DOI: 10.1542/pir.23-7-237 2002


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DOI: 10.1542/pir.23-7-237 2002

  1. 1. Nephrotic Syndrome: Pathogenesis and Management Karl S. Roth, Barbara H. Amaker and James C.M. Chan Pediatr. Rev. 2002;23;237 DOI: 10.1542/pir.23-7-237 The online version of this article, along with updated information and services, is located on the World Wide Web at: Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2002 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Downloaded from by Shruti Kant on August 27, 2008
  2. 2. Article renal disease Nephrotic Syndrome: Pathogenesis and Management Karl S. Roth, MD,* Objectives After completing this article, readers should be able to: Barbara H. Amaker, MD,* James C.M. Chan, MD† 1. Describe the signs and symptoms of minimal-change nephrotic syndrome. 2. Characterize the laboratory findings in children who have minimal-change nephrotic syndrome. 3. Plan a treatment program for a young child who has an initial episode of minimal- change nephrosis. 4. Recognize the major complications of minimal-change nephrotic syndrome. Introduction The estimated annual incidence of nephrotic syndrome in healthy children is 2 to 7 new cases per 100,000 children younger than 18 years of age, making it a relatively common major disease in pediatrics. The peak age of onset occurs at 2 to 3 years except for the rare, congenital type of nephrosis. Approximately 50% of affected children are ages 1 to 4 years; 75% are younger than age 10 years. In addition, even the most benign form of the nephrotic syndrome is, by nature, a recurrent disorder, so each new-onset case likely will continue to manifest disease for some time. Nephrotic syndrome is one of the most frequent reasons for referral to a pediatric nephrologist for evaluation, although its insidious onset frequently causes delay in diagnosis. Careful examination of the anatomy of a nephron permits characterization of the glomerular basement membrane as the barrier between the circulation and the external environment. Thus, the glomerular membrane, which permits passage in an adult of approximately 180 L/d of fluid, is the final determinant of how much of the solute originally contained in this volume enters the tubular lumen. The normal glomerular membrane is remarkably selective for protein compared with other solutes (Table 1). Once this selectivity is lost, the ensuing proteinuria defines not only the diagnosis of nephrotic syndrome, but many pathophysiologic consequences as well. It is the purpose of this article to discuss the definition, causes, pathophysiologic consequences, and management of nephrotic syndrome. The emphasis is on the idiopathic form, which most often occurs in children as minimal-change nephrotic syndrome; other types of the nephrotic syndrome are mentioned briefly. Definition As anticipated from the name, the composite of clinical findings can be found either alone or in association with a number of systemic disorders, including toxicities. The sine qua non of the diagnosis of nephrotic syndrome is the presence of urinary protein, with the albumin disproportionately greater than the globulin, deriving from a loss of glomerular membrane selectivity. In the pediatric age group, urinary protein loss of 50 mg/kg per 24 hours or greater is a firm diagnostic criterion. It is imperative to recognize the distinctive origin of the proteinuria in the glomerulus rather than the tubule; nephrotic syndrome may be seen as exclusively glomerular in origin without any associated tubular dysfunction. Addition- ally, as a syndrome, the clinical picture may be either primary or secondary, and underlying causes must be excluded. *Departments of Pediatrics and Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA. † Department of Pediatrics, The Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME. Pediatrics in Review Vol.23 No.7 July 2002 237 Downloaded from by Shruti Kant on August 27, 2008
  3. 3. renal disease nephrotic syndrome Selected Materials in Table 1. (VLDL and LDL, respectively) cholesterol are character- istic findings. VLDL-cholesterol is increased as a conse- Glomerular Filtrate Versus Urine* quence of decreased hepatic catabolism, thus increasing circulating triglyceride and cholesterol. LDL-cholesterol 24-hour Glomerular is increased due to an enhanced synthetic rate. What Material Filtrate Urine (24 hour) remains to be elucidated is the cause for these distur- bances in hepatic lipid metabolism. Sodium 24,000 mEq 50 to 200 mEq Potassium 680 mEq 10 to 100 mEq Primary nephrotic syndrome may occur at any age, Calcium 7 to 10,000 mg Approximately 200 mg from the neonate to the adult. The neonatal or congen- Glucose 200 g <50 mg ital nephrotic syndrome, also called Finnish congenital Amino Acids 10 g 50 to 150 mg nephrosis, is clearly defined as a genetic mutation in the Protein ** <150 mg/L nephrin gene and has been mapped to chromosome Water 180 L 1.5 L 19q13.1. Nephrin is a glomerular basement membrane *Data are presented for a “standard adult male”; values for infants and protein that participates in formation of anionic-rich children vary with gestational age, age in years, and stage of renal tubular development. sites, causing electrochemical repulsion of plasma pro- **Data are lacking in the literature. teins. The mutation also has been reported in a Menno- nite group in Pennsylvania who have no Finnish heritage and is believed to have arisen independent of the Finnish Clinical Diagnostic Criteria type. Primary childhood nephrotic syndrome rarely ap- The diagnostic criteria are: 1) generalized edema; 2) hy- pears before 18 months to 2 years of age and peaks in poproteinemia ( 2 g/dL [20 g/L]), with dispropor- incidence at about 3 years of age. tionately low albumin in relation to globulin; 3) urine protein (mg/dL) to urine creatinine (mg/dL) ratio in Laboratory Findings excess of 2 in a first morning void or a 24-hour urine The primary laboratory feature of the nephrotic syn- protein that exceeds 50 mg/kg body weight; and 4) hy- drome is a marked proteinuria, in excess of 50 mg/kg per percholesterolemia ( 200 mg/dL [5.17 mmol/L]). 