October 1975
The Journal o f P E D I A T R I C S
519
Late nonresponsiveness to steroids in children with the nephrotic syndrome Among 195 nephrotic children, ten developed resistance to prednisone therapy after responding to this drug on one or more occasions (late nonresponders). All were found to have "minimal lesions'on renal biopsy. Nine o f these patients went into remission: one responded to further prednisone therapy, one went into remission while receiving azathioprine, and the remaining seven children responded to cyclophosphamide. Five of these seven patients subsequently relapsed; three of them have continued to respond to prednisone. The other two eventually became steroid resistant a second time, but in both instances a second course of cyclophosphamide again induced a remission. These nine patients have been followed for periods ranging from 6 months to 9.5 years (median = 53 months)," all are doing well and have normal renal function. The tenth patient died from sepsis four months after the onset o f steroid resistance.
Eugene B. Trainin, M.D., Hayim Boichis, M.D., Adrian Spitzer, M.D., Chester M. Edelmann, Jr., M.D., and Ira Greifer, M.D.,* Bronx, N. Y.
CHILDREN with the nephrotic syndrome can be divided into two groups according to their response or lack of response to prednisone therapy. In general, those who respond have "minimal lesions ''1 on renal biopsy, whereas those who remain proteinuric have some form of glomerulopathy? Many patients with "minimal lesions" have a relapsing course, but as a rule they continue to respond to prednisone? There are, however, patients who after having responded to prednisone on one or more occasions become resistant to this agent (late nonresponders). This group has only occasionally been referred to in the literature, 3-~ and the underlying histology, clinical course, and prognosis of these patients is unclear. We have reviewed the records of 195 children with the From the Department of Pediatrics, Hospital o f the Albert Einstein College of Medicine, and Division o f Pediatric Nephrology, Albert Einstein College o f Medicine and Rose F Kennedy Center. Supported in part by Public Health Service Program Project Grant A M 14877, The Kidney Disease Institute of the State of New York, The Kidney Foundation of New York, and the Rath Foundation. *Reprint address: Department of Pediatrics, Hospital of the Albert Einstein College of Medicine, 1825 Eastehester Rd, Bronx, N. Y. 10461.
nephrotic syndrome seen at our center in the past ten years and have found among them ten late nonresponders. The histology in all cases was that of "minimal lesions." Nine of these patients eventually went into remission, seven of them following treatment with cyclophosphamide. The tenth patient died of septicemia. Five of the patients treated with cyclophosphamide subsequently relapsed but they all responded again to prednisone therapy. Abbreviation used FSS: focal segmental glomerular sclerosis
I
MATERIAL AND METHODS Definitions. The following definitions were arbitrarily chosen for the purpose of this study: 1. Nephrotic syndrome: proteinuria of more than 40 mg per hour per square meter body surface area and a serum albumin value of less than 2.5 gm/dl. 2. Remission: demonstration of a "protein-free" urine on three consecutive examinations of the first morning specimen. 3. Relapse: the presence of at least 2 + proteinuria in a first morning specimen on three consecutive days in a patie'~t previously in remission.
Vol. 87, No. 4, pp. 519-523
520
Trainin et al.
The Journal of Pediatrics October 1975
Table I. Clinical course and treatment with cytotoxic drugs Treatment with cytotoxic drugs and subsequent course
i Case No. Sex
tge at onset (mo)
Interval between clinical onset and No. resisof tance relapses* (mo)
Interval between clinical onset and biopsy (mo)
1
F
64
4
24
26
2
F
18
7
12
3
M
25
3
5
4 16 7
4
M
24
3
6
1
5
F
45
4
5
6
6
F
23
1
4
8
7
F
37
1
2
1
8
M
20
3
4
3
9 10
F M
32 19
1 1
3 4
5 4
Drug
6-Thioguanine Azathioprine Cyclophosphamide Azathioprine Cyclophosphamide Azathioprine Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide
Dosage (mg/kg/ day)
Duration of treatment (wk)
Interval from onset of treatment to "emission (wk)
1.0 1.5 3.0
4 64 12
-36 8
9 54
5 0
54 56
2.0 3.0
6 16
24
30
1
60
2.0 3.0
6 12
3
12
6
25
3.0
6
3
2
3
27
3.0
12
2
13
5
25
3.0
12
3
20
5
33
2.5
6
1
24
0
24
2.0
7
11
24
0
27
2.5
6
2
9
3
15
t t
Duration of remission (mo)
No. oJ relapses
Length of observation (mo)~.
