Pediatric Annals

Nephrotic Syndrome in Children

Barry L Warshaw, MD

Abstract

Nephrotic syndrome of childhood is a complex, often chronic disorder that typically responds to careful management with a gratifying longterm outcome.1 This article focuses on those aspects of diagnosis and management thought to have greatest relevance to practicing pediatricians. Because the nephrotic syndrome is not a common disorder, with an annual incidence of approximately two cases per 100 000 children,2 practitioners other than nephrologists may encounter relatively few such children during the course of a typical career. Nevertheless, the relapsing nature of many cases of childhood nephrotic syndrome may result in repeated physician contacts with affected individuals, and the chronicity of the disorder increases its overall prevalence to 16 cases per 100 000 children.2 Practitioners, therefore, should be prepared to properly diagnose children with nephrotic syndrome and to follow and manage such children over extended courses that may last many years.

DEFINITIONS

The four features comprising the classical definition of the nephrotic syndrome include proteinuria, hypoproteinemia (hypoalbuminemia), hyperlipidemia, and edema. Occasionally, one or more of these features may be absent but, at a minimum, both proteinuria and hypoalbuminemia must be present to establish this diagnosis.3 The other features may not be present in certain cases or at certain times during the course of the disorder in an individual patient. For example, a child with nephrotic syndrome having all of the typical features may be given diuretic treatment with resulting resolution of edema. Such a patient would still be considered to have an active nephrotic syndrome if proteinuria persists,3,4 typically with hypoalbuminemia present as well. Remission of the nephrotic syndrome is diagnosed only when urinary protein excretion normalizes3,4; resolution of edema alone should not be confused with a remission. For a remission to be considered complete, the serum albumin concentration should have returned to normal.5

A relapse is defined as a recurrence of proteinuria and hypoalbuminemia in a patient who has previously achieved a complete remission. Because the evolution of a relapse begins with the recurrence of proteinuria, patients undergoing home urinary protein monitoring are considered to be in an early stage of relapse when they develop persistent proteinuria 2*2+ (>100 mg/dL) on a qualitative dipstick, even though other criteria for active nephrotic syndrome may not yet be present.3,4 Most children with persistent proteinuria will progress to develop hypoalbuminemia and edema; however, some may experience spontaneous resolution of the proteinuria within 4 to 14 days.6 Decisions on whether to reinstitute treatment during an early stage of relapse must take these opposing possibilities into account.

Most cases of nephrotic syndrome of childhood will be steroid responsive, indicating the achievement of a complete remission following a course of treatment with prednisone.3 Of those who fail to achieve a complete remission, a minority are partial responders and show subtotal improvement, whereas most are steroid resistant and show little to no improvement in response to prednisone treatment.7 Thus, childhood nephrotic syndrome is typically an "all or none" disease with respect to its responsiveness to steroid therapy.

HISTOPATHOLOGIC CLASSIFICATION AND PATHOGENESIS

Minimal Lesion Nephrotic Syndrome

Nephrotic syndrome can result from any glomerular lesion that causes massive proteinuria.8,9 The underlying histopathology of the most common form in childhood is that of so-called minimal lesion nephrotic syndrome (MLNS), which is characterized by minimal to no visible alterations on light microscopy, negative immunofluorescence findings, and reversible alterations of the glomerular epithelial cell foot processes on electron microscopy. This form of nephrotic syndrome, to which the older term nephrosis might best apply, is distinguished from nephritis or glomerulonephritis both pathologically by the absence of glomerular inflammatory changes and clinically by the absence of signs and symptoms associated with glomerular inflammation…

Nephrotic syndrome of childhood is a complex, often chronic disorder that typically responds to careful management with a gratifying longterm outcome.1 This article focuses on those aspects of diagnosis and management thought to have greatest relevance to practicing pediatricians. Because the nephrotic syndrome is not a common disorder, with an annual incidence of approximately two cases per 100 000 children,2 practitioners other than nephrologists may encounter relatively few such children during the course of a typical career. Nevertheless, the relapsing nature of many cases of childhood nephrotic syndrome may result in repeated physician contacts with affected individuals, and the chronicity of the disorder increases its overall prevalence to 16 cases per 100 000 children.2 Practitioners, therefore, should be prepared to properly diagnose children with nephrotic syndrome and to follow and manage such children over extended courses that may last many years.

