| Abstract|| |
Minimal Change Disease (MCD) is the lesion most commonly associated with nephrotic syndrome in children, accounting for over 75% of cases. Although less common, MCD still accounts for up to 30% of adult onset nephrotic syndrome. Unlike children, in whom MCD is primarily idiopathic, secondary causes of MCD are seen in 13% of adults and must be considered, as the therapeutic approach to these patients is defined by the underlying cause. Clinical features at presentation in nephrotic adults with MCD can include microscopic hematuria, hypertension, and renal insufficiency, making MCD indistinguishable clinically from focal segmental glomerulosclerosis. As a result, a renal biopsy is required in adults in order to correctly diagnose and manage the nephrotic syndrome. As in children, response to therapy leads to a complete remission of proteinuria in up to 97% of adults, although, adults require a more prolonged course of therapy (16-28 weeks) compared to children (8 weeks). Relapse of MCD is extremely common in children (71%) and can be seen in up to 85% of adult patients. Relapses occur more frequently in younger adults (<45 years) and are often seen in the first 6-12 months after the onset of a remission. Successful treatment of relapses can often be achieved with a second course of steroids. However, up to 50% of relapsing adults become frequent relapsers or steroid dependent. In these patients, a stable remission can be induced by treatment with either cyclophosphamide or cyclosporine. Overall, the long-term outcome of adult onset MCD is excellent, with fewer than 5% of patients progressing to end-stage renal disease and a patient survival of 83%-98% at 15 years.
Keywords: Minimal change disease, Nephrotic syndrome, Proteinuria, Treatment.
|How to cite this article:|
Colattur SN, Korbet SM. Long-term Outcome of Adult Onset Idiopathic Minimal Change Disease. Saudi J Kidney Dis Transpl 2000;11:334-44
|How to cite this URL:|
Colattur SN, Korbet SM. Long-term Outcome of Adult Onset Idiopathic Minimal Change Disease. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2021 Apr 10];11:334-44. Available from: https://www.sjkdt.org/text.asp?2000/11/3/334/36655
| Introduction|| |
Minimal Change Disease (MCD) is responsible for idiopathic nephrotic syndrome in > 75% of children and up to 30% of adults. ,, In Saudi Arabia however, the reported incidence of MCD is less than 2%.  While secondary causes of MCD (i.e. non-steroidal anti-inflammatory drugs, lithium and lymphoproliferative disorders) are rare in children, they account for up to 13% of MCD in adults. ,,, It is therefore important to assess adult patients with MCD for secondary causes as the prognosis and therapeutic approach in such patients is dictated by the underlying etiology. While our understanding of the presentation, response to therapy and clinical course in idiopathic MCD is based on prospective studies in children, ,, few such studies are available in adults. , The overwhelming majority of our current insight into the approach to, and long-term outcome of, adults with idiopathic MCD stems from retrospective studies.
| Clinical Presentation|| |
In adults and children with idiopathic MCD, signs and symptoms of the nephrotic syndrome characteristically present abruptly with marked edema and massive proteinuria. In children, this often manifests after an upper respiratory tract infection, and presents as anasarca more commonly than in adults.  While the nature of the proteinuria in children with MCD is highly selective (predominantly albumin), the proteinuria in adults with MCD is often less selective. 
Clinical features at presentation in nephrotic adults with MCD are shown in [Table - 1] and contrasted to those of children in the International Study of Kidney Diseases in Children (ISKDC). Striking gender differences in MCD have been noted in children with a male:female ratio of 2-3:1. , However, this male predominance is not uniformly seen in adult onset MCD with some series reporting a more even gender distribution. ,, Hypertension is more commonly encountered in adults with MCD than children at presentation, while microscopic hematuria occurs in 20-30% of both adults and children. ,,,, Mild renal insufficiency is seen in 24% of children with MCD, while clinically significant renal failure is uncommon at the time of presentation  . Renal insufficiency is more common at presentation in adults with MCD, being seen in up to 61% of patients, with 12% of cases presenting in acute renal failure  . The acute renal failure (ARF) in MCD is usually self limited with complete resolution seen in most cases after successful treatment of nephrotic syndrome.  The etiology of the ARF is thought to be hemodynamic in nature as histologic evidence of acute tubular necrosis (ATN) has been reported in up to 60% of cases.  Presenting features in adults with MCD at risk of developing acute renal insufficiency include age > 60 years, hypertension and evidence of atherosclerosis on renal biopsy.  Occasionally, ARF in MCD may be irreversible and this is most often seen in patients presenting over the age of 60 years and in patients with persistent, high-grade proteinuria. 