24 hours (Table 2). The excreted protein is predomi- The reduced serum albumin, which can fall to as low nantly albumin, although immunoglobulins (Igs) also as 0.5 g/dL (5 g/L), causes a marked reduction in are lost. In uncomplicated cases of idiopathic nephrotic plasma oncotic pressure. Consequently, circulatory vol- syndrome, it is unusual to see gross hematuria in the ume is lost to the interstitial spaces, resulting in general- presence of proteinuria, although microscopic hematuria ized edema. Often, the initial swelling is observed as occurs in a sizeable proportion of cases. For patients who facial (especially periorbital) and pretibial edema, with have gross hematuria and proteinuria, IgA nephropathy prominent swelling of the scrotum or labia also seen. An always must be a diagnostic consideration. additional consequence of the lowered oncotic pressure In the presence of clinical edema, measurement of is reduced perfusion of the splanch- nic capillary bed, which can cause abdominal pain. Pleural effusions Table 2. Laboratory Findings in the Nephrotic may form, and frank pulmonary edema also may occur, with either Syndrome or both resulting in tachypnea and Primary Finding Diagnostic Concentration chest pain. Levels of serum cholesterol, Proteinuria >50 mg/kg per 24 h triglyceride, and lipoprotein cho- Hypoproteinemia <2.0 g/dL (20 g/L) Cholesterolemia >200 mg/dL (5.17 mmol/L) (frequently lesterol are consistently elevated. >500 mg/dL [12.9 mmol/L]) The mechanism(s) underlying these changes are not understood Secondary Finding Frequently Found Values completely, in part due to the com- Hypocalcemia (ionized <9.0 mg/dL (2.25 mmol/L) plexity of lipid transport and the fraction normal) Hyperkalemia >5.0 mEq/L (5.0 mmol/L) difficulties inherent in human clini- Hyponatremia <136 mEq/L (136 mmol/L) cal studies. Increases in very-low Hypercoaguability 2partial thromboplastin time (PTT) density and low-density lipoprotein 238 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  4. 4. renal disease nephrotic syndrome serum protein will yield low values; the serum albumin is likely to be 2.0 g/dL (20 g/L) or lower. Albumin Primary and Secondary Table 3. concentrations as low as 0.5 g/100 mL can be seen, and the albumin/globulin ratio is commonly less than 1.0. Glomerulopathies Concomitantly, and directly related to the reduced se- Idiopathic Minimal-change Nephrosis rum protein, hypocalcemia is found frequently, as re- flected in reduced total and ionized fractions. However, Focal Segmental Glomerulosclerosis hypocalcemia rarely is manifested clinically. Idiopathic Of much greater significance than hypocalcemia to Obesity patients who have nephrotic syndrome is the increased Unilateral renal agenesis concentrations of coagulation factors, especially those of Glycogen storage disease Postinfectious glomerulonephritis high molecular weight. Thrombin also is increased, while Obstructive uropathy fibrinolytic activity and circulating quantities of platelet Lupus nephropathy adhesion inhibitors are decreased. As a consequence of Sickle cell disease these changes, as well as the intravascular hypovolemia, Alport syndrome affected patients are at greatly increased risk of thrombo- Membranous Glomerulonephritis sis. In addition, IgG in plasma is reduced, which in Idiopathic combination with large steroid doses, may predispose to Lupus nephropathy infection. Sickle cell disease Children who become oliguric from diminished intra- Sarcoidosis vascular volume have a tendency to develop hyperkale- Hashimoto thyroiditis Heavy metal toxicity mia. The use of diuretics may complicate the electrolyte Captopril disturbances further, necessitating close monitoring of Penicillamine serum electrolyte levels during treatment. Nonsteroidal anti-inflammatory drugs Syphilis Hepatitis B and C The Need for a Renal Biopsy Membranoproliferative Glomerulonephritis In the acute stage of childhood nephrotic syndrome, Chronic bacterial infection especially during the initial episode, renal biopsy usually Chronic viral infection is unnecessary. The key indications for biopsy in any renal Lupus nephropathy disorder are the need to make a specific diagnosis for Rheumatoid arthritis Chronic liver disease therapeutic reasons or to provide a prognosis. The treat- Sickle cell disease ment of initial-onset nephrotic syndrome is the same, Renal transplant irrespective of cause, and the need for determining a Bone marrow transplant prognosis never can outweigh the risks of thrombosis, bleeding, and infection due to a biopsy in the acute stage of the disorder. family’s anxieties over the immediate medical problems The subsequent disease course in a patient can help to have dissipated. determine the timing of a renal biopsy. In an uncompli- In contrast, when there is poor or no response of the cated case in which proteinuria clears within a few weeks initial episode after 4 to 6 weeks of standard treatment in response to orally administered corticosteroids and (defined as steroid-resistance disease), biopsy should be normal renal function, the diagnosis is presumed to be considered as soon as the patient is medically