DEFINITIONS

The four features comprising the classical definition of the nephrotic syndrome include proteinuria, hypoproteinemia (hypoalbuminemia), hyperlipidemia, and edema. Occasionally, one or more of these features may be absent but, at a minimum, both proteinuria and hypoalbuminemia must be present to establish this diagnosis.3 The other features may not be present in certain cases or at certain times during the course of the disorder in an individual patient. For example, a child with nephrotic syndrome having all of the typical features may be given diuretic treatment with resulting resolution of edema. Such a patient would still be considered to have an active nephrotic syndrome if proteinuria persists,3,4 typically with hypoalbuminemia present as well. Remission of the nephrotic syndrome is diagnosed only when urinary protein excretion normalizes3,4; resolution of edema alone should not be confused with a remission. For a remission to be considered complete, the serum albumin concentration should have returned to normal.5

A relapse is defined as a recurrence of proteinuria and hypoalbuminemia in a patient who has previously achieved a complete remission. Because the evolution of a relapse begins with the recurrence of proteinuria, patients undergoing home urinary protein monitoring are considered to be in an early stage of relapse when they develop persistent proteinuria 2*2+ (>100 mg/dL) on a qualitative dipstick, even though other criteria for active nephrotic syndrome may not yet be present.3,4 Most children with persistent proteinuria will progress to develop hypoalbuminemia and edema; however, some may experience spontaneous resolution of the proteinuria within 4 to 14 days.6 Decisions on whether to reinstitute treatment during an early stage of relapse must take these opposing possibilities into account.

Most cases of nephrotic syndrome of childhood will be steroid responsive, indicating the achievement of a complete remission following a course of treatment with prednisone.3 Of those who fail to achieve a complete remission, a minority are partial responders and show subtotal improvement, whereas most are steroid resistant and show little to no improvement in response to prednisone treatment.7 Thus, childhood nephrotic syndrome is typically an "all or none" disease with respect to its responsiveness to steroid therapy.

HISTOPATHOLOGIC CLASSIFICATION AND PATHOGENESIS

Minimal Lesion Nephrotic Syndrome

Nephrotic syndrome can result from any glomerular lesion that causes massive proteinuria.8,9 The underlying histopathology of the most common form in childhood is that of so-called minimal lesion nephrotic syndrome (MLNS), which is characterized by minimal to no visible alterations on light microscopy, negative immunofluorescence findings, and reversible alterations of the glomerular epithelial cell foot processes on electron microscopy. This form of nephrotic syndrome, to which the older term nephrosis might best apply, is distinguished from nephritis or glomerulonephritis both pathologically by the absence of glomerular inflammatory changes and clinically by the absence of signs and symptoms associated with glomerular inflammation such as severe hematuria, azotemia, or hypertension. Confusion is understandable, however, because nephrotic syndrome also can result from and thus coexist with various histopathologic forms of glomerulonephritis, whenever proteinuria and hypoalbuminemia are sufficiently severe. Accordingly, the catch-all term nephrosis is best relegated to history in favor of more specific clinicopathologic terms, and the designation MLNS should be used to refer to the majority of nephrotic children who lack evidence of glomerular inflammation.

Progress in our understanding of the various histopathologies that may underlie nephrotic syndrome has outstripped advances in our understanding of the pathogenesis of these disorders.10 In particular, the pathogenesis of MLNS "remains a tantalizing riddle, wrapped in mystery," just as Arneil described it in 197 1.11 A growing body of evidence points to an immunopathogenesis, with an increasing focus on an abnormality of T-lymphocyte function, as articulated in 1974 by Shalhoub.12 To date, however, proof of this hypothesis is lacking, and the nature of the putative lymphocyte abnormality is unknown. Shalhoub suggested that lymphocytes might produce a factor - a lymphokine - that reversibly alters glomerular permeability to protein.12 If proof of this hypothesis is forthcoming, we might come to realize that MLNS is not a primary kidney disorder but rather a primary disorder of some immunocompetent cell such as T-lymphocytes.

OTHER HISTOPATHOLOGIC FORMS

Minimal lesion nephrotic syndrome accounts for 77% of all children with primary nephrotic syndrome.8,13,14 The remainder have a variety of underlying glomerular lesions, including mesangial proliferative glomerulonephritis, focal segmental and focal global glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis.8,13,14 In addition, a small percentage of patients with IgA nephropathy (Berger's disease), an important cause of isolated recurrent hematuria during childhood, may develop nephrotic syndrome,15 as may occasional patients with Henoch-Schönlein anaphylactoid purpura nephritis,16 a systemic disorder with renal pathology identical to that of IgA nephropathy.