The presenting clinical features in nephrotic adults with MCD can be indistinguishable from those of focal and segmental glomerulosclerosis (FSGS). The distinction is important as FSGS is a lesion which, unlike MCD, is highly unresponsive to steroid therapy and is associated with a poor prognosis.  Thus, renal biopsy is a critical diagnostic tool in the management of adults with the nephrotic syndrome.
| Histological Features|| |
Minimal change disease is characterized by the absence of pathological changes on light microscopy. The glomerular capillaries are open and the basement membranes are thin and delicate. The mesangial matrix and cellularity are not increased in most cases. Tubular epithelium may contain periodic acid schiff (PAS) positive granules, also known as "hyaline droplet degeneration". These are lysosomes filled with reabsorbed protein and lipid vacuoles containing reabsorbed lipoproteins. Interstitial nephritis and ATN can occasionally be seen, and they are often attributed to therapeutic interventions (diuretics, antibiotics) or hemodynamic changes, and are usually reversible. Immunofluorescence is negative for immunoglobulins and complement except in rare instances. The pathologic feature which defines MCD is diffuse epithelial foot process effacement seen on electron microscopy. 
The ISKDC identified histologic variants of MCD, defined by varying degrees of increase in mesangial cellularity.  Children with these variants did not differ significantly in clinical or laboratory characteristics at presentation. However, there were significant differences in the initial response to eight weeks of steroid treatment with the proportion of patients categorized as non-responders greatest in patients with diffuse mesangial hypercellularity (45%) compared to those patients with mild mesangial hypercellularity (15%) or pure MCD (4.7%). However, by 52 weeks of follow-up, the differences in remission disappeared as persistent proteinuria was present in only 7% of patients with diffuse mesangial hypercellularity. 
The presence of diffuse mesangial IgM in patients otherwise felt to have MCD is regarded by some to be another variant of MCD and referred to as IgM nephropathy. , Initially considered a steroid resistant lesion, subsequent studies in both adults and children have confirmed no significant differences in response to therapy or prognosis for patients with mesangial deposits of IgM compared to MCD patients without deposits. ,
In nephrotic patients with diffuse foot process fusion, the presence of even one segmental scar is abnormal, prohibiting the diagnosis of MCD, and categorizes the lesion as FSGS. This is an important distinction as patients with FSGS are poorly responsive to steroid therapy and commonly progress to ESRD, unlike those with MCD. Since a segmental scar can be missed due to sampling error, a subtle clue to the diagnosis of FSGS is the presence of tubular atrophy in an otherwise normal appearing biopsy by light microscopy. Ultimately, the prognosis for patients with MCD or FSGS is defined by the response to treatment.
| Treatment and Course of Adult Minimal Change Disease|| |
Spontaneous remission of the nephrotic syndrome is common in MCD, occurring in up to 70% of adults over the course of months to years [Table - 2].  However, since MCD is highly sensitive to steroid therapy, and serious complications associated with untreated nephrosis can be life threatening,  essentially all nephrotic patients with MCD should receive a trial of steroid therapy.
