September 1975
TheJournalofPEDIATRICS
377
Minimal-lesion nephrotic syndrome with early resistance to steroid therapy The initial and long-term clinical course o f six children with steroid-resiktant, minimal-lesion nephrotic syndrome was evaluated. All children experienced remission after two to five weeks o f combined cyclophosphamide-prednisone therapy. Following eyclophosphamide treatment, three patients have relapsed and have become steroid sensitive. The clinical outcome was quite favorable. These data suggest: (1) cyclophosphamide may induce a prompt remission in patients with minimal glomerular lesions who have early resistance to eortieosteroids," (2) relapses which occur after cyclophosphamide should be treated with prednisone alone, even though the patient was previously steroid resistant," (3) the ultimate outcome is related more to the nature o f the histopathologic lesion than to a lack of steroid responsiveness.
Norman
J. Siegel, M.D.,* Ayfer Gur, M.D., Leonard S. Krassner, M.D.,
M i c h a e l Kashgarian, M.D., N e w H a v e n ,
and
Conn.
OVER THE PAST SEVERAL YEARS it has become apparent that 85% of children with the nephrotic syndrome will have minimal glomerular lesions as evidenced in biopsied renal tissue. 1-:~Although treatment with corticosteroids is associated with a clinical remission in most of these patients, 5 to 10% fail to achieve a remission after eight to ten weeks of steroid therapy. 1, 3 The latter group of patients has been termed either steroid resistant~ or early steroid nonresponsive.4 Alternatively, it has been estimated that of nephrotic children with early steroid resistance, 30 to 40% have minimal glomerular lesions.4 Although a great deal of attention has been focused on patients with frequently relapsing, steroid-responsive nephrotic syndrome'-9 and on patients with focal glomerular sclerosis evident at or near the onset of disease, ~~ little data have been available concerning the initial and long-term clinical course of children with steroid-resistant, minimal-lesionnephrotic syndrome. This report deals with the natural history and prognosis in six children with From the Departments o f Pediatrics and Pathology, Yale University School o f Medicine. Presented in part at the Third International Congress o f Pediatric Nephrology, Washington, D.C., Sept., 1974. *Reprint address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, Conn.
minimal-lesionnephrotic syndrome which was resistant to prednisone early in the course of the disease. METHODS
AND MATERIALS
Patients. Six children with insidious onset of the idiopathic nephrotic syndrome (defined as the presence of heavy proteinuria, hypoalbuminemia [serum albumin < 2.0 gm/dl], and edema) which failed to respond initially to corticosteroid treatment form the basis of this report. Abbreviation used ISKDC: International Study of Kidney Disease in Children Definitions. A remission or response in association with treatment was defined as the absence of proteinuria on three consecutive examinations by qualitative testing and the disappearance of edema. Relapse was denoted by the recurrence of heavy proteinuria after the urine had been protein free for at least one month. The clinical response associated with treatment of the initial episode or subsequent relapses was designated as: (1) steroid r e s i s t a n t - n o remission during eight to ten consecutive weeks of daily therapy with prednisone, 2 to 3 mg/kg/day; (2) steroid r e s p o n s i v e - c o m p l e t e remission of proteinuria during treatment with prednisone and persistence of remission for at least two months after termination of treatment; (3)
Vol. 87, No. 3, pp. 377-380
378
Siegel et al.
The Journal of Pediatrics September 1975
Table I. Clinical features and response to therapy at onset
Duration of initial steroid resistace
Age Patient
Sex
M.H. R.M. W.L. M.C. D.J. D.B.
2 5 2 3 2 3
Male Male Male Male Male Female
Table II. Response of relapses to prednisone after cyclophosphamide therapy
No. of Time to respond to prednisone therapy relapses during relapsefollowing Patient per patient ] cyclophosphamidetherapy D.J.
1 2
M. C.
2
e . M.