In systemic lupus erythematosus, nephrotic syndrome may be found with various histopathologic forms of lupus nephritis.17 A variety of glomerular lesions also are seen accompanying the congenital nephrotic syndrome, a condition distinguished by its early presentation during the first few days, weeks, or months of life.18 Finally, it is important to recognize that certain infectious disorders and drug toxicities may cause or be associated with nephrotic syndrome, with or without specific renal histopathologic findings. Infectious causes include syphilis, a potential cause of congenital or infantile nephrotic syndrome19; hepatitis B virus, which may be associated with a nephropathy commonly of the membranous type20; human immunodeficiency virus (HIV), sometimes associated with glomerular immunocomplex deposition and mesangial hypercellularity or focal segmental glomerulosclerosis21; and malaria, a common cause of nephrotic syndrome in endemic areas worldwide.22

Drugs that should be recognized as potential, albeit rare, causes of nephrotic syndrome include nonsteroidal anti-inflammatory drugs,23 with occasional reports implicating other drugs such as mephenytoin.24 These reports serve to remind us that a possible association with any previously prescribed drug should be given consideration.

CLINICAL FEATURES AND DIAGNOSTIC WORK-UP

Edema is the most common sign heralding the diagnosis of nephrotic syndrome of childhood. Specifically, periorbital edema frequently may be the presenting complaint. The dependent nature of the edema is striking and sometimes perplexing to the uninitiated. Parents often observe that the periorbital swelling noted in the morning when the child first arises disappears as the day progresses. This dependent shift of edema fluid should not be confused with improvement or resolution of the underlying problem. In some cases, periorbital edema may be unilateral in its early stages, again owing to gravitational shifts and vagaries of sleep position. Accordingly, attention must be paid to a history of early morning facial edema even if none is apparent by the time the child is seen later in the day. Moreover, because far more children will develop periorbital swelling as a result of infections or allergies than as a result of the nephrotic syndrome, practitioners naturally will suspect these more common disorders first; thus, the challenge practitioners face is to remain alert to the possibility of systemic edema whenever local inflammatory or allergic manifestations are absent.

Once nephrotic syndrome is suspected, a simple dipstick test for urine protein should be performed. Most confirmed cases will show 5=3 + (^300 mg/dL) protein, but qualitative values of ^1+ (30 mg/dL) warrant further investigation. Additional laboratory studies should include an extended blood chemistry profile (electrolytes, blood urea nitrogen, creatinine, total protein, albumin, cholesterol, and liver enzymes), a complete blood cell count, a complete urinalysis, serum C3 and C4 complement and antinuclear antibody determinations, and a quantitative measurement of urinary protein excretion, using either a 24-hour urine collection or a quantitative protein/creatinine ratio on a random urine sample. The latter test is a convenient and useful substitute for the 24-hour urine measurement, especially in young children in whom 24-hour collections are notoriously difficult. Optimally, the random urine sample should be a first morning specimen following overnight supine posture in order to avoid confusion with orthostatic proteinuria.

Table

TABLE IClinical Features of Minimal Lesion Nephrotlc Syndrome

TABLE I

Clinical Features of Minimal Lesion Nephrotlc Syndrome

The criteria for diagnosis of nephrotic syndrome are satisfied if the serum albumin is ^2.5 g/dL and either the 24-hour urine protein exceeds 40 mg/rr^/hour3 or the urine protein/creatinine ratio is 5s 1.0 (mg/mg).25

Additional laboratory work-up that should be considered during the initial evaluation, depending on an assessment of risk factors, may include tests for syphilis, hepatitis B surface antigen, HIV, or malaria. A skin test to exclude the presence of tuberculosis may be prudent in the event that prednisone or other immunosuppressive treatments will be required.

A constellation of clinical and laboratory features characterize the child likely to have MLNS who would be considered an appropriate candidate to begin specific treatment without the requirement for a renal biopsy (Table 1). The age of the child represents one of the strongest clinical associations predictive of this disorder. More than 70% of nephrotic children between the ages of 1 and 7 years old fell into the MLNS category, whereas only 50% of older children do,13,14 even fewer adolescents,13 and only 25% to 30% of adults.26

Beyond the positive association with young age, patients with MLNS typically lack clinical or laboratory findings associated with glomerular inflammation, renal failure, intravascular volume expansion, or complement activation. Accordingly, gross hematuria or cellular casts on urinalysis should be absent, as should elevated serum creatinine, significant hypertension, clinical evidence of congestive heart failure, and depressed C3 or C4 complement values. Transient microhematuria may be present in some 13% to 23% of patients at presentation,7,13,14 and transient azotemia (blood urea nitrogen level >40 mg/dL) has been observed in 19%. 13 There should be no clinical evidence of systemic disorders such as anaphylactic purpura or systemic lupus erythematosus nor laboratory evidence of antinuclear or other autoimmune antibodies. Antistreptococcal antibodies are typically negative, but they may be positive in some patients as an epiphenomenon; the presence of such antibodies without other corroborating evidence of glomerular inflammation does not establish a diagnosis of poststreptococcal glomerulonephritis. Given the appropriate clinical findings, MLNS can be predicted with a high degree of accuracy without a renal biopsy, and treatment can be implemented accordingly.