stable. In minimal-change nephrotic syndrome. If there is no sig- such cases, the biopsy is essential to distinguish the nificant proteinuria between relapses that continue to nature and severity of the glomerular process, which may respond promptly to corticosteroids, this diagnosis is be primary or secondary (Table 3). It should be clear strengthened. If the child is younger than 10 years of age from the plethora of types and causes of glomerular at the initial presentation, no renal biopsy need be con- nephropathy that treatments and prognoses vary consid- sidered. At age 10 years or older, the increasing risk of erably, making specific diagnosis imperative. Because underlying primary disease compels the need to obtain a proteinuria and microscopic hematuria are injury re- biopsy for histologic diagnosis. In such cases, renal bi- sponses of the glomerulus, the need for clarification opsy can be deferred until the child is stable and the through renal biopsy is plain. The underlying pathology Pediatrics in Review Vol.23 No.7 July 2002 239 Downloaded from by Shruti Kant on August 27, 2008
  5. 5. renal disease nephrotic syndrome Figure 1. A. Light microscopic view of a normal glomerulus Figure 2. A. Light microscopic view of minimal-change dis- (Jones silver stain). B. Electron micrograph showing normal ease. The glomerulus is normal at the light microscopic level glomerulus with well-defined epithelial cell foot processes. (PAS stain). B. Diffuse epithelial cell foot process effacement is seen, and lipid droplets are present in the cytoplasm of the (Figs. 1 to 5) varies with age; the incidence is summa- visceral epithelial cell. rized in Table 4. The indications for initial kidney biop- sies in the nephrotic syndrome are summarized in Table essential to good medical care, and its use should be 5. viewed judiciously in all patients. Beyond the issue of renal biopsy for initial diagnosis, there are circumstances in which a subsequent biopsy Treatment may be considered. Glomerular injury may evolve over The treatment of primary childhood nephrotic syndrome time such that the clinical findings (eg, increasing pro- is supportive and will be determined largely by the pa- teinuria, development of chronic renal insufficiency) tient’s clinical status. Boys can experience scrotal edema, change significantly. Such cases may represent progres- which may cause testicular torsion. Other children may sion of a disease that initially was diagnosed as minimal- become short of breath due to pulmonary edema; still change nephrosis by biopsy or progressive injury to the others may become oliguric and develop a functional kidney by an underlying disease such as lupus nephrop- azotemia. The latter is due to reduced circulating volume athy. In these situations, a second renal biopsy should be in the vascular space that results in temporary renal considered for evaluation of progressive renal disease. insufficiency. Any of these presentations, alone or in Technological developments in ultrasonography have combination, demands immediate attention to symp- reduced significantly the risk associated with percutane- tomatic treatment. ous renal biopsy in children. Moreover, the improve- ments in electron microscopy equipment and technique, Treatment of Acute-onset Disease coupled with decades of observation, have enhanced the The unifying factor in this disease is depleted blood ability of the histopathologist to interpret the specimen volume as a consequence of low oncotic pressure. There- accurately. Nonetheless, a renal biopsy is not always fore, treatment should be directed at returning fluid to 240 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  6. 6. renal disease nephrotic syndrome Figure 3. A. Segmental sclerosis of the glomerular tuft as seen with light microscopy (PAS stain). B. Immunofluorescence demonstrates the presence of IgM in the segmentally sclerotic portion of the glomerulus. C. The visceral epithelial cell contains vacuoles, and focal foot process effacement is seen. the vascular space and encouraging diuresis to avoid heart failure. Accordingly, intravenous albumin should volume overload (Table 6). The intuitive solution to the be infused continuously over 8 to 12 hours under close diminished oncotic pressure is to restore serum albumin supervision. concentration to better than 2 g/dL (20 g/L) by intra- As intravascular space expands, renal perfusion im- venous infusion. However, the effectiveness of this mea- proves, and with it, the opportunity to reduce accumu- sure is reduced considerably because of the hypoalbu- lated fluid volume is enhanced. Administration of a di- minemia resulting from glomerular leakage of serum uretic is the obvious means by which to maximize this protein. The degree of urinary loss can be illustrated by opportunity. Keeping in mind that a normal or low the hepatic rate of albumin synthesis, which in adults can serum sodium concentration is likely to represent the be as high as 12 to 14 g/d. If a patient becomes hy- result of a dilutional effect, the choice of diuretic should poalbuminemic at such endogenous rates of replace- be directed at sodium as well as at water excretion. An ment, it is apparent that replacement by infusion can only ideal choice is a loop diuretic such as furosemide, which be a temporary remedy. Nonetheless, for a patient who can be administered at a dose of 1 to 2 mg/kg intrave- has pulmonary edema or renal shutdown, intravenous nously and acts within 15 minutes. Furosemide-induced albumin (1 g/kg of a 25% solution) can be very effective inhibition of active chloride reabsorption in the ascend- in mobilizing fluid into the vascular space. The rate of ing loop of Henle results in urinary excretion of sodium, increase in oncotic pressure is directly proportional to the chloride, and water. A portion of the calculated furo- rate of expansion of intravascular volume. Thus, too semide dose can be administered during the albumin rapid an infusion will place the child at risk for congestive infusion or it all can be administered at the end of the Pediatrics in Review Vol.23 No.7 July 2002 241 Downloaded from by Shruti Kant on August 27, 2008