4 days 8 days first relapse 10 days second relapse 10 days first relapse 12 days second relapse
steroid dependent-complete remission during prednisone therapy but recurrence when the dosage was reduced below a critical level or relapse within one month after therapy was stopped on two successive occasions. The term steroid sensitive is used to denote a clinical course which is either steroid responsive or dependent. A patient whose initial episode of the nephrotic syndrome is steroid resistant could also be designated as an early nonresponder according to the criteria of the International Study of Kidney Disease in Children? Treatment. All patients were initially treated with prednisone, 2 to 3 mg/kg/day in three or four divided doses for 8 to 12 weeks. Children who failed to respond to corticosteroid therapy had a renal biopsy to determine histopathologic changes. Following this evaluation, all children with minimal glomerular lesions were given a 12week course of cyclophosphamide in a dosage of 1.5 to 2 mg/kg/day. Prednisone, 2 to 3 mg/kg/day, was continued only during the first six weeks of cyclophosphamide therapy. Relapses, which occurred after the 12-week course of cyclophosphamide, were treated with prednisone alone in a dosage of 2 to 3 mg/kg/day, and when the urine had been free of protein for three to four weeks, the dosage of prednisone was tapered until administration was discontinued. Histopathology. Renal tissue was obtained in all
(wlc) 8 9 10 10 12 12
Interval from beginning cyclophosphamide therapy to remission (wk) 2 5 3 2 4 5
Duration
of remission
(mo) 21 38 48 12 8 34
patients by percutaneous biopsy for evaluation by light and electron microscopy. Criteria for histopathologic classification are consistent with those of the ISKDC? RESULTS The clinical features of the six patients are shown in Table I. Five of them were male, and all were between 2 and 5 years of age at the onset of their disease. All patients were treated initially with prednisone, 2 to 3 mg/kg/day in three or four divided doses. No patient achieved a clinical remission during 8 to 12 weeks of continuous daily therapy with prednisone. Because of this early initial steroid resistance, a renal biopsy was performed and an adequate sample was obtained in each case. On light microscopy there was a conspicuous absence of abnormality. A n occasional focal increase in mesangial matrix a n d / o r hypercellularity was not of sufficient degree to warrant either the term "sclerosis" or "proliferative." On ultrastructural examination there was a diffuse fusion of the epithelial cell foot processes which involved all portions of all glomeruli without any evidence of sclerosis or capillary collapse. Based on these clinical and histopathologic observations, all six children were considered to have steroid-resistant, minimal-lesion nephrotic syndrome. Following evaluation Of the renal biopsy specimen, each child was treated with cyclophosphamide. As indicated in Table I, each of the children experienced a loss of proteinuria and a clearing of edema within two to five weeks after starting combined cyclophosphamide-prednisone therapy. Following treatment with cyclophosphamide, remission persisted for 12 months or more in five patients and for only eight months in one patient. The number of relapses and the response to treatment of each relapse in the three children who had a relapsing clinical course after treatment with cyclophosphamide are shown in Table II. Because of the potential gonadal toxicity of cyclophosphamide,13 treatment of relapses in each
Volume 87 Number 3
Minimal-lesion nephrotic syndrome
379
Table III. Clinical status at end of follow-up
Blood urea nitrogen (mg/dl)
Serum ereatinine
Patient
Duration of follow-up from onset of disease (mo)
M.H. D.B. W.L. M.C. D.J. R.M.