When the clinical evaluation of a nephrotic child suggests a disorder other than MLNS, referral to a pediatric nephrologist is warranted and a renal biopsy frequently is indicated. Many of the disorders in this group are progressive, and specific treatment for them is often problematic. The reader is referred to recent reviews for further discussion of these entities.27

SUPPORTIVE TREATMENTS

A major goal of supportive treatment is to control edema while awaiting a definitive remission. A brief review of the distribution of nephrotic edema among the various body fluid spaces is necessary as background. Edema develops when low plasma oncotic pressure, a consequence of the hypoalbuminemia, permits excessive movement of fluid from the vascular to the interstitial compartments. The resulting vascular volume contraction stimulates renal sodium conservation,28 leading to reexpansion of the vascular space; the sequence then repeats itself in a vicious cycle. According to this paradigm, the vascular volume of edematous patients with active nephrotic syndrome may vary from low to normal. While studies have shown that certain nephrotic patients also may have expanded vascular volumes,28,29 the recognition that the vascular space may be contracted in the presence of massive generalized edema is an important one when determining appropriate therapy.

Controlling edema is fundamentally dependent on preventing or correcting positive sodium balance. Dietary salt restriction is recommended for all patients during active disease. In general, a 1-g sodium diet is recommended for young children and a 2-g sodium diet for older children and adolescents. One should keep in mind, however, that these recommendations are based largely on the palatability and practicality of the diet, and they may not prevent a positive sodium balance in all cases even if compliance is good. The problem is that renal sodium excretion is so limited in many nephrotic children28 that reducing the intake sufficiently low to match output may be virtually impossible. Nevertheless, dietary salt restriction is considered important in order to mitigate if not always prevent progression of edema. In contrast, limitation of fluid intake generally is not necessary except in those patients with significant hyponatremia. In the presence of an intact thirst mechanism and intact renal tubular concentrating and diluting capacities, most patients will spontaneously adjust their fluid intake apropos to their salt intake and remain isonatremic.

Mild, generalized edema should be treated with dietary sodium limitations alone while awaiting steroidinduced remission and the resulting diuresis. This response occurs on average about 10 days after initiating therapy in steroid-responsive patients.30 For patients presenting with moderate or severe anasarca, administration of intravenous albumin and diuretics should be considered, especially those with discomforting edema, eg, periorbital swelling beginning to compromise vision, ascites compromising mobility or ease of respirations, or any degree of genital edema. Concentrated 25% albumin should be given in an initial dose of 0.5 g/kg body weight; a maximum dose of 25 g is usually effective in larger individuals.

Although higher doses of up to 1 g/kg have been recommended,2t31*33 lower amounts have proven adequate in most cases and are considerably less expensive given the high cost (the current acquisition fee for our hospital is $70 per 12.5-g vial) and the need to repeat the treatments two to three times daily for several days in severe cases. Cost concerns also justify using doses that are whole multiples of available vial sizes, currently either 5 or 12.5 g. The albumin should be infused quickly - over 30 to 60 minutes - in order to take advantage of the expected increment in oncotic pressure and the resulting shift of edema fluid from the interstitial to the vascular space. Because much of the infused albumin will be lost via the urine within 24 hours, much slower rates of infusion may not produce the desired benefits. Patients with signs of vascular volume expansion (eg, those with an enlarged heart, pulmonary edema, or significant hypertension) should not be given albumin despite the presence of hypoalbuminemia.33 Albumin infusions should be followed immediately by a potent diuretic such as furosemide given in an initial dose of 1 to 2 mg/kg.

The diuresis resulting from the combination of albumin and furosemide tends to be both safer and more effective than that from furosemide alone in typical cases of nephrotic edema. Furosemide alone generally is not recommended in this situation, as such treatment may further contract an already contracted intravascular volume and predispose to prerenal azotemia, vascular stasis, or thrombotic complications. On the other hand, in edematous patients with preserved plasma oncotic pressure and signs of expanded intravascular volume (eg, those with typical poststreptococcal glomerulonephritis), furosemide alone is the preferred therapy.

