apparent discrepancy results from low levels of protein-bound calcium in patients with low serum albumin levels. For practical purposes, the patient's serum calcium can be adjusted to allow for the hypoalbuminemia by adding 1 mg/dL to the serum calcium level for each 1 g/dL decrease in serum albumin below 4 g/dL. For example: the adjusted serum calcium in a child with a measured total serum calcium of 7.5 mg/dL and serum albumin 2.5 g/dL is 9.0 mg/dL (7.5 + [4.0 - 2.5] = 7.5 + 1.5).

Infections. The two infectious agents that cause most concern in children with NS are varicella-zoster and pneumococcus. Obtain a varicella antibody titer in children with NS if they have neither been vaccinated against nor have a history of chickenpox. Varicella may cause serious systemic disease in nephrotic children who are taking steroids or other immunosuppressive agents. Indeed, if a varicella nonimmune child with NS is on steroids or other immunosuppressive medication when exposed to chickenpox, varicella- zoster immunoglobulin (VZIG) should be given within 72 hours of the exposure to prevent or lessen the severity of the disease. In such a patient, the dose of glucocorticoid should be tapered to no more than 1 mg/kg/day until the incubation period has passed. Therapy with acyclovir or valacyclovir should be given if varicella develops, but only after consulting an infectious disease specialist or pediatric nephrologist.

Children with active NS are also prone to develop "primary" peritonitis (spontaneous bacterial peritonitis), with pneumococcus being the most common causative organism.¹³ It should be noted, however, that not all primary peritonitis is pneumococcal in origin. Gram-negative bacilli such as Escherichia coli and, rarely, other bacteria may also be found in such patients.

It is not uncommon for children with NS who present with primary peritonitis to be misdiagnosed as having acute appendicitis since they have features of "an acute abdomen." This is especially true in patients with new-onset NS or in whom the possibility of primary peritonitis is not considered. Some physicians give prophylactic antibiotics to children during NS relapses. There are no studies showing this approach to be effective in preventing peritonitis, however.

Immunization recommendations for NS patients from pediatric nephrologists have been published in detail.^14,15 Although the risk of precipitating a relapse of NS may cause a physician to hesitate to immunize children with this condition, there are no data to support this stance. In general, the benefits conferred by a standard vaccination program appear to outweigh the risks, with the exception that live viral vaccines should not be given to children with NS who are either in relapse or receiving steroids or other immunosuppressive drugs. As with all our recommendations, the advantages and disadvantages of this aspect of management should be considered on an individual basis with the child's parents.

Pneumococcal vaccine is recommended for all nephrotic children,¹⁵ preferably when they are in remission and off daily prednisone. It should be noted, however, that not all common pneumococcal serotypes are included in the standard 23-serotype vaccine. Moreover, antibody levels in nephrotic patients may fall during a NS relapse. Consequently, even vaccinated children should be considered "at risk" for developing pneumococcal peritonitis and pneumococcal sepsis. In February 2000, a new heptavalent pneumococcal conjugate vaccine (PCV7 [Prevnar]) was approved for use in children by the Food and Drug Administration. Whether this vaccine will be more effective for children with NS than the 23-serotype vaccine has not been established. It is reasonable at this point to give PCV7 to children who present with NS prior to 24 months of age.

The safety and efficacy of varicella vaccine in children with NS is currently under investigation. Preliminary results show that a two-dose regimen of live, attenuated varicella virus vaccine (Varivax) is both safe and effective.¹⁶ A specific recommendation regarding the use of this vaccine in children with NS cannot be made at this time, however.

Hyperlipidemia. High levels of serum cholesterol (300 to 500 mg/dL or more) are often seen in patients with NS but usually resolve if the NS can be treated successfully. In contrast, very high cholesterol and triglyceride levels often persist in patients who have treatment- resistant NS. Hyperlipidemia is cause for concern since preliminary data indicate that atherosclerosis may develop at a relatively young age in children with persistent nephrotic-range proteinuria.⁴ Treatment of hyperlipidemia has not been well studied in children, however, and dietary modification is usually of limited benefit. Cholestyramine is the only drug currently approved for children, but small, uncontrolled studies suggest that 3-hydroxy-3 methylglutaryl-coenzyme A (HMG Co-A) reductase inhibitors may be safe and effective for treating hypercholesterolemia in children with refractory NS.^17,18

Thromboembolism. Patients with NS usually have a hypercoagulable state and are at risk for venous or, less commonly, arterial thrombosis. Because reduced intravascular volume may predispose a patient to thrombotic events, it is important to recognize and treat hypovolemia promptly. Use diuretics judiciously and avoid them in patients known to have had a thromboembolic event. Antiplatelet drugs or anticoagulants are recommended to manage such patients. Whether prophylactic use of these agents prevents thrombosis in children with NS has not been studied carefully. In children with treatment-resistant NS, it may be warranted to investigate inherited conditions that may predispose the patient to thromboembolism, such as Factor V-Leiden, which has an incidence of about 5% in Americans of European origin. We recommend considering such measures only after consulting a pediatric nephrologist or hematologist.