-
Died of septicemia
*Number includes the relapse during which the patients failed to respond. tThese patients were treated only with prednisone (see text). ~Refers to the period from the beginning of cytotoxic therapy to the present. (In Cases 4 and 6 the first number refers to the period from the first course of cytotoxic therapy to the second steroid-resistant relapse.) 4. Late nonresponder: a patient who went into remission after steroid therapy on one or more occasions but who fails to remit after four weeks of daily therapy with prednisone, 60 mg per square meter body surface area in divided doses given for a subsequent relapse. Patient material. During~a 10-year period (1964 to 1974), 195 patients with the nephrotic syndrome have been studied at our center and ten have been identified as late nonresponders. Only two o f them were seen by us from the clinical onset of their disease. N o n e o f the patients had a history or signs suggesting a specific etiology for their disease. All had normal antistreptolysin-O titers and negative LE cell preparations or antinuclear antibody titers. Serum c o m p l e m e n t levels were found tO be normal in all patients on at least one occasion. The urine o f all patients was tested daily for protein by semiquantitative methods; quantitative deter-
mination of urine protein, Addis counts, blood chemistries, and renal clearances of urea and creatinine were performed at intervals of three to six months.
RESULTS The clinical features of the ten patients are presented in Table I. The age at onset of the nephrotic syndrome ranged from 19 to 64 months with a m e a n o f 30 months. F o u r o f the patients were male and six were female. Percutaneous renal biopsies were p e r f o r m e d in all patients; one patient (Case 2) had a repeat biopsy. Seven of the biopsies were performed at the time the patients became steroid resistant, and four were p e r f o r m e d earlier in the course of the disease. In all cases, renal biopsy revealed "minimal lesions." Steroid resistance appeared three months to two years
Volume 87 Number 4
after the clinical onset of the nephrotic syndrome with a mean interval of 7.4 months. Three patients (Cases 7, 9, and 10) became late nonresponders at the first relapse, three patients (Cases 3, 4, and 8) at the third, two patients (Cases 1 and 5) at the fourth, and one patient (Case 2) at the seventh relapse. Since eight of the ten patients were referred to us, there was some variation in treatment regimens. However, all were treated daily with prednisone (60 mg per square meter in divided doses) for at least one month before a diagnosis of steroid resistance was made. In addition, four patients (Cases 1, 3, 7, and 10) were treated with daily or intermittent prednisone for one more month, three patients (Cases 2, 4, and 6) for two more months, and one patient (Case 9) for three more months. There was no clinical evidence in any patient of any acute or chronic infection at the time the diagnosis of steroid resistance was made. Eight of the ten patients were given cytotoxic drugs for the treatment of steroid-resistance. Case 1 remained proteinuric after four weeks of 6-thioguanine administration and went into remission only after 36 weeks o f treatment with azathioprine. Azathioprine was given for six weeks without success to two other patients (Cases 3 and 4). Nine courses of cyc!ophosphamide were given to seven patients (Cases 2 to 8) for periods ranging from 6 to 16 weeks. On seven occasions a remission occurred during the administration of the drug, whereas in two instances (Cases 3 and 7) a remission occurred eight and four weeks, respectively, after the cessation of treatment. The remissions lasted for two and nine months, respectively, in two instances (Cases 4 and 8) and ranged from 13 months to more than four years after the other seven courses of therapy. Relapses occurred subsequent to treatment with cyclophosphamide in five patients. In two instances (Cases 4 and 6) steroid resistance eventually recurred. In both o f these patients a second course of cyclophosphamide induced a remission again; in one patient (Case 6) there have been no further relapses; the other one (Case 4) has had several relapses, each responding to prednisone therapy. Case 9 was not treated with cytotoxic drugs. Instead, following one month of daily prednisone therapy, she was continued on intermittent ]~rednisone therapy; went into remission after two weeks of this treatment. She has since had two more relapses, each responding to prednisone given for less than one month. Case 10 died of septicemia four months after the onset of a steroid-resistant relapse. He was treated with prednisone for one month daily and for three months intermittently but no remission occurred. The consent needed for