In some patients, assessing the status of the vascular volume may prove difficult, as conflicting signs may be present (eg, hypertension and hemoconcentration). No single laboratory parameter is reliable in this regard; clinical judgment based on thorough physical examination and perhaps imaging studies usually can result in a proper noninvasive assessment on which to base therapeutic decisions. Daily weights, physical examinations, and biochemical profiles are essential for monitoring patients undergoing vigorous diuretic therapy. Electrolyte disturbances, especially hypokalemia, should be anticipated. Foods high in potassium may be helpful if the serum potassium concentration is in the low normal range. If overt hypokalemia develops, potassium chloride supplements (1 to 2 mEq/kg/day in divided doses) should be given, or the diuretic treatment should be interrupted until the potassium concentration returns to normal. The goal of diuretic treatment should be to eliminate symptoms and relieve most if not all of the edema; excessive diuresis is possible with these potent regimens and should be avoided.

Muscle cramps and frank tetanic spasms of the hands occur commonly during the active phase of nephrotic syndrome and during the diuretic phase signalling remission. Both the total serum calcium concentration and the physiologically significant ionized fraction of calcium tend to be low in such cases and may account for these clinical symptoms.34 Most episodes last only a few seconds, and treatment generally is not required. The cramps cease once remission is well established. For frequently recurrent episodes, oral calcium supplements can be tried. If diuretics are being used, their omission often is helpful.

INFECTIONS AND IMMUNIZATIONS

Active nephrotic syndrome is associated with increased susceptibility to bacterial infections with Streptococcus pneumoniae and gram-negative organisms including Escherichia coli, Pseudomonas, and Hemophilus influenzae.2 Pneumonitis, peritonitis, cellulitis, or septicemia are the conditions most commonly encountered. Children presenting with features suggesting any of these conditions should be given broad-spectrum antibiotic coverage initially until the specific organism is identified. Patients who have been receiving corticosteroids for prolonged periods of time may have adrenal suppression and must continue to receive steroids during the treatment of their infection. The minimum dose should be that recommended for stress situations (about 50 mg of hydrocortisone, or its equivalent, per m2 per day). Prophylactic antibiotics have no proven benefit in the prevention of infections in nephrotic children.35

Immunizations for children with nephrotic syndrome should be considered in the context of their underlying immunodeficiency, evidenced in part by their low IgG levels during active disease and their iatrogenic immunosuppression resulting from treatment with corticosteroids, cytotoxic agents, and other immunosuppressive drugs. Ideally, all routine immunizations should be administered during remission of the disease and at least 3 months after all immunosuppressive drugs have been discontinued; these guidelines are particularly essential for all live-virus vaccines, including oral polio and measles, mumps, and rubella vaccines, as well as the soon-to-be available livevaricella vaccine, in accordance with recommendations in the Red Book Report of the Committee on Infectious Diseases from the American Academy of Pediatrics (1991). Data on the safety and efficacy of these vaccines during active nephrotic syndrome in the absence of immunosuppressive drugs are not available; consultation with local experts is advisable in these situations. The Red Book does recommend the administration of pneumococcal vaccine to nephrotic children in view of their increased susceptibility to infections with S pneumoniae. However, it should be recognized that there has been no formal demonstration of vaccine efficacy in these children, and failures have been reported.36,37

SPECIFIC TREATMENTS

Because the etiology of childhood nephrotic syndrome remains unknown, no form of therapy can be considered entirely specific. However, corticosteroids are known to be capable of eliminating most signs and symptoms of nephrotic syndrome and represent the mainstay of therapy. Unfortunately, the condition tends to be a relapsing one in the majority of patients, and attempts to find a corticosteroid regimen that can prevent relapses, once therapy is withdrawn, have been unsuccessful or only partially successful.3,5,30,38 Accordingly, corticosteroids should be viewed as palliative rather than curative.39

Table

TABLE 2Prednisone Treatment of Minimal Lesion Nephrotic Syndrome

TABLE 2

Prednisone Treatment of Minimal Lesion Nephrotic Syndrome

Prednisone should be administered in an initial dose of 2 mg/kg/day or 60 mg/m2/day (maximum 60 mg/day)3,5·30 (Table 2). Historically, two or three divided daily doses have been recommended, but no evidence exists that such a regimen is superior to single-dose daily morning administration, which has proven equally successful compared with the divided dose regimen.30,40 Administering a single daily morning dose offers the practical advantage of convenience along with the theoretical advantage of conforming more closely to the normal diurnal rhythmicity of adrenal corticosteroid secretion, which might in turn reduce steroid side effects during prolonged usage.

Although liquid preparations of prednisone or prednisolone are available and are potentially more convenient for use in small children, both their high cost and objectionable taste make it advisable to consider use of tablet forms for most patients. Although prednisone tablets have a bitter taste, they usually can be crushed and disguised in a small amount of pleasant-tasting food such as applesauce. The taste of the liquid preparations may be more difficult to disguise than the tablets; moreover, they cost 5 to 10 times more than generic prednisone tablets. Given the fact that steroid treatment often continues for several months or longer, attention to these practical considerations can significantly reduce the burden imposed by this disease on patient and family alike.