  7. 7. renal disease nephrotic syndrome Figure 4. A. Hypercellularity and lobulation is seen in this Figure 5. A. Diffuse uniform thickening of the capillary walls glomerulus (PAS stain). B. Broad granular staining for com- is seen (PAS stain). B. Finely granular staining with IgG is seen plement 3 is present along glomerular capillary walls. C. along the capillary walls. C. Electron micrograph showing Electron micrograph showing a large, discrete, electron-dense idiopathic membranous glomerulonephropathy, stage II to III. subendothelial deposit and “reduplication” of the glomerular Columns (“spikes”) of basement membrane-like material pro- basement membrane. trude between the subepithelial electron-dense deposits. Some of the deposits are embedded in the glomerular base- infusion, depending on the volume of urine output and ment membrane. the degree of edema. Debate continues over the true benefit of albumin infusion, and no resolution is in sight. Nonetheless, it is The child should be started on oral corticosteroid difficult to argue against its use in the clinical settings of therapy after a negative tuberculosis skin test result has pleural effusion, pulmonary edema, or impending renal been determined. Prednisone is the usual drug of choice, shutdown due to depleted intravascular volume. and the recommended maximum daily dose is 60 mg/m2 242 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  8. 8. renal disease nephrotic syndrome Underlying Renal Pathology in Nephrotic Table 4. protein excretion should not be an- ticipated for at least 7 to 10 days Syndrome in Childhood following the initiation of treat- ment, so the patient’s degree of 1 to 12 Years 13 to 19 Years of Age of Age proteinuria should not determine the length of a hospital stay. Chil- Minimal-change nephrotic syndrome 76% 43% dren who have mild-to-moderate Focal segmental glomerulonephropathy (FSGS) 7%* 13% Membranoproliferative glomerulonephropathy 7% 14% edema, no pulmonary edema, and a Membranous nephropathy 2% 22% good diuretic response generally re- Others 8% 8% quire a hospital stay of no more *In Asian and African-American children, the risk of FSGS is 14%. than 2 to 3 days. Fluid balance must be moni- tored closely in the early stages of treatment. Optimal nutrition, in- or 2 mg/kg. The daily dose should be maintained for cluding high-quality protein in amounts required for 4 to 6 weeks. Opinion varies regarding this recommen- growth, is essential because the demand for albumin dation, ranging from daily treatment administered just replacement is increased. The child should follow a “no long enough to achieve remission to 6 weeks of daily salt-added” diet, with maintenance sodium provided for treatment. Following remission, the dose should be kept replacement during diuresis. Daily weights are key to constant while changing to an alternate-day schedule for assessing the therapeutic progress. Other adjunctive an additional 6 weeks. A measurable decrease in urine treatment, such as anticoagulation therapy, should be used judiciously. If laboratory evidence is sufficient to consider coagulopathy, heparin may be used at a dose of Indications for Initial Table 5. Kidney Biopsies in Nephrotic Treatment of Acute- Table 6. Syndrome onset Nephrotic Syndrome 1. Patients who have steroid-resistant nephrotic syndrome and continue to have proteinuria and Steroids (a negative tuberculosis skin test result must edema despite a full course of prednisone. be determined before starting steroid medications) 2. Patients who have steroid-responsive nephrotic Prednisone syndrome and have more than two relapses in a 6- 60 mg/m2 or 2 mg/kg daily for 6 weeks month period (the so-called “frequent relapsers”) 60 mg/m2 or 2 mg/kg every other day for 6 weeks 3. Patients who have low serum complement at the time of initial presentation of nephrotic syndrome Diuretics not related to acute postinfectious Furosemide glomerulonephritis. A biopsy is indicated to rule out 0.5 to 2.0 mg/kg per dose intravenously hypocomplementemic membranoproliferative glomerulonephropathies. Protein Replacement* 4. Nephrotic syndrome with hypertension at Salt-free albumin presentation. The risk of focal segmental 1.0 g/kg infused intravenously over 8 to 12 hours glomerulonephropathy (FSGS) is higher. 5. Patients younger than 1 year of age at presentation. Additional Measures Biopsy is indicated because of a high likelihood of Heparin if sufficient hypercoagulability is congenital nephrotic syndrome. demonstrated 6. Patients older than 10 years of age at presentation. Adequate protein in diet for endogenous synthesis of Biopsy is indicated to rule out more serious renal albumin pathology than minimal-change disease. No salt-added diet to reduce fluid retention 7. Systemic lupus erythematosus with proteinuria or nephrotic syndrome. *Many authorities dispute the need for or safety of this measure. The degree of urinary protein loss makes any long-term improvement of 8. Evidence of chronic renal insufficiency with serum albumin concentrations unlikely. Such a measure is indicated persistent elevation of serum urea nitrogen and only when edema is sufficiently severe to cause potential compromise to creatinine. pulmonary function or integumental integrity. Pediatrics in Review Vol.23 No.7 July 2002 243 Downloaded from by Shruti Kant on August 27, 2008