The treatment approach for MCD used in children is that which has been defined by the ISKDC [Table - 3]. Using this regimen 95% of children respond to therapy by eight weeks [Table - 4],[Table - 5], with over 99% achieving a complete remission by 28 weeks.  In nephrotic adults with MCD, the therapeutic approach is not as well defined due to the paucity of large prospective studies. Only two small prospective trials have been conducted in nephrotic adults with MCD. Black et al,  compared 20-30 mg/day of prednisone for six months to a control group receiving only symptomatic treatment. Although remission rates were high in both groups over the course of study, 70% of treated patients were in remission by six months compared to only 10% of control patients [Table - 2]. Similarly, Coggins 11 found a 100% remission rate in the treated patients compared to 60% in the control group by two years of follow-up. These studies confirm the rapid and high response rate to treatment in adults with MCD, but do not provide clear guidance on the optimal dose or duration of therapy.
Recent experience in the initial treatment of adults with MCD is based solely on retrospective studies. Nonetheless, additional insight into the therapeutic approach for adults with MCD has arisen from this experience. Using various regimens of daily high-dose steroid therapy [Table - 6], complete remission rates of 76% to 97% have been achieved in adults with MCD [Table - 4]. Compared to children however, the time to response is longer in adults. A complete remission is achieved in only 51% to 76% of adults by eight weeks on therapy [Table - 5], and it is not until > 16 weeks of treatment that the majority of adult patients (73% to 97%) attain remission. Based on these observations, adults appear to require a more prolonged course of therapy than children to achieve the same optimal results. As a result, it has been suggested that adults with MCD be treated with highdose prednisone for two to three months [Table - 3] before they are considered steroid resistant. ,,
The use of a more prolonged course of steroids in adults is not without risk due to potential adverse effects of this therapy. Black et al,  found that the mortality from non-renal causes was significantly greater in the steroid treated group (18% vs 2% for controls), occurred early in the course of treatment and most often in patients >49 years of age. The increased mortality was most often due to cardiovascular events (cardiovascular mortality was 11% vs 2% for controls), but infection and cancer were also noted. Thus, in an attempt to minimize the risk of steroid therapy, regimens utilizing lower doses of steroids have been evaluated in adult patients with MCD.
Imbasciatti et al,  compared the use of a low-dose steroid regimen (3 pulse doses of methylprednisolone [20 mg/kg] followed by daily low-dose [0.5 mg/kg] prednisone for four weeks and then alternate days for five months) to conventional high-dose prednisone therapy (1 mg/kg/day in divided doses for four weeks and then as a single dose for four weeks, and tapered over four months) in adults with MCD.  A complete remission was achieved in 73% of adults receiving low-dose prednisone by eight weeks of therapy compared to 100% of patients receiving high-dose prednisone. Relapse rates were similar between the two groups (69% for the low-dose group vs 63% for the high-dose group), but the relapse rate was greater at six months for patients treated with low-dose prednisone (46% vs 30% for high-dose group). However, steroid side effects were significantly lower in the low-dose prednisone group (40% vs 87% for high-dose group), suggesting that low-dose oral prednisone may be an alternative therapy for MCD in patients at high risk for steroid toxicity. However, any benefit of the low-dose regimen may be offset by the increased relapse rate resulting in more courses of treatment. High-dose alternate day steroid therapy (60 to 120 mg orally as a single dose for 9-12 months) has also been tried as a steroid sparing measure in adult onset MCD.  A complete remission was attained in only 66% of patients by six months, while the total duration of therapy resulted in a cumulative dose of steroids comparable to patients receiving more conventional therapy. Thus, adults appear to require a more prolonged course of highdose prednisone to attain the same excellent remission rates as children, and attempts at minimizing steroid exposure, by lower doses or alternate day regimens may result in suboptimal outcomes with either decreased remission rates or higher relapse rates.
The use of cytotoxic agents as the initial treatment of MCD has also been evaluated as a steroid sparing approach. Cyclophosphamide, given for an average of four months, was compared to treatment with diuretics alone in patients with MCD.  A complete remission was observed in 88% of cyclophosphamide treated patients by 10 weeks compared to 25% in the control group, and after six years of follow-up, none of the cyclophosphamide treated patients had relapsed. Although no serious side effects were encountered during the course of study, the cumulative dose of cyclophosphamide received was quite large and in a range which can be associated with gonadal toxicity and malignancy.  Hence, caution should be exercised in initially treating such a steroid responsive lesion with prolonged courses of cyclophosphamide.
| Relapse in Minimal Change Disease|| |
Although response to therapy is usually good in adults with MCD, relapses are common in adults and children alike [Table - 7]. Relapses occur in 65% to 80% of adults with MCD and up to 70% of relapses are seen within the first three months of a remission. , Younger adult patients (<45 years) tend to relapse more frequently than those > 45 years of age (88% vs 57%).  The frequency of relapse in children is similar to that seen in adults, with 71% of children having at least one relapse. 