The response to prednisone therapy should be monitored with the aid of a dipstick to qualitatively assess urine protein concentration. A single-purpose dipstick that tests only for protein, such as the Ames Albustix (Miles Ine, Elkhart, Indiana) is preferred. The cost for a bottle of 100 sticks is about $34- For families with limited financial resources, cutting the sticks longitudinally in half reduces the cost per test without compromising the interpretation of the result. The urine should be monitored initially on a daily basis.

Response to steroid therapy will be characterized by a rather abrupt normalization of the qualitative urine protein excretion (defined as either a negative or trace reaction on the Albustix) and a concomitant diuresis. As this diuresis is completed, parents often will observe a sunken look about the eyes that will resolve in 1 or 2 days without therapy and need not raise concerns in the absence of any symptoms; forewarning families about this may be helpful.

The vast majority (92% to 94%) of patients responding to prednisone therapy will do so within the first month of treatment; most of the remaining responses occur during the second month.7,41 The mean response time is about 10 to 13 days.9,30 Ninety-three percent of children with MLNS respond to an 8-week course of steroid therapy, and 92% of children responding to steroids have MLNS.40

Daily prednisone administration should be continued for 1 month. Treatment for responding patients then should be changed to an every-other-morning schedule of administration, using the same dose as was given daily (eg, 60 mg daily would be changed to 60 mg every other day), followed by tapering of the alternate day dose gradually over 6 months. This prolonged tapering period is recommended for new onset nephrotic syndrome based on a small amount of controlled data suggesting its superiority over more rapid tapering schedules.5,38 The trade-off inherent with such prolonged steroid exposure, however, is the possibility of increased drug toxicity Although the alternate-day schedule of administration significantly reduces this risk, the prolonged duration of treatment nevertheless may potentiate steroid side effects, and these must be sought carefully during regular medical check-ups. A growth chart should be maintained to detect linear growth impairment and examinations should be conducted with a direct ophthalmoscope, taking care to focus at the level of the lens, to detect the development of steroid- induced (posterior subcapsular) cataracts. Surveillance for more obvious side effects such as cushingoid body habitus changes, excess weight gain, skin striae, etc also should be carried out.

Relapse, ie, recurrence of proteinuria at a ^2 + (2*100 mg/dL) level for 3 consecutive days, should be treated initially with daily prednisone in a manner similar to that used at the onset of disease. Once remission is again achieved, however, alternate-day prednisone is begun 4 days after resolution of proteinuria rather than continuing daily treatment for a full month.30 The alternate-day schedule is resumed earlier after controlling relapses in an effort to avoid excessive cumulative prednisone toxicity; more intensive therapy at this stage does not improve the subsequent course.3 Tapering of the alternate-day dose then is accomplished over approximately 8 weeks. Patients who have responded well to daily prednisone but who experience frequent relapses (three or more per year) or those who relapse repeatedly during steroid tapering may be treated for relapses with progressively lower daily prednisone doses (0.25 mg/kg to 1.5 mg/kg), the goal being to determine the minimum amount of prednisone necessary to control the relapses while minimizing prednisone toxicity. The use of lower doses is recommended primarily for recurrent proteinuria only and not when significant anasarca is evident. Some patients, particularly those who tend to relapse during tapering, may benefit from a low maintenance dose of prednisone given on alternate days42 or a low daily dose of hydrocortisone43 to reduce the frequency of relapses and thus avoid the need to repeatedly increase the dose.

Patients who experience frequent relapses or who develop evidence of significant steroid toxicity or those who fail to respond to prednisone within the first month of daily treatment should be referred to pediatric nephrologists for possible renal biopsy and recommendations regarding other forms of therapy, which will be reviewed here only briefly. The alkylating agents, chlorambucil and cyclophosphamide, represent the second line of therapy for steroidresponsive nephrotic syndrome.44 Because of the potential toxicity of these agents, their use should probably be reserved for those patients experiencing significant steroid toxicity, regardless of the actual number or frequency of relapses. The myelosuppressive potential of these medications dictates the need for careful monitoring of the white blood cell count, which should be measured weekly throughout the typical 6- to 12-week course of therapy. Careful attention to fever or any other sign of significant infection is extremely important while patients are receiving one of these agents.