25 38 51 48 48 53
18 11 10 13 15 16
0.8 0.6 0.8 0.5 0.2 0.9
Clinical course
(mg/dl)
case was initiated with prednisone alone. In each case, relapses which followed cyclophosphamide therapy responded within two weeks after treatment with only prednisone was begun. One of these children has had only one relapse and remains in complete remission after 53 months of follow-up. Each of the other two children has had two relapses, and on each occasion responded promptly to prednisone on conventional doses. The clinical course and renal function of the six children at the end of follow-up are shown in Table III. The duration of follow-up from onset of disease ranged from 25 to 53 months with a mean of 42 months. Renal function, as measured by serum creatinine and blood urea nitrogen values, is normal in all six patients. Three children have not experienced any relapses following termination of treatment with cyclophosphamide, which has been 23, 35, and 48 months, respectively. The other three children have had one or more relapses, each of which has responded to steroid therapy. Two of these patients are presently considered steroid dependent, and one is steroid responsive. DISCUSSION Since the findings in this group of children are uncontrolled, no conclusions regarding the efficacy of cyclophosphamide in the treatment of steroid-resistant, minimal-lesion nephrotic syndrome can be drawn. However, several observations are of particular interest. First, the interval from the start of combined treatment with cyclophosphamide and prednisone to attainment of a complete remission was quite short. Five of the six children achieved a complete remission within one month after starting cyclophosphamide therapy. Similarly, the ISKDC has recently reported that the interval from the onset of treatment to the time of response was significantly shorter in early steroid nonresponders treated with cyclophosphamide than in corresponding patients treated with prednisone alone? Second, when relapses occurred after cyclophosphamide-induced remissions, patients who were early nonre-
No relapses No relapses No relapses Two relapses; steroid dependent Two relapses; steroid dependent One relapse; steroid responsive sponders to steroid therapy had become steroid sensitive. Since we had not previously observed patients whose disease became more steroid sensitive, TM this was a unique and somewhat unexpected finding. Unfortunately, comparable data concerning the long-term clinical course of early steroid-nonresponsive patients with minimal glomerular lesions were not available in the recent report from the ISKDC2 Bergstrand and associates 15 have reported similar observations following cyclophosphamide treatment in five patients whose disease had become progressively steroid refractory, but only one of their patients was steroid resistant early in the course. Whether this change in steroid sensitivity was due to spontaneous variation in the steroid responsiveness of the disease, as suggested by Chiu and Drummond, 9 or to a specific effect of cyclophosphamide on the pathogenesis of this lesion, as proposed by Bergstrand and associates, ~ could not be determined. The data presented in the present report, however, do suggest that prednisone alone should be given as the initial treatment for relapses which occur following successful therapy with cyclophosphamide, even in patients who are initially steroid resistant. Finally, the long-term clinical outcome in this group of patients has been quite favorable. After a mean follow-up of almost four years, all of the children (both those who have remained in remission and those who have relapsed) have normal renal function. It has generally been felt that early steroid unresponsiveness is associated with a poor prognosis ........ ; therefore this observation is worthy of note. Since all of the children in this study have minimal glomerular lesions, it would appear that the ultimate outcome is more related to the nature of the underlying histopathologic lesion than to a lack of steroid responsiveness, per se. REFERENCES
1. White RHR, Glasgow EF, and Mills RJ: Clinicopathological study of nephrotic syndrome in childhood, Lancet 1:1353, 1970. 2. Habib R, and Kleinknecht C: The primary nephrotic syn-
380
3.
4.
5. 6.
7.
8.
9.
Siegel et al.
drome of childhood-classification and clinicopathologic study of 406 cases, Pathol Annu, 1971, p 417. Churg J, Habib R, and .White RHR: A report of the International Study of Kidney Disease in Children: pathology of the nephrotic syndrome in childhood, Lancet 1:1299, 1970. Spitzer A, Gordillo-P G, Houston IB, and Travis LB: A report of the International Study of Kidney Disease in Children: prospective, controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome, Lancet 2:423, 1974. Grupe WE: Chlorambucil in steroid-dependent nephrotic syndrome, J PEDIATR82:598, 1973. Chiu J, McLaine P, and Drummond KW: A controlled prospective study of cyclophosphamide in relapsing corticosteroid-responsive, minimal-lesion nephrotic syndrome in childhood, J PEDIATR82:607, 1973. McCrory WW, Shibuya M, Lu W-H, and Lewy JE: Therapeutic and toxic effect observed with different dosage programs of cyclophosphamide in treatment of steroidresponsive but frequently relapsing nephrotic syndrome, J PEDIATR 82:615, 1973. McDonald J, Murphy AV, and Arneil GC: Long-term assessment of cyclophosphamide therapy for nephrosis in children, Lancet 2:980, 1974. Chiu J, and Drummond KW: Long-term follow-up of cy-
The Journal of Pediatrics September 1975
10. 11. 12.