Treating NS in children

Choosing a course of treatment for the child with NS should be done in consultation with a pediatric nephrologist.¹² A number of standard terms have been developed to describe responses to treatment in childhood NS. Table 3 lists these terms and their definitions.

TABLE 3
Responses to treatment in children with NS

Steroids are the first-line treatment for NS. When steroid side effects become troublesome following multiple courses or when the patient fails to respond to steroid therapy, other strategies, such as cytotoxic drugs, cyclosporine A, and levamisole, should be considered.

Diuretics should be used cautiously in children with NS. They should never be given to children with mild edema. They may be employed judiciously (1 to 2 mg/kg/day of furosemide, for example) under the direction of a pediatric nephrologist if edema is severe. Another approach to severe edema is a combination of IV albumin and furosemide to raise serum albumin and induce diuresis. This therapy requires caution as well, however, because it carries a significant risk of hypertension and even pulmonary edema. Hypertension also may be a serious problem when patients with NS take over-the-counter decongestants, especially while they are on daily steroids.

Oral corticosteroids

Patients with typical clinical features of idiopathic NS are usually given a trial of steroid therapy before a renal biopsy is considered. Prednisone and prednisolone are the most commonly used forms of glucocorticoid. For young children, liquid preparations of prednisolone, such as Prelone and Pediapred (prednisolone sodium phosphate) allow more accurate dosing and are more palatable. A typical protocol would be to treat the initial episode of NS with prednisone or prednisolone at a dose of 60 mg/m²/day (maximum 80 mg/day) in one to three divided doses for a period of four weeks, followed by 40 mg/m² (maximum 60 mg) every other day in the morning for an additional four weeks—that is, 4 + 4 weeks.

It has been proposed recently that six weeks of daily therapy, followed by six weeks of alternate-day therapy (6 + 6 weeks) may be superior to the standard 4 + 4 week regimen. Although the benefits of the more intensive approach have not been determined with certainty, a controlled trial in Germany showed a higher percentage of children with sustained remissions on the 6 + 6 week schedule.¹⁹ The incidence of steroid adverse effects is higher with the longer course, however, and the degree of benefit has varied in some other studies. Thus, no consensus exists at this time on the optimal duration of the initial course of therapy.

Most children with idiopathic NS respond to corticosteroids in 10 to 14 days, but many have relapses, even if the longer initial course of prednisone is given. Such relapses are usually treated with a short course of daily steroids at the dose described above until the patient is free of proteinuria for three days, followed by a tapering course of alternate-day therapy for four to eight weeks. Subsequent management depends on the patient's responsiveness and number of relapses.

Corticosteroids can have many side effects, and it is important to discuss these at length with the family of a nephrotic child, as well as with the child if he or she is old enough to understand. Steroids not only cause Cushingoid habitus and ravenous appetite in a relatively short period of time in some children but may be associated with other well-known short- and long-term effects, including behavioral and psychological changes (mood lability), gastric irritation (including ulcer), fluid retention, hypertension, steroid-induced bone disease (generalized bone demineralization and, rarely, avascular necrosis), decreased immune function, growth retardation, night sweats, and cataracts. Pseudotumor cerebri, depression, steroid psychosis, and steroid-related diabetes are rare but very serious potential complications of steroid therapy. It is essential to discuss the potential for steroid side effects as part of parent and patient education about NS.

Intravenous pulse steroids

Infusions of high-dose methylprednisolone (30 mg per kg body weight up to 1 g per infusion) have been used recently with success in some patients with NS that is resistant to therapy with oral steroids.²⁰ The first six infusions are usually given every other day, followed by a tapering regimen for periods up to 18 months. The decision to administer this type of treatment to children should be made only by a pediatric nephrologist.

Side effects of IV steroids are similar to those of oral prednisone but may be more severe because of the much higher doses that are used. In addition, patients may become hypertensive during the infusions, and cardiac arrhythmias have occurred (rarely) in adults receiving such therapy.

Cytotoxic drugs

Many pediatric reports indicate that cyclophosphamide or chlorambucil, each given over eight to 12 weeks, can achieve long periods of remission and reduce the need for steroids in children with NS.²¹ Because bone marrow suppression is a general problem with cytotoxic drugs, the peripheral white blood cell count should be monitored regularly during therapy. In addition, the possibility of future malignancy must be considered. Other long-term risks of cyclophosphamide in children include oligospermia, azoospermia, and ovarian fibrosis. The risk is highest in children close to or in puberty and children given large doses over many months.