The treatment for relapses depends on the frequency with which they occur in a given patient. The majority of adult onset MCD patients have only an occasional relapse (i.e., one a year or less). In this situation, a second course of therapy with steroids results in a remission in over 95% of patients.  The duration of treatment that is sufficient to prevent further relapses has not been clearly established in adults. In children, a more prolonged course of steroid treatment was compared to the standard ISKDC protocol.  After six months of follow-up there was no significant difference in the frequency of relapses between the two groups. Thus, in children, a more prolonged course of steroids in the treatment of a relapse did not appear to offer any added benefit.  In patients with more than an occasional relapse (frequent relapsers or steroid dependent) a different therapeutic approach is taken to ensure a more sustained remission in order to minimize steroid use.
| Frequent Relapsers and Steroid Dependency|| |
Frequent relapsers are defined by > two relapses within six months or > four within 12 months,, and those patients having two relapses with steroid taper or within one month of ending therapy are referred to as steroid dependent. , Frequent relapsers account for up to 16% of relapses in adults with MCD [Table - 7], while 10% to 50% of adults become steroid dependent. ,,, The prolonged and repeated use of steroids in frequently relapsing or steroid dependent adults increases the risk of severe adverse effects. In this setting, an eight to 12-week course of cytotoxic therapy (cyclophosphamide or chlorambucil) can be beneficial in inducing a more sustained remission than observed with steroids alone.  In steroid dependent patients a 12-week course of cyclophosphamide is associated with a lower relapse rate at one year (8% vs 42%) and higher remission rate at 42 months of follow-up (63% vs 21%) compared to an eight-week course of cyclophosphamide. 
Cyclosporine (CsA) has also been effective in the treatment of steroid dependent MCD resulting in a complete remission rate of 86%.  Relapse of nephrotic syndrome is extremely frequent during CsA tapering, often leading to the need for ongoing CsA treatment. Thus, the use of CsA essentially results in substituting CsA-dependency, with its associated nephrotoxicity, for steroid-dependency. , The risk of cyclos porine nephrotoxicity is greatest in patients treated with a daily dose of >5.5 mg/kg for prolonged periods of time (>18 months).  Histologic evidence of nephrotoxicity can be seen even in patients in remission with normal renal function. Hence, a repeat renal biopsy to assess CsA nephrotoxicity is recommended in patients with MCD who are on CsA for over one year. 
Few studies have compared response to cytotoxic agents with CsA in adult onset MCD.
In a randomized, prospective, controlled trial, Ponticelli et al,  evaluated the efficacy of a nine-month course of CsA with a twomonth course of oral cyclophosphamide in patients with steroid-dependent or frequently relapsing nephrotic syndrome. At the end of nine months, 74% of CsA treated patients and 64% of cyclophosphamide treated patients were in complete remission. At two years only 25% of patients treated with CsA were in remission compared to 63% of those patients treated with cyclophosphamide. Both therapies were well tolerated, but cyclophosphamide treatment resulted in a more stable and sustained remission. Based on this, cyclophosphamide appears to be the first line drug in patients with frequently relapsing or steroid dependent nephrotic syndrome. Cyclosporine may be reserved for those patients who have failed a trial of cyclophosphamide or in whom it is contraindicated. Whether recurrent relapses portend a poor long-term renal prognosis in adults with MCD has not been clearly established.
| Steroid Resistance in Minimal Change Disease|| |
Fortunately, steroid resistance is an infrequent problem in MCD (3% to 9%), but when it arises, this poses a significant challenge. In this situation one must carefully reassess the initial renal biopsy or possibly obtain a second biopsy to exclude the diagnosis of FSGS (a lesion which may be missed).