13.
14.
15.
16. 17.
clophosphamide therapy in frequent relapsing minimal lesion nephrotic syndrome, J PEDIATR84:825, 1974. Habib R: Focal glomerular sclerosis, Kidney Int 4:355, 1973. Hyman LR, and Burkholder PM: Focal sclerosing glomerulonephropathy with hyalinosis, J PEDIATR84:217, 1974. Bohle A, Fischbach H, Wehner H, Woerz U, Edel HH, Kluth R, and Scheler F: Minimal change lesion with nephrotic syndrome and focal glomerular sclerosis, Clin Nephrol 2:52, 1974. Fairley KF, Barrie JU, and Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy, Lancet 1:568, 1972. Siegel NJ, Goldberg B, Krassner LS, and Hayslett JP: Long-term follow-up of children with steroid-responsive nephrotic syndrome, J PEDIATR81:251, 1972. Bergstrand A, Bollgren I, Samuelsson A, Tornroth T, Wasserman J, and Winberg J: Idiopathic nephrotic syndrome of childhood: cyclophosphamide induced conversion from steroid refractory to highly steroid sensitive disease, Clin Nephrol 1:302, 1973. Arneil GC, and Lam CW: Long term assessment of steroid therapy in childhood nephrosis, Lancet 2:819, 1966. Schwartz MW, Schwartz GJ, and Cornfeld D: A 16-year follow-up study of 163 children with nephrotic syndrome, Pediatrics 54:547, 1974.
TheJournalofPEDIATRICS
377
Minimal-lesion nephrotic syndrome with early resistance to steroid therapy The initial and long-term clinical course o f six children with steroid-resiktant, minimal-lesion nephrotic syndrome was evaluated. All children experienced remission after two to five weeks o f combined cyclophosphamide-prednisone therapy. Following eyclophosphamide treatment, three patients have relapsed and have become steroid sensitive. The clinical outcome was quite favorable. These data suggest: (1) cyclophosphamide may induce a prompt remission in patients with minimal glomerular lesions who have early resistance to eortieosteroids," (2) relapses which occur after cyclophosphamide should be treated with prednisone alone, even though the patient was previously steroid resistant," (3) the ultimate outcome is related more to the nature o f the histopathologic lesion than to a lack of steroid responsiveness.
Norman
J. Siegel, M.D.,* Ayfer Gur, M.D., Leonard S. Krassner, M.D.,
M i c h a e l Kashgarian, M.D., N e w H a v e n ,
and
Conn.
OVER THE PAST SEVERAL YEARS it has become apparent that 85% of children with the nephrotic syndrome will have minimal glomerular lesions as evidenced in biopsied renal tissue. 1-:~Although treatment with corticosteroids is associated with a clinical remission in most of these patients, 5 to 10% fail to achieve a remission after eight to ten weeks of steroid therapy. 1, 3 The latter group of patients has been termed either steroid resistant~ or early steroid nonresponsive.4 Alternatively, it has been estimated that of nephrotic children with early steroid resistance, 30 to 40% have minimal glomerular lesions.4 Although a great deal of attention has been focused on patients with frequently relapsing, steroid-responsive nephrotic syndrome'-9 and on patients with focal glomerular sclerosis evident at or near the onset of disease, ~~ little data have been available concerning the initial and long-term clinical course of children with steroid-resistant, minimal-lesionnephrotic syndrome. This report deals with the natural history and prognosis in six children with From the Departments o f Pediatrics and Pathology, Yale University School o f Medicine. Presented in part at the Third International Congress o f Pediatric Nephrology, Washington, D.C., Sept., 1974. *Reprint address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, Conn.