The total cumulative dose of cyclophosphamide should be restricted to less than 170 mg/kg in most cases. Hemorrhagic cystitis may occur with cyclophosphamide but not with chlorambucil. Seizures may occur rarely with chlorambucil but not with cyclophosphamide.

Cyclosporine A

The immunosuppressant cyclosporine A offers an alternative treatment for patients with steroid- dependent or resistant NS.^22,23 Patients who respond to this drug tend to relapse once the medication is withdrawn, however.

Cyclosporine A may increase blood pressure or aggravate preexisting hypertension. Some patients develop nephrotoxicity, as indicated by a rise in serum creatinine. Serum potassium may increase, and serum magnesium may occasionally decrease. Hypertrichosis and gingival hyperplasia are common. A pediatric nephrologist should manage all children with renal disease who are taking cyclosporine A.

Levamisole

Levamisole has been used to treat frequently relapsing NS in children outside the US and is reportedly effective and well tolerated. The mechanism of action of this immunomodulator in children with NS is unknown. In general, levamisole appears to restore depressed immune functions. Early side effects that have been associated with the drug, such as neutropenia, rash, gastrointestinal disturbances, and seizures, were rarely seen in two small trials in children with NS.^24,25

Levamisole must be given for relatively long periods in most patients to maintain them in remission. Such patients must be monitored for long-term side effects, including leukemia, elevated liver enzymes, and proteinuria.

Other management considerations

Every child with NS should be individually assessed for any changes that might be needed in day care, school, activities, and diet. Most nephrotic children can and do limit their own activities. Recommendations about sports participation during treatment with high-dose steroids should be considered on an individual basis. Age-appropriate explanations about the appetite-stimulating effects of steroids and recommendations for a nutritious, relatively low-fat diet with age-adjusted RDA of protein, carbohydrates, and other components help children avoid large weight gains.²⁶ Patients should limit salt intake to control edema and reduce the risk of hypertension, especially when they are receiving daily glucocorticoids. Setting a fluid intake limit of about twice the rate of insensible water loss may be helpful in an edematous child. Discontinue the restriction when urine output increases in response to specific treatment.

In practice, most patients with NS are monitored closely at home by their parents (or themselves when old enough). Frequent monitoring and recording of body weight and urine dipstick protein levels are very important in clinic evaluation of patients. Such records often provide the first indication of a relapse, leading the parents to ask the health-care provider to modify therapy before edema is apparent. While individual pediatric nephrologists may take varying approaches to managing relapses, it is important to stress the vital role of parents in identifying relapses and treatment complications. Waiting for edema to herald a relapse of NS often results in much higher patient morbidity.

Patients who do not respond to any of the immunosuppressive regimens described above are candidates for therapy with angiotensin converting enzyme inhibitors (ACEi). Such therapy may decrease the severity of proteinuria by as much as 50%. The long-term benefit of ACEi in childhood NS is unproven, however, so these agents should be used only under the direction of a pediatric nephrologist. Children with NS should not be given ACEi while they are receiving their initial course of prednisone because they could become hypotensive and incur an increased risk of thrombosis if rapid diuresis occurs.

A team effort

Although the management of children with persistent proteinuria or NS should be supervised by physicians who are experienced in treating patients with these problems, the best approach is a combined effort by a primary care physician and pediatric nephrologist working in close cooperation with a well-educated family. We recommend that pediatricians and family practitioners screen their patients periodically for proteinuria (by dipstick) even though no consensus exists as to the optimal frequency for such screening in children. Primary care physicians should not hesitate to consult with a pediatric nephrologist if they find an abnormality. Early consultation and, if necessary, early intervention may provide patients with the best outcome—often with the least invasive studies.

REFERENCES

1. Eddy AA, McCulloch L, Kiu E, et al: A relationship between proteinuria and acute tubulointerstial disease in rats with experimental nephrotic syndrome. Am J Pathol 1991;138:1111

2. Peterson JC, Adler S, Burkart JM, et al: Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995;123:754

3. Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Kidney Int 1997;51:2

4. Portman RJ, Hawkins E, Verani R: Premature atherosclerosis in pediatric renal patients: Report of the Southwest Pediatric Nephrology Study Group. Pediatr Res 1991;29:349A

5. Grimm RH, Svendsen KH, Kasiske B, et al: Proteinuria is a risk factor for mortality over 10 years of follow-up: MRFIT Research Group. Multiple Risk Factor Intervention Trial. Kidney Int Suppl 1997; 3: S10