Transformation in a MCD patient from steroid-responsive to steroid-resistant is often associated with the appearance of the lesion of FSGS and has been described primarily in children.  Although the exact incidence of this transformation in children is not known, it appears to be extremely rare. In a study of 61 children with MCD, none developed FSGS after 14 years of observation.  The late development of steroid-resistant FSGS is equally unusual in adult MCD, seen in < 5% of patients. 
Presently, the approach to patients with steroid-resistant nephrotic syndrome consists of a trial of CsA. The use of cytotoxic agents in steroid-resistant patients has not proved beneficial and thus, they are best avoided given their potential toxicity. The results with CsA have been optimistic in treatment of patients with steroid-resistant nephrotic syndrome, with remissions (complete and partial) occurring in up to 60% of patients.  Furthermore, the remission persisted in 38% of patients after CsA was slowly tapered over a year. Recently, a complete remission was achieved with tacrolimus in a MCD patient who had been resistant to steroids and CsA.  After 20 months of therapy the patient remained in complete remission on a daily maintenance dose of tacrolimus alone. As with CsA, the potential nephrotoxicity of prolonged tacrolimus must be evaluated.
| Long-term Outcome in Adult Onset Minimal Change Disease|| |
The overall long-term prognosis for adults and children with MCD is excellent. After over 14 years of follow-up 77% to 94% of adult MCD patients remain in remission while less than 20% of patients continue to be nephrotic [Table - 8]. The presence of hypertension in adults with MCD, may be as high as 25% after 11 years of follow-up,  many of these patients having been hypertensive at presentation. Chronic renal insufficiency is seen in 6% to 14% of adult MCD patients on long-term follow-up, and this is most commonly encountered in patients > 60 years of age, over half of whom had evidence of renal insufficiency at presentation. , Progression to end-stage renal disease is uncommon occurring in < 5% of adults with MCD and is often associated with the development of FSGS., In children with MCD, end-stage renal disease is extremely unusual with no child progressing to ESRD after 14 years of follow-up in one study. ,
Complications directly attributed to the nephrotic syndrome have been reported in 21% of adults with MCD during long-term follow-up.  The complications observed included thrombotic events in 13% of patients, serious infections and acute renal failure in 11% each, and myocardial infarction in 9% of patients.
The mortality rate is higher in adults, particularly older adults with MCD than children (up to 17% in adults vs 3% in children) [Table - 8]. Nolasco et al  found an overall 15-year patient survival of 83% in MCD, with adults >60 years of age at onset of MCD having a 15-year survival of 40% compared to 90% for patients < 60 years of age.  They observed that over 70% of deaths occurred in the first three years of follow-up and 33% of these deaths were directly attributed to complications of the nephrotic syndrome.  Mak et al  observed the long-term patient survival in adult MCD to be even better at 98% after 14 years of follow-up with the one death attributed to a pulmonary embolus resulting from the nephrotic syndrome. Thus, the morbidity and mortality associated with the nephrotic syndrome in adult MCD justifies an aggressive approach in the treatment these patients.
| Conclusion|| |
Minimal change disease is a lesion which is highly responsive to steroids with an excellent prognosis in adults and children alike. The paucity of prospective trials in adult onset MCD makes therapeutic recommendations difficult. However adults appear to require a more prolonged course of high-dose steroid therapy to attain remission rates comparable to children. Relapses of MCD are common in adults. Fortunately, the majority of adults are able to re-attain a remission with a second course of steroid treatment alone. In frequent relapsers or steroid dependent patients the use of a cytotoxic agent is beneficial, resulting in a more sustained remission. Steroid-resistance is uncommon in MCD and should lead to a search for FSGS. The long-term prognosis for MCD is excellent for adults with few patients having persistent nephrotic syndrome or progressing to ESRD. The long-term patient survival is also excellent in these patients, with the greatest morbidity and mortality resulting from complications of the nephritic syndrome. Thus, the aggressive use of steroids is obligatory in adult MCD.