minimal-lesionnephrotic syndrome which was resistant to prednisone early in the course of the disease. METHODS
AND MATERIALS
Patients. Six children with insidious onset of the idiopathic nephrotic syndrome (defined as the presence of heavy proteinuria, hypoalbuminemia [serum albumin < 2.0 gm/dl], and edema) which failed to respond initially to corticosteroid treatment form the basis of this report. Abbreviation used ISKDC: International Study of Kidney Disease in Children Definitions. A remission or response in association with treatment was defined as the absence of proteinuria on three consecutive examinations by qualitative testing and the disappearance of edema. Relapse was denoted by the recurrence of heavy proteinuria after the urine had been protein free for at least one month. The clinical response associated with treatment of the initial episode or subsequent relapses was designated as: (1) steroid r e s i s t a n t - n o remission during eight to ten consecutive weeks of daily therapy with prednisone, 2 to 3 mg/kg/day; (2) steroid r e s p o n s i v e - c o m p l e t e remission of proteinuria during treatment with prednisone and persistence of remission for at least two months after termination of treatment; (3)
Vol. 87, No. 3, pp. 377-380
378
Siegel et al.
The Journal of Pediatrics September 1975
Table I. Clinical features and response to therapy at onset
Duration of initial steroid resistace
Age Patient
Sex
M.H. R.M. W.L. M.C. D.J. D.B.
2 5 2 3 2 3
Male Male Male Male Male Female
Table II. Response of relapses to prednisone after cyclophosphamide therapy
No. of Time to respond to prednisone therapy relapses during relapsefollowing Patient per patient ] cyclophosphamidetherapy D.J.
1 2
M. C.
2
e . M.
4 days 8 days first relapse 10 days second relapse 10 days first relapse 12 days second relapse
steroid dependent-complete remission during prednisone therapy but recurrence when the dosage was reduced below a critical level or relapse within one month after therapy was stopped on two successive occasions. The term steroid sensitive is used to denote a clinical course which is either steroid responsive or dependent. A patient whose initial episode of the nephrotic syndrome is steroid resistant could also be designated as an early nonresponder according to the criteria of the International Study of Kidney Disease in Children? Treatment. All patients were initially treated with prednisone, 2 to 3 mg/kg/day in three or four divided doses for 8 to 12 weeks. Children who failed to respond to corticosteroid therapy had a renal biopsy to determine histopathologic changes. Following this evaluation, all children with minimal glomerular lesions were given a 12week course of cyclophosphamide in a dosage of 1.5 to 2 mg/kg/day. Prednisone, 2 to 3 mg/kg/day, was continued only during the first six weeks of cyclophosphamide therapy. Relapses, which occurred after the 12-week course of cyclophosphamide, were treated with prednisone alone in a dosage of 2 to 3 mg/kg/day, and when the urine had been free of protein for three to four weeks, the dosage of prednisone was tapered until administration was discontinued. Histopathology. Renal tissue was obtained in all
(wlc) 8 9 10 10 12 12
Interval from beginning cyclophosphamide therapy to remission (wk) 2 5 3 2 4 5
Duration
of remission
(mo) 21 38 48 12 8 34
patients by percutaneous biopsy for evaluation by light and electron microscopy. Criteria for histopathologic classification are consistent with those of the ISKDC? RESULTS The clinical features of the six patients are shown in Table I. Five of them were male, and all were between 2 and 5 years of age at the onset of their disease. All patients were treated initially with prednisone, 2 to 3 mg/kg/day in three or four divided doses. No patient achieved a clinical remission during 8 to 12 weeks of continuous daily therapy with prednisone. Because of this early initial steroid resistance, a renal biopsy was performed and an adequate sample was obtained in each case. On light microscopy there was a conspicuous absence of abnormality. A n occasional focal increase in mesangial matrix a n d / o r hypercellularity was not of sufficient degree to warrant either the term "sclerosis" or "proliferative." On ultrastructural examination there was a diffuse fusion of the epithelial cell foot processes which involved all portions of all glomeruli without any evidence of sclerosis or capillary collapse. Based on these clinical and histopathologic observations, all six children were considered to have steroid-resistant, minimal-lesion nephrotic syndrome. Following evaluation Of the renal biopsy specimen, each child was treated with cyclophosphamide. As indicated in Table I, each of the children experienced a loss of proteinuria and a clearing of edema within two to five weeks after starting combined cyclophosphamide-prednisone therapy. Following treatment with cyclophosphamide, remission persisted for 12 months or more in five patients and for only eight months in one patient. The number of relapses and the response to treatment of each relapse in the three children who had a relapsing clinical course after treatment with cyclophosphamide are shown in Table II. Because of the potential gonadal toxicity of cyclophosphamide,13 treatment of relapses in each