6. Keane VYT, Eknoyan G: Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation. Am J Kidney Dis 1999;33:1004

7. Houser MT: Assessment of proteinuria using random urine samples. J Pediatr 1984;104:845

8. Houser MT, Jahn MF, Kobayashi A, et al: Assessment of urinary protein excretion in the adolescent: Effect of body position and exercise. J Pediatr 1986;109:556

9. Vehaskari V, Rapola J: Isolated proteinuria: Analysis of a school-age population. J Pediatr 1982;101:661

10. Ryland DA, Spreiter S: Prognosis in postural (orthostatic) proteinuria: Forty- to fifty-year follow-up of six patients after diagnosis by Thomas Addis. N Engl J Med 1981;305(11):618

11. Berns JS, McDonald B, Gaudio KM, et al: Progression of orthostatic proteinuria to focal and segmental glomerulosclerosis. Clin Pediatr 1986;25:165

12. 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, Albuminemia, Risk, Assessment, Detection, and Elimination (PARADE). Pediatrics 2000;105:1242

13. Feinstein EI, Chesney RW, ZeUovic I: Peritonitis in childhood renal disease. Am J Nephrol 1988;8:147

14. Schnaper HW: Immunization practices in childhood nephrotic syndrome: A survey of North American pediatric nephrologists. Pediatr Nephrol 1994;8:4

15. Steele RW: Current status of vaccines and immune globulins for children with renal disease: Pediatr Nephrol 1994;8:7

16. Fivush B, Arbus G, Tarver J, Hogg I, Furth S: Immunogenicity and persistence of antibody levels following Varivax in children and adolescents with nephrotic syndrome: A report of the Southwest Pediatric Nephrology Study Group. J Am Soc Nephrol 1999;10:72A

17. Coleman J, Watson A: Hyperlipidaernia, diet, and simvastatin therapy in steroid-resistant nephrotic syndrome of childhood. Pediatr Nephrol 1996;10:171

18. Sanjad S, Al-Abbad A, Al-Shorafa S: Management of hyperlipidernia in children with refractory nephrotic syndrome: The effect of statin therapy. J Pediatr 1997;130:470

19. Brodehl J, Ehrich JHH: Long vs. standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Eur J Pediatr 1993;152:357

20. Tune BM, Lieberman E, Mendoza SA: Steroid- resistant nephrotic focal segmental glomerulosclerosis: A treatable disease. Pediatr Nephrol 1996;10:772

21. Takeda A, Ohgushi H, Niimura F, et al: Long-term effects of immunosupressants in steroid-dependent nephrotic syndrome. Pediatr Nephrol 1998;12:746

22. Gregory MJ, Smoyer WE, Sedman A, et al: Long-term cyclosporine therapy for pediatric nephrotic syndrome: A clinical and histologic analysis. J Am Soc Nephrol 1996;7:543

23. Lieberman KV, Tejani A: A randomized, double-blind, placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children. J Am Soc Nephrol 1996;7:56

24. Bagga A, Sharma A, Srivastava RN: Levamisole therapy in corticosteroid-dependent nephrotic syndrome. Pediatr Nephrol 1997;11:415

25. Tenbrock K, Muller-Berghaus J, Fuchshuber A, et al: Levamisole treatment in steroid-sensitive and steroid-resistant nephrotic syndrome. Pediatr Nephrol 1998;12:459

26. Zukerman E, Ingelfinger JR: Coping with Prednisone. New York, St Martin's Press, 1997

DR. HOGG is Director of Pediatric Nephrology at the North Texas Hospital for Children at Medical City, Dallas. He has received medication for a research project from Upjohn and grant support for research from Merck and Parke-Davis.

DR. PORTMAN is Professor and Director, Division of Pediatric Nephrology and Hypertension, University of Texas-Houston, Medical School.

DR. MILLINER is Associate Professor of Pediatrics and Chair, Division of Pediatric Nephrology at the Mayo Clinic and Mayo Eugenio Litsa Children's Hospital, Rochester, MN.

DR. LEMLEY is Assistant Professor of Pediatrics, Division of Pediatric Nephrology, Stanford University, School of Medicine, Stanford, CA.

DR. EDDY is Professor of Pediatrics and Head, Division of Nephrology at Children's Hospital and Regional Medical Center, Seattle, WA.

DR. INGELFINGER is Chief, Pediatric Nephrology, Massachusettes General Hospital for Children and Professor of Pediatrics, Harvard Medical School, Boston.

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Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the author of "Recognizing and treating the nephrotic syndrome: Avoid unnecessary delays."

Ronald J. Hogg, MD, has received medication for a research project from Upjohn and grant support for research from Merck and Parke-Davis.

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Ronald Hogg. Recognizing and treating the nephrotic syndrome: Avoid unnecessary delays. Contemporary Pediatrics 2000;11:84.