| Acknowledgment|| |
The authors wish to thank Dr. Edmund J. Lewis for his review of this manuscript and helpful comments.
| References|| |
|1.||Grupe WE. Minimal change disease. Semin Nephrol 1982;2:241-52. |
|2.||Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int 1978;13:159-65. |
|3.||Korbet SM, Genchi RM, Borok RZ, Schwartz MM. The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 1996;27:647-51. |
|4.||Mitwalli AH, Al Wakeel JS, Al Mohaya SS, et al. Pattern of glomerular disease in Saudi Arabia. Am J Kidney Dis 1996;27: 797-802. [PUBMED] |
|5.||Korbet SM. Management of idiopathic nephrosis in adults, including steroidresistant nephrosis. Curr Opin Nephrol Hypertens 1995;4:169-76. [PUBMED] |
|6.||Warren GV, Korbet SM, Schwartz MM, Lewis EJ. Minimal change glomerulopathy associated with nonsteroidal antiinflammatory drugs. Am J Kidney Dis 1989;13: 127-30. [PUBMED] |
|7.||Richman AV, Masco HL, Rifkin SI, Acharya MK. Minimal change disease and the nephrotic syndrome associated with lithium therapy. Ann Intern Med 1980;92:70-2. [PUBMED] |
|8.||Eagen JW. Glomerulopathies of neoplasia. Kidney Int 1977;11:297-303. [PUBMED] |
|9.||Primary nephrotic syndrome in children: Clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A report of the International Study of Kidney Disease in Children. Kidney Int 1981;20:765-71. [PUBMED] |
|10.||The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981;98:561-4. |
|11.||Coggins CH. Minimal change nephrosis in adults. Proc 8th Int Congr Nephrol, Athens 1981;336-44. |
|12.||Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. BMJ 1970; 3:421-6. [PUBMED] [FULLTEXT]|
|13.||Cameron JS, Turner DR, Ogg CS, Sharpstone P, Brown CB. The nephrotic syndrome in adults with minimal change glomerular lesions. Q J Med 1974;43: 461-88. [PUBMED] [FULLTEXT]|
|14.||Korbet SM, Schwartz MM, Lewis EJ. Minimal-change glomerulopathy of adulthood. Am J Nephrol 1988;8:291-7. [PUBMED] |
|15.||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: 1215-23. [PUBMED] |
|16.||Mak SK, Short CD, Mallick NP. Long-term outcome of adult-onset minimal change nephropathy. Nephrol Dial Transplant 1996;11:2192-201. [PUBMED] [FULLTEXT]|
|17.||Fujimoto S, Yamamoto Y, Hisanaga S, Morita S, Eto T, Tanaka K. Minimal change nephrotic syndrome in adults: response to corticosteroid therapy and frequency of relapse. Am J Kid Dis 1991;17:687-92. [PUBMED] |
|18.||Smith J, Hayslett JP. Reversible renal failure in the nephrotic syndrome. Am J Kidney Dis 1992;19:201-13. |
|19.||Jennette JC, Falk RJ. Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 1990;16:432-7. [PUBMED] |
|20.||Raij L, Keane WF, Leonard A, Shapiro FL. Irreversible acute renal failure in idiopathic nephrotic syndrome. Am J Med 1976;61: 207-14. [PUBMED] |
|21.||Schwartz MM. The nephrotic syndrome and proteinuria: Renal biopsy interpretation, in Silva FG, D'Agati VD, Nadasdy T. (eds): Pathology of the kidney. New York, Churchill Livingstone 1996; pp 118-125. |
|22.||Pardo V, Riesgo I, Zilleruelo G, Strauss J. The clinical significance of mesangial IgM deposits and mesangial hypercellu-larity in minimal change nephrotic syndrome. Am J Kidney Dis 1984;3:264-9. [PUBMED] |