  9. 9. renal disease nephrotic syndrome Table 7. Steroidal and Nonsteroidal Treatment Medication Dosage Comments Steroidal Agents Prednisone 2 mg/kg per day orally Daily for 6 wk, followed by alternate-day dosing for 6 wk. (maximum, 60 mg/d) This 12-wk regimen is more effective than an 8-wk regimen in reducing relapse. Adverse effects: growth retardation, cataracts, osteoporosis Methylprednisolone 30 mg/kg per week intravenously; In partial steroid-resistant cases, this relatively high-dose sodium succinate combined with prednisone regimen may aid in moderating development of FSGS 2 mg/kg on alternate days for variable duration according to underlying diseases Nonsteroidal Agents Cyclophosphamide 2 mg/kg per day for 8 wk; May induce steroid sensitivity in later relapses. Adverse prednisone 60 mg/m2 on effects: sterility, bone marrow depression, sepsis, alternate days alopecia. To avoid hemorrhagic cystitis, administer medication early in the day and encourage oral fluid intake Chlorambucil 0.2 mg/kg per day for 8 to 12 wk Same as for cyclophosphamide. Adverse effects as for cyclophosphamide; risk of marrow depression may be higher Cyclosporine 5 mg/kg per day to maximum Effectively maintains remission, but relapses occur on 20 mg/kg per day for up to 4 y discontinuation. Adverse effect: nephrotoxicity Levamisole 2.5 mg/kg per day during May help to maintain remission in steroid-dependent remissions disease Angiotensin-converting 5 to 10 mg/kg per day chronically Renoprotective by reducing glomerular hyperfiltration. Enzyme Inhibitors Adverse effects: hypotension, cough Indomethacin 50 kg/day for short term (<3 Reduces glomerular hyperfiltration. Adverse effect: mo) hepatorenal toxicity Mizoribine 2 to 5 mg/kg per day for 24 wk Reduces relapsing nephrotic syndrome. Blocks purine biosynthesis, inhibits mitogen-stimulated T- and B-cell proliferation. Adverse effect: hyperuricemia Mycophenolate mofetil 25 mg/kg per day in two divided Effective in conjunction with prednisone to control diffuse doses for up to 1 y proliferative lupus nephropathy. Primary adverse effects are gastrointestinal. Generally well tolerated 50 U/kg intravenously and 100 U/kg every 4 hours tively. For many such patients, different steroid-based intravenously for maintenance. strategies or alternative treatments may be required Using the treatment outlined previously, 85% to 90% (Table 7). of children who have an initial onset of minimal-change Long-term maintenance on daily or alternate-day nephrotic syndrome will achieve satisfactory therapeutic low-dose oral prednisone may be appropriate for patients responses. For the few who do not experience a remission who experience frequent relapses. Many children remain with absence of proteinuria within the first 2 to 3 months in long-term remission on such a regimen with few, if after onset, alternative therapies are available. any, adverse effects. If the child can be kept in remission with relatively low steroid doses in the absence of adverse Chronic and Outpatient Treatment effects, this approach is optimal because it is the least For most children who have minimal-change nephrotic harmful of the available choices. On the other hand, syndrome, the proteinuria will clear by the third week of when high steroid doses are required for maintenance or oral prednisone treatment. This is a sufficient diagnostic when steroid-related adverse effects supervene, alterna- criterion to confirm the diagnosis. The small percentage tive medications are required because the child clearly has of children who are not completely free of proteinuria for a steroid-resistant nephrotic syndrome. at least 3 to 5 days or those whose proteinuria continues Among the alternative medications are several immu- beyond 3 months are classified as frequent relapsing/ nosuppressive agents as well as an antihelminthic and steroid-dependent or steroid-resistant patients, respec- certain nonsteroidal medications (Table 7). The usual 244 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  10. 10. renal disease nephrotic syndrome choices are cyclophosphamide and chlorambucil, each of Because minimal-change nephrosis occurs most com- which can be used to achieve an initial remission or to monly in young children, there may be problems related render the steroid-resistant child relatively more steroid- to routine childhood immunizations. It is clear that no responsive. The recommended dose of each is listed in child should receive immunizations during treatment Table 7. However, each is associated with a rather im- with high-dose steroids to gain remission or with immu- pressive list of systemic and specific organ toxicities, nosuppressive agents to address frequent relapses. How- which is the key reason for their general use as alternative ever, because relapses often are related to viral illness, use modalities. Either may be used over 2 to 3 months to of live virus vaccines during remissions are viewed with induce a complete remission, but after completion of disfavor by some nephrologists. A recent study suggested treatment, more than 50% of patients experience a re- no unanimity of opinion among pediatric nephrologists lapse, usually within 2 years. Moreover, in many such with respect to immunization practices for children who relapses, the degree of steroid resistance is greater than have nephrotic syndrome. Because affected patients are prior to the use of the