Volume 87 Number 3
Minimal-lesion nephrotic syndrome
379
Table III. Clinical status at end of follow-up
Blood urea nitrogen (mg/dl)
Serum ereatinine
Patient
Duration of follow-up from onset of disease (mo)
M.H. D.B. W.L. M.C. D.J. R.M.
25 38 51 48 48 53
18 11 10 13 15 16
0.8 0.6 0.8 0.5 0.2 0.9
Clinical course
(mg/dl)
case was initiated with prednisone alone. In each case, relapses which followed cyclophosphamide therapy responded within two weeks after treatment with only prednisone was begun. One of these children has had only one relapse and remains in complete remission after 53 months of follow-up. Each of the other two children has had two relapses, and on each occasion responded promptly to prednisone on conventional doses. The clinical course and renal function of the six children at the end of follow-up are shown in Table III. The duration of follow-up from onset of disease ranged from 25 to 53 months with a mean of 42 months. Renal function, as measured by serum creatinine and blood urea nitrogen values, is normal in all six patients. Three children have not experienced any relapses following termination of treatment with cyclophosphamide, which has been 23, 35, and 48 months, respectively. The other three children have had one or more relapses, each of which has responded to steroid therapy. Two of these patients are presently considered steroid dependent, and one is steroid responsive. DISCUSSION Since the findings in this group of children are uncontrolled, no conclusions regarding the efficacy of cyclophosphamide in the treatment of steroid-resistant, minimal-lesion nephrotic syndrome can be drawn. However, several observations are of particular interest. First, the interval from the start of combined treatment with cyclophosphamide and prednisone to attainment of a complete remission was quite short. Five of the six children achieved a complete remission within one month after starting cyclophosphamide therapy. Similarly, the ISKDC has recently reported that the interval from the onset of treatment to the time of response was significantly shorter in early steroid nonresponders treated with cyclophosphamide than in corresponding patients treated with prednisone alone? Second, when relapses occurred after cyclophosphamide-induced remissions, patients who were early nonre-
No relapses No relapses No relapses Two relapses; steroid dependent Two relapses; steroid dependent One relapse; steroid responsive sponders to steroid therapy had become steroid sensitive. Since we had not previously observed patients whose disease became more steroid sensitive, TM this was a unique and somewhat unexpected finding. Unfortunately, comparable data concerning the long-term clinical course of early steroid-nonresponsive patients with minimal glomerular lesions were not available in the recent report from the ISKDC2 Bergstrand and associates 15 have reported similar observations following cyclophosphamide treatment in five patients whose disease had become progressively steroid refractory, but only one of their patients was steroid resistant early in the course. Whether this change in steroid sensitivity was due to spontaneous variation in the steroid responsiveness of the disease, as suggested by Chiu and Drummond, 9 or to a specific effect of cyclophosphamide on the pathogenesis of this lesion, as proposed by Bergstrand and associates, ~ could not be determined. The data presented in the present report, however, do suggest that prednisone alone should be given as the initial treatment for relapses which occur following successful therapy with cyclophosphamide, even in patients who are initially steroid resistant. Finally, the long-term clinical outcome in this group of patients has been quite favorable. After a mean follow-up of almost four years, all of the children (both those who have remained in remission and those who have relapsed) have normal renal function. It has generally been felt that early steroid unresponsiveness is associated with a poor prognosis ........ ; therefore this observation is worthy of note. Since all of the children in this study have minimal glomerular lesions, it would appear that the ultimate outcome is more related to the nature of the underlying histopathologic lesion than to a lack of steroid responsiveness, per se. REFERENCES
1. White RHR, Glasgow EF, and Mills RJ: Clinicopathological study of nephrotic syndrome in childhood, Lancet 1:1353, 1970. 2. Habib R, and Kleinknecht C: The primary nephrotic syn-
380
3.