|23.||Looi LM, Wang F, Lam KL, Chua CT. Mesangial IgM in minimal change glomerular disease: a clinicopathological study in a Malaysian population. Pathology 1985;17:41-4. [PUBMED] |
|24.||Harris RC, Ismail N. Extrarenal complications of the nephrotic syndrome. Am J Kidney Dis 1994;23:477-97. [PUBMED] |
|25.||Glassock RJ. Therapy of idiopathic nephrotic syndrome in adults. A conservative or aggressive therapeutic approach. Am J Nephrol 1993;13:422-8. |
|26.||Meyrier A, Noel LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Kidney Int 1994;45:1446-56. |
|27.||Imbasciati E, Gusmano R, Edefonti A, et al. Controlled trial of methylprednisolone pulses and low dose oral prednisone for the minimal change nephrotic syndrome. BMJ 1985;291:1305-8. [PUBMED] [FULLTEXT]|
|28.||Bolton WK, Atuk NO, Sturgill BC, Westervelt FB Jr. Therapy of the idiopathic nephrotic syndrome with alternate day steroids. Am J Med 1977;62:60-70. [PUBMED] |
|29.||Al-Khader AA, Lien JW, Aber GM. Cyclophosphamide alone in the treatment of adult patients with minimal change glomerulonephritis. Clin Nephrol 1979; 11:26-30. [PUBMED] |
|30.||Lewis EJ. The natural history and treatment of lupus nephritis, in Lewis EJ, Schwartz MM, Korbet SM (eds): Lupus Nephritis. Oxford, Oxford University Press 1999;pp 185-218. |
|31.||Nephrotic syndrome in children: a randomized trial comparing two prednisone regimens in steroid-responsive patients who relapse early. Report of the Inter-national Study of Kidney Disease in Children. J Pediatr 1979;95:239-43. |
|32.||Pennisi AJ, Grushkin CM, Lieberman E. Cyclophosphamide in the treatment of idiopathic nephrotic syndrome. Pediatrics 1976;57:948-51. [PUBMED] |
|33.||Meyrier A, Condamin MC, Broneer D. Treatment of adult idiopathic nephrotic syndrome with cyclosporin A: Minimalchange disease and focal-segmental glomerulosclerosis. Clin Nephrol 1991; 35(Suppl 1):S37-42. [PUBMED] |
|34.||Melocoton TL, Kamil ES, Cohen AH, Fine RN. Long-term cyclosporine A treat-ment of steroid-resistant and steroid- dependent nephrotic syndrome. Am J Kidney Dis 1991;18:583-8. [PUBMED] |
|35.||Ponticelli C, Edefonti A, Ghio L, et al. Cyclosporin versus cyclophosphamide for patients with steroid dependent and frequently relapsing idiopathic nephrotic syndrome: a multicenter randomized controlled trial. Nephrol Dial Transplant 1993;8:1326-32. [PUBMED] [FULLTEXT]|
|36.||Nash MA, Bakare MA, D'Agati V, Pirani CL. Late development of chronic renal failure in steroid-responsive nephrotic syndrome. J Pediatr 1982;101:411-4. [PUBMED] |
|37.||Mallick NP. Epidemiology and natural course of idiopathic nephrotic syndrome. Clin Nephrol 1991;35(Suppl 1):S3-7. [PUBMED] |
|38.||Ponticelli C, Rizzoni G, Edefonti A, et al. A randomized trial of cyclosporine in steroid resistant idiopathic nephrotic syndrome. Kidney Int 1993;43:1377-84. [PUBMED] |
|39.||Schweda F, Liedl R, Rigger GA, Kramer BK. Tacrolimus treatment for steroid- and cyclosporine-resistant minimal change nephrotic syndrome. Nephrol Dial Transplant 1997;12:2433-5. |
|40.||Lewis MA, Baildom EM, Davis N, Houston IB, Postlethwaite RJ. Nephrotic syndrome: From toddlers to twenties. Lancet 1989;1:255-9. [PUBMED] |
Stephen M Korbet
Department of Medicine, Rush Presbyterian St. Luke’s Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8]