A variety of other therapeutic agents and protocols have been used for nephrotic patients who have significant steroid toxicity as well as those who prove steroid resistant. These include cyclosporine, levamisole, FK-506, and a protocol of high-dose intravenous pulse methylprednisolone. The exact role of these therapeutic modalities continues to evolve, and few data are available to define the relative value of one versus another. The reader is referred to other sources for further information.45

HOSPITALIZATION

Should children with new-onset nephrotic syndrome always be hospitalized? Obviously, health-care delivery systems are changing, and these changes may impact such decisions. Clearly, those patients with moderate or severe anasarca who need intravenous diuretic regimens will require inpatient management. Among those with milder edema, the decision must be based on other considerations. Foremost among these is the fact that nephrotic syndrome of childhood is usually a chronic relapsing disorder, the optimal management of which requires considerable family education and long-term family involvement. In order to prepare the family members properly for their roles, the input of several health-care professionals is sought, including nurses, a dietitian, and a social worker. As a general rule, this process can be earned out most effectively and efficiently during a brief hospitalization.

The educational process should be directed toward helping the family understand the nature of the disorder, its tendency to relapse, and the expected side effects from its treatment with prednisone. Dietary counseling should focus on the salt, total calorie, and fat contents of the diet. The technique for urine Albustix usage for home monitoring should be taught. In some cases, the family may be instructed in the technique of blood pressure determinations and appropriate equipment obtained for home use. It should be noted that lay publications can be obtained through the National Kidney Foundation and the American Kidney Fund on the subject of childhood nephrotic syndrome.

REFERENCES

1. Siegel NJ, Goldberg B, Krassner LS, Hayslett JP. Long-term follow-up of children wich steroid-responsive nephrotic syndrome. J Pediatr. 1972;81:251-258.

2. McEnery PT, Strife CF. Nephrotic syndrome in childhood. Pediatr Clin North Am. 1982;29:875-894.

3. Internacional Study of Kidney Disease in Children. Nephrotic syndrome in children: a randomized trial comparing two prednisone regimens in steroid-responsive patients who relapse early. J Pediatr. 1979;95:239-243.

4. International Study of Kidney Disease in Children. Early identification of frequent relapsere among children with minimal change nephrotic syndrome. J Pediatr. 1982i101:514-518.

5. Arbeitsgemeinschaft fur Rdiatrische Nephrologie. Short versus standard prednisone therapy fer initial treatment of idiopathic nephrotic syndrome in children. Lancet. 1988;1:380-383.

6. Wingen A-M, Muller-Wiefel DE1 Scharer K. Spontaneous remissions in frequently relapsing and steroid dependent idiopathic nephrotic syndrome. Clin Nephrol. 1985i23:35-40.

7. Makker SR Heymann W. The idiopathic nephrotic syndrome of childhood. Am J Dis Child. 1974;127:830-837.

8. Churg J, Habib R, White RHR. Pathology of the nephrotic syndrome in children. Lancet. 1970;1:1299-1302.

9. International Study of Kidney Disease in Children. Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. Kidney Int. 1981;20:765-771.

10. Bakker WW, van Luijk WHJ. Do circulating factors play a role in the pathogenesis of minimal change nephrotic syndrome? Pediatr Nephrol. 19893:341-349.

11. AmeilCC. The nephrotic syndrome. Pediatr Clin North Am. 1971;18:547-559.

12. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet. 1974;2:556-559.

13. White RHR, Glasgow EF, Mills RJ. Clinicopathological study of nephrotic syndrome in childhood. Lancet. 1970;1:1353-1359.

14. International Study at Kidney Disease in Children. Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int. 1978;13:159-165.

15. Yoshikawa N, Ito H, Yoshiara S1 et al. Clinical course of immunoglobulin A nephropathy in children. J Pediatr. 1987;1 10:555-560.

16. Hurley RM, Drummond KN. Anaphylactoid purpura nephritis: clinicopathological correlations. J Pediatr. 1972;81:904-911.

17. McCurdy DK1 Lehman TJA, Bernstein B, et al. Lupus nephritis: prognostic factors in children. Pediatrics. 1992;89:240-246.

18. Sibley RK, Mahan J, Mauer SM, Vernier RL. A clinicopathologic study of 48 infants with nephrotic syndrome. Kidney Int. 1985;27:544-552.

19. Repetto HA, Vazquez LA, Russ C, Costa JA. Late appearance of nephrotic syndrome in congenital syphilis. J Pediatr. 1982;100:591-592.

20. Johnson RJ, Couser WC. Hepatitis B infection and renal disease: clinical, immunoparhogenetic and therapeutic considerations. Kidney Jn!. 1990;37:663-676.

21. Ingulli E, Tejani A, Fikrig S, Nicasrri A, Chen CK, Pomrantz A. Nephrotic syndrome associated with acquired immunodeficiency syndrome in children J Pediatr. 1991; 119:710716.