4.
5. 6.
7.
8.
9.
Siegel et al.
drome of childhood-classification and clinicopathologic study of 406 cases, Pathol Annu, 1971, p 417. Churg J, Habib R, and .White RHR: A report of the International Study of Kidney Disease in Children: pathology of the nephrotic syndrome in childhood, Lancet 1:1299, 1970. Spitzer A, Gordillo-P G, Houston IB, and Travis LB: A report of the International Study of Kidney Disease in Children: prospective, controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome, Lancet 2:423, 1974. Grupe WE: Chlorambucil in steroid-dependent nephrotic syndrome, J PEDIATR82:598, 1973. Chiu J, McLaine P, and Drummond KW: A controlled prospective study of cyclophosphamide in relapsing corticosteroid-responsive, minimal-lesion nephrotic syndrome in childhood, J PEDIATR82:607, 1973. McCrory WW, Shibuya M, Lu W-H, and Lewy JE: Therapeutic and toxic effect observed with different dosage programs of cyclophosphamide in treatment of steroidresponsive but frequently relapsing nephrotic syndrome, J PEDIATR 82:615, 1973. McDonald J, Murphy AV, and Arneil GC: Long-term assessment of cyclophosphamide therapy for nephrosis in children, Lancet 2:980, 1974. Chiu J, and Drummond KW: Long-term follow-up of cy-
The Journal of Pediatrics September 1975
10. 11. 12.
13.
14.
15.
16. 17.
clophosphamide therapy in frequent relapsing minimal lesion nephrotic syndrome, J PEDIATR84:825, 1974. Habib R: Focal glomerular sclerosis, Kidney Int 4:355, 1973. Hyman LR, and Burkholder PM: Focal sclerosing glomerulonephropathy with hyalinosis, J PEDIATR84:217, 1974. Bohle A, Fischbach H, Wehner H, Woerz U, Edel HH, Kluth R, and Scheler F: Minimal change lesion with nephrotic syndrome and focal glomerular sclerosis, Clin Nephrol 2:52, 1974. Fairley KF, Barrie JU, and Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy, Lancet 1:568, 1972. Siegel NJ, Goldberg B, Krassner LS, and Hayslett JP: Long-term follow-up of children with steroid-responsive nephrotic syndrome, J PEDIATR81:251, 1972. Bergstrand A, Bollgren I, Samuelsson A, Tornroth T, Wasserman J, and Winberg J: Idiopathic nephrotic syndrome of childhood: cyclophosphamide induced conversion from steroid refractory to highly steroid sensitive disease, Clin Nephrol 1:302, 1973. Arneil GC, and Lam CW: Long term assessment of steroid therapy in childhood nephrosis, Lancet 2:819, 1966. Schwartz MW, Schwartz GJ, and Cornfeld D: A 16-year follow-up study of 163 children with nephrotic syndrome, Pediatrics 54:547, 1974.