immunosuppressive agent. Cyclo- prone to pneumococcal infection, the American Acad- sporine also has been used for induction of a remission in emy of Pediatrics recommends use of the polyvalent steroid-resistant patients. Although effective in this re- vaccine (Pneumovax ) in children older than 2 years and spect, relapse occurs on drug discontinuation, unlike prophylactic penicillin in those younger than 2 years. chlorambucil and cyclophosphamide. Thus, the primary advantage of all three drugs in steroid-resistant nephrotic Complications syndrome is to permit use of smaller doses of steroids, Because minimal-change nephrotic syndrome is a self- thereby minimizing steroid-related adverse effects. limited disease in the majority of affected children, a clear Recently, the results of a clinical trial have been pub- distinction should be made between complications of the lished for a new agent for induction of remission in disease and those that more likely are related to the relapsing nephrotic syndrome. The double-blind, treatment. For example, a patient treated with high-dose placebo-controlled, multicenter trial examined the im- prednisone is at greater risk for the development of many munosuppressive drug mizoribine (Table 7). The agent steroid-related disorders (eg, gastrointestinal ulcer, insu- decreased the relapse rate and prolonged remission in lin resistance), which are not among the known compli- children 10 years of age and older, with relatively few cations of nephrotic syndrome (Table 8). adverse effects. However, additional experience with this One true complication of nephrotic syndrome is the drug must be acquired before it can be considered for tendency to develop infections (eg, peritonitis, cellulitis, routine use. A clinical trial of the drug mycophenolate sepsis). A major source of morbidity from infection in mofetil in treatment of diffuse proliferative lupus nephri- those who have nephrosis is peritonitis, which results tis documented equivalent efficacy to cyclophosphamide from multiple abnormalities of the humoral antibody with far fewer adverse effects. Its use in treatment of system. IgG antibody is lost in the urine, and comple- idiopathic nephrotic syndrome has not yet been re- ment activation is impaired by concomitant loss of factor ported, nor can its safety for use in children be assumed at B. Other events in the bowel may contribute to the this time. tendency. Marked intravascular depletion causes dimin- Nonsteroidal agents (Table 7), such as anti- ished splanchnic blood flow and hypoxia, and a marked inflammatory drugs and angiotensin-converting enzyme tendency to thrombosis may cause microinfarctions, low- inhibitors, may be of limited use as alternative therapeu- ering resistance of the bowel wall to bacterial passage. tic agents in those very few patients who are refractory to The organisms causing peritonitis include Streptococcus steroids. A combination of captopril and indomethacin pneumoniae and Escherichia coli. Peritonitis is a major has been reported as effective for treatment of early-onset contributor to the 1% to 2% mortality in nephrotic syn- (within the first several months of life) nephrotic syn- drome and always should be considered in an affected drome. The mechanism of action is related to effects on patient who complains of abdominal pain. Abdominal renal blood flow and glomerular filtration rather than to paracentesis then should be performed. Bacterial inva- immunosuppression, so the decrease in proteinuria sion of the skin, usually by gram-positive organisms, achieved is not a result of alterations in the basic disease appears as erysipelas, with sharply demarcated borders mechanism. Secondary effects of altered renal perfusion and associated lymphangitis. may predispose the already intravascularly depleted pa- The second major contributor to both mortality and tient to acute renal failure, requiring careful monitoring morbidity in this disease is thromboembolism. There is a when using these agents. real risk of thrombosis in children experiencing an initial Pediatrics in Review Vol.23 No.7 July 2002 245 Downloaded from by Shruti Kant on August 27, 2008
  11. 11. renal disease nephrotic syndrome Table 8. Complications of Nephrotic Syndrome Complications Cause Comments Infection Superficial peritonitis Edema Stretching of the skin contributes to breakdown of its integrity 2Serum IgG Decreased antibody and complement activation predispose to 2Factor B infection; decreased flow and sludging cause microinfarction 2Mesenteric blood flow 1Coagulability Thromboembolus Generally venous 1Platelet aggregation Depending on site, may become devastating; contributing cause 1[Fibrinogen] in peritonitis; can be treated with heparinization Loss of antithrombin-III 1Blood viscosity 2Blood flow Growth Disturbance Marked stunting Loss of IGF-binding protein High-dose steroids may cause growth retardation; use of rhGH 2Serum IGF-I in treatment not yet proven to be of benefit 2Serum IGF-II 2IGF-receptor mRNA IgG circulating immune gamma-globulin, IGF insulin-like growth factor, mRNA messenger RNA, rhGH recombinant human growth hormone or recurrent episode of nephrotic syndrome. However, chronic situations, it may become necessary to institute there is no justifiable reason to use anticoagulant therapy long-term dietary changes and, possibly, drug therapy. during remission because coagulopathy is a result of Finally, growth often is impaired in the nephrotic serum protein abnormalities introduced by renal protein syndrome. Clinical evidence suggests that the proteinuria wasting. In those very few outpatients who have refrac- may cause