22. Hendrickse RG, Adeniyi A, Edington GM1 Glasgow EF, White RHR, Houba V. Quartan malarial nephrotic syndrome. Lancet. 1972;1:1143-1149.

23. Robinson J, Malleson P, Lirenman D, Carter J. Nephrotic syndrome associated with nonsteroidal anti-inflammatory drug use in two children. Pediatrics. 1990:85:844847.

24. Snead C, Siegel N, Hayslett J. Generalized lymphadenopathy and nephrotic syndrome as a manifestation of mephenytoin (mesantoin) toxicity, Pediatrics. 1976;57:98-101.

25. Abitbol C, Zilleruelo G, Freundlich M, Strauss J. Quantitation of proteinuria with urinary protein/creatinine ratios and random testing with dipsticks in nephrotic children. J Pediatr. 1990;116:243-247.

26. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG. Adult-onset minimal change nephrotic syndrome: a long-term follow-up. Kidney Int. 1986;29: 12151223.

27. Chesney RW, Novello AC Forms of nephrotic syndrome more likely to progress to renal impairment. Pediatr CIm North Am. 1987;34:609-627.

28. Bohlin A-B, Berg U. Renal sodium handling in minimal change nephrotic syndrome. Arch Dis ChM. 1984;59:825-830.

29. Geers AB, Koomans HA, Boer P, Doorhout-Mees EJ. Blood and plasma volumes in patients with nephrotic syndrome. Nephron. 1984;38:170-173.

30. Warshaw BL1 Hymes LC. Daily single-dose and daily reduced-dose prednisone therapy for children with the nephrotic syndrome. Pediatrics. 1989;5:694-699.

31. Davison AM, Lambie AT, Verth AH, Cash JD. Salt-poor human albumin in management of nephrotic syndrome. Br Med J. 1974;1:481-484.

32. Barran TM, Clark G. Minimal change nephrotic syndrome and focal segmental glomerulosclerosis. In: Holliday MA, Barran TM, Avner ED eds. Pediatric Nephrology. 3rd ed. Baltimore, Md: Williams & Wilkins; 1994:767-787.

33. Haws RM, Baum M. Efficacy of albumin and diuretic therapy in children with nephrotic syndrome. Pediatrics. 1993;91:1142-1146.

34. Strauss J, Zilleruelo G, Freundlich M, Abitbol C. Less commonly recognized features of childhood nephrotic syndrome. Pediatr CIm North Am. 1987;34:591-607.

35. Krensky AM, lngelfinger JR, Grupe WE Peritonitis in childhood nephrotic syndrome. Am J Dis Child. 1982;136:732-736.

36. Spika JS, Halsey NA, Le CT, et al. Decline of vaccine-induced anti-pneumococcal antibody in children with nephrotic syndrome. Am J Kidney Dis. 1986;7:466-470.

37. Moore DH, Shackelford PG, Robson AM, Rose GM. Recurrent pneumococcal sepsis and defective opsonization after pneumococcal capsular polysaccharide vaccine in a child with nephrotic syndrome. I Pediatr. 1980;96:882-885.

38. Ueda N, Chibara M, Kawaguchi S, et al. Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome. J Pediatr. 1988;112:122-126.

39. Glassock RJ, Adler SG, Ward HJ, Cohen AH. Primary glomerular diseases. In: Brenner BM, Rector FC Jr, eds. The Kidney. Philadelphia. Pa: WB Saunders Co; 1991:1182-1279.

40. Choonara IA, Heney D, Meadow SR. Low dose prednisolone in nephrotic syndrome. Arch Dis Child. 1989;64:610-621.

41. International Study of Kidney Disease in Children. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J Pediatr. 1981;98:561-564.

42. Soyka LF, Saxena KM. Alternate-day steroid therapy for nephrotic children. JAMA. 1965;192:125-130.

43. Schoeneman MJ. Minimal change nephrotic syndrome: treatment with low doses of hydrocortisone. J pediarr. 1983;102:791-793.

44. Arbeitsgemeinschaft fur Pädiatrische Nephrologie. Effect of cytotoxic drugs in frequently relapsing nephrotic syndrome with and without steroid dependence. N Engl; Med. 1982306:451-454.

45. Kim MS, Grupe WE. The management of primary glomerular disease: alternatives to steroid therapy. In: Edelman CM Jr, ed. Pediatric Kidney Disease. Boston, Mass: Little, Brown & Co; 1992:1355-1380.

TABLE I

Clinical Features of Minimal Lesion Nephrotlc Syndrome

TABLE 2

Prednisone Treatment of Minimal Lesion Nephrotic Syndrome

10.3928/0090-4481-19940901-08

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