the marked stunting that is seen in congenital tory nephrosis, it may be worthwhile to consider chronic, nephrosis. There may be losses of insulin-like growth low-dose anticoagulants. In all children experiencing an factor (IGF)-binding protein, which could account for acute nephrotic episode, platelets are hyperaggregable. the depressed serum concentrations of IGF-I and IGF- There is limited experience with dipyridamole, an agent II. Moreover, experimental evidence shows that IGF- that interferes with platelet aggregation, in this disease. receptor mRNA also is depressed. Because high doses of Several factors converge to create a marked propensity steroids also may impair growth, the effects of loss of for thrombus formation: increased platelet aggregation, intrinsic growth factors may be compounded by treat- increased fibrinogen concentration combined with uri- ment. Finally, there is experimental evidence that admin- nary loss of antithrombin-III, increased blood viscosity, istration of growth hormone to nephrotic rats worsens and decreased blood flow. Venous thrombosis predom- the severity of glomerulosclerosis. Much more study is inates and can be found in deep vessels of the extremities, required before use of recombinant human growth hor- the renal vein, the pulmonary venous system, and the mone becomes accepted treatment for growth distur- cerebral cortical system. Arterial occlusion is uncommon bances in the nephrotic syndrome. but has been associated with serious morbidity and even mortality. The potential for this particular complication Prognosis should be carefully considered. Initial coagulation stud- Mortality in minimal-change nephrotic syndrome is ies should be obtained on admission for treatment and approximately 2%, with the majority of deaths due to anticoagulants used judiciously only when appropriate, peritonitis or thrombus, which may occur even under based on the results. the best of treatment circumstances. These complica- The well-known hyperlipidemia associated with the tions may occur in the acute phase of the disease, nephrotic syndrome generally is not a source of clinical despite steroid responsiveness. Thus, although those complications. Because most cases of minimal-change who have congenital nephrosis are steroid- and nephrosis are steroid-responsive, the hyperlipidemia gen- immunosuppressant-resistant, mortality cannot be at- erally is reversed within 4 to 6 weeks. However, in more tributed to this form of the disorder alone. Nonetheless, 246 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  12. 12. renal disease nephrotic syndrome the rare patient who has congenital nephrotic syndrome For those patients whose chronic renal insufficiency represents a considerable therapeutic challenge, requir- progresses to end-stage renal disease, there is always the ing constant attention to serum protein and fluid levels, promise of hemodialysis/renal transplantation. How- monitoring of nutrition balance, and treatment of infec- ever, for patients who have FSGS, there is a 25% risk of tion. recurrence of FSGS in the transplanted kidney, and ne- Of the remaining 98% of children who have minimal- phrotic syndrome occasionally occurs after renal trans- change nephrosis, most are steroid-responsive and can be plantation independent of whether it was previously expected to return eventually to a normal state. By its present. nature, minimal-change nephrotic syndrome results in The long-term prognosis for all categories of ne- relapses; about two thirds of patients experience at least a phrotic syndrome (Table 4) in patients younger than 19 single relapse, with another third possibly developing a years of age is as follows: 20% will continue in remission, protracted series of such relapses over many years. It is 50% will have one or two relapses in any 5-year follow-up important to note that a child who is steroid-responsive period, and the remaining 30% will develop either at the initial presentation may relapse more than once frequent-relapsing nephrosis or steroid-resistant nephro- before the disease ultimately disappears. Many clinical sis. The third category of patients requires diagnostic observers have reported an inverse relationship between renal biopsy. If minimal-change disease is confirmed, the age of presentation and the length of the disease there is a 50% chance for these children to go into course. In general, most patients who have minimal- remission after a course of combined cytotoxic and pred- change disease do very well, ultimately become disease- nisone therapy. free, and have a normal life expectancy. Recovery is deemed permanent if the child is Most patients who have presumptive minimal-change symptom-free and off medications for more than 2 years. nephrotic syndrome and become steroid-resistant later in the disease course have developed focal segmental glo- merular sclerosis (FSGS) (Fig. 3), which arguably is a later evolutionary stage of minimal-change disease to Suggested Reading which some patients progress. The early clinical signs of De Sain-van der Velden MG, Kaysen GA, Barrett HA, et al. In- FSGS are indistinguishable from minimal-change dis- creased VLDL in nephrotic patients results from a decreased ease, but at least one third of patients whose disease catabolism while increased LDL results from increased synthe- sis. Kidney Int. 1998;53:994 –1001 evolves to FSGS progress to end-stage renal failure Fliser D, Zurbruggen I, Mutschler E, et al. Coadministration of within 5 years. In general, those who have more severe albumin and furosemide in patients with the nephrotic syn- nephrotic syndrome, with hypertension and active urine drome. Kidney Int. 1999;55:629 – 634 sediments, and those who are older than 12 years of age Furth SL, Neu AM, Sullivan EK, et al. Immunization practices in at onset are the most likely to develop FSGS. However, it children with renal disease: a report of the North American is not clear whether the severity of disease is a true Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol. 1997;11:443– 446 prognostic marker, rather than a factor that may be more Liang K, Vaziri ND. Down-regulation of hepatic high-density likely to result in intrinsic renal damage. lipoprotein receptor, SR-B1, in nephrotic syndrome. Kidney The hypovolemia and decreased renal perfusion in- Int. 1999;56:621– 626 trinsic to the nephrotic syndrome render the affected Licht C, Eifinger F, Gharib M, et al. A stepwise approach to the individual susceptible to acute renal failure during an treatment of early onset nephrotic syndrome. Pediatr Nephrol. 2000;14:1077–1082 acute episode. Acute renal failure is defined as a sudden Srivastava T, Simon SD, Alon US. High incidence of focal segmen- loss of renal function that is easily and physiologically tal glomerulosclerosis in nephrotic syndrome of childhood. reversible if no significant cellular injury has occurred due Pediatr Nephrol. 1999;13:13–18 to hypoxia. In the latter event, there is a high risk of acute Tune BM, Lieberman E, Mendoza SA. Steroid-resistant nephrotic tubular necrosis, which greatly increases the risk of irre- focal segmental glomerulosclerosis: a treatable disease. Pediatr Nephrol. 1996;10:772–778 versible damage to the kidneys. If such damage occurs, Yoshioka K, Ohashi Y, Sakai T, et al. A multicenter trial of mizor- chronic renal insufficiency supervenes and reverses the ibine compared with placebo in children with frequently relaps- relatively good prognosis of minimal-change nephrosis. ing nephrotic syndrome. Kidney Int. 2000;58:317–324 Pediatrics in Review Vol.23 No.7 July 2002 247 Downloaded from by Shruti Kant on August 27, 2008
  13. 13. renal disease nephrotic syndrome PIR Quiz Quiz also available online at 6. A 5-year-old previously healthy boy presents with headache and swelling of the face of 1 day’s duration. The mother has noticed that his urine is tea-colored. Physical examination reveals an oral temperature of 98°F (36.3°C), respiratory rate of 20 breaths/min, heart rate of 90 beats/min, and blood pressure of 145/ 105 mm Hg. There is mild puffiness of the eyelids. Urinalysis shows dark urine that is strongly positive for blood and has 1 protein, a specific gravity of 1.030, numerous red blood cells (RBCs), and RBC and epithelial casts. Hemoglobin is 11 g/dL (110 g/L) with a normal peripheral smear, blood urea nitrogen is 38 mg/dL (13.6 mmol/L), serum creatinine is 1.6 mg/dL (141.4 mcmol/L), and albumin is 3.0 g/dL (30 g/L). Which of the following is the most likely diagnosis? A. Acute glomerulonephritis. B. Goodpasture syndrome. C. Hemolytic-uremic syndrome. D. Minimal-change nephrotic syndrome. E. Renal vein thrombosis. 7. A 3-year-old previously healthy boy presents with swelling of his face and extremities of 1 day’s duration. Physical examination reveals an oral temperature 98°F (36.3°C), heart rate of 94 beats/min, respiratory rate of 24 breaths/min, and blood pressure of 86/50 mm Hg. His face is markedly puffy, and 3 pitting edema is noted on the dorsum of hands and feet. Urinalysis reveals 4 protein and a specific gravity of 1.030. Serum albumin is 1.5 g/dL (15 g/L) and cholesterol is 340 mg/dL (8.8 mmol/L). Abnormality of which of the following structures best explains his clinical condition? A. Glomerulus. B. Loop of Henle. C. Proximal tubule. D. Renal artery. E. Renal vein. 8. A 5-year-old previously healthy girl presents with periumbilical abdominal pain of increasing severity over the past 2 days. She has been receiving treatment for nephrotic syndrome with prednisone for the last 3 weeks. Physical examination reveals an oral temperature 102°F (38.5°C), heart rate of 124 beats/min, respiratory rate of 34 breaths/min, and blood pressure of 80/50 mm Hg. Peripheral perfusion is poor. Her face appears mildly puffy, and 3 pitting edema is noted on the dorsum of hands and feet. There is generalized abdominal tenderness with guarding and rebound tenderness. Bilateral shifting dullness and a fluid wave are noted on abdominal examination. Urinalysis reveals 4 protein and a specific gravity of 1.030. Abdominal ultrasonography shows considerable ascites. Which of the following is the next most appropriate diagnostic step? A. Abdominal paracentesis. B. Barium enema. C. Computed tomography of the abdomen. D. Doppler ultrasonography of renal vessels. E. Exploratory laparotomy. 9. Which of the following conditions constitutes the need for renal biopsy in a patient who has nephrotic syndrome? A. Age between 2 to 6 years at initial presentation. B. Lack of response after 1 week of prednisone therapy. C. Low serum complement level at initial presentation. D. Relapse 1 year after initial diagnosis. E. Serum albumin level less than 2 g/dL (20 g/L). 248 Pediatrics in Review Vol.23 No.7 July 2002 Downloaded from by Shruti Kant on August 27, 2008
  14. 14. Nephrotic Syndrome: Pathogenesis and Management Karl S. Roth, Barbara H. Amaker and James C.M. Chan Pediatr. Rev. 2002;23;237 DOI: 10.1542/pir.23-7-237 Updated Information including high-resolution figures, can be found at: & Services Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant born_infant Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Reprints Information about ordering reprints can be found online: Downloaded from by Shruti Kant on August 27, 2008