Nonresponsiveness to steroids
521
administering cyclophosphamide was not obtained for this patient because both the family and the private physician were concerned about the possibility of gonadal damage. The nine surviving patients have been followed for periods of 6 months to 9.5 years (median = 53 months) after the clinical onset of the nephrotic syndrome, and they continue to do well and have normal renal function. Five patients (Cases l, 2, 3, 6, a n d 7) have been in remission for more than two years. DISCUSSION It is common knowledge that the nephrotic syndrome is associated with various histologic lesions and that the most benign of these is that termed "minimal lesions." The reason for the over-all good prognosis in children with the nephrotic syndrome 3, 7-9 is the frequency of "minimal lesions" in this age group: it accounts for approximately 80% of affected children, 9 whereas this diagnosis is made in only about 25% of affected adults/~ It is also known that patients who respond to steroids have a better long-term prognosis than those who do not~; this is also due to the high frequency of"minimal lesions" in the former group. ~ What, then, is the prognosis of the patient who initially responds to steroid treatment but subsequently becomes steroid resistant? More specifically, what is the histologic lesion associated with such a course? One of the lesions which should be considered in this context is focal segmental glomerular sclerosis. This is both because FSS is the most common lesion associated with steroid resistance ~n children 11 and because Habib and Gubler ~2 reported that late nonresponsiveness to steroids occurred in three of their 98 patients with FSS. All ten of our patients had "minimal lesions" on renal biopsy despite their becoming steroid resistant. It may be argued that because of its focal nature and its tendency to begin in the juxtamedullary glomeruli? 3 FSS may easily be missed, especially early in the course of the disease, if the biopsy specimen is too superficial; indeed, all but two o f the biopsies in our patients were performed in the first year of illness, and only one patient had a repeat biopsy. In addition, several authors 14-1~ have described, and we have also observed, patients in whom an initial biopsy showed no apparent changes on light microscopy whereas a subsequent biopsy revealed histologic features typical of FSS. There are several reasons, however, why we can be reasonably certain that our patients have "minimal lesions" rather than FSS. First, as defined here, late nonresponsiveness to steroids is most unusual in patients with FSS since almost all, in our experience, are nonre-
522
Trainin et al.
sponders from the outset. Thus of 21 children with FSS identified and studied at our center, 20 were nonresponders from the onset and only one responded repeatedly to steroid treatment? 7 Second, a remission occurred in all o f our patients who were treated with cyclophosphamide, and in all but one patient this remission lasted for nine months or longer; moreover, two patients responded to this drug on two separate occasions. This response to cyclophosphamide is highly unusual in patients with FSSll, 15 but has been frequently reported to occur in those with "minimal lesions."', 16-20 Third, the five patients who relapsed following cyclophosphamide treatment regained responsiveness to steroids. Such a course has been described in patients with "minimal lesions ''~ but to our knowledge not in patients with FSS. Finally, our patients have been followed for a median period of 53 months, all but one have done well, and none has shown evidence of functional deterioration. One patient has died; however, his death was secondary to sepsis and his renal function remained normal until that time. Siegel and associates~ described six patients with the nephrotic syndrome and a relapsing course who developed resistance to steroids. However, they became resistant after a long period of responsiveness (4 to 15 years as compared to less than two years in our series) and, unlike our patients, developed renal insufficiency. In a subsequent report by these authors, ~1 three such patients were biopsied and were found to have focal, segmental, sclerotic lesions. These reports are of considerable interest since they suggest that the clinical and pathologic features of FSS may develop after many years in patients who, by all accepted criteria, seem to have followed an initial course typical of "minimal lesions." Such a course of events has not been reported previously and we have not seen it among our patients. The response of our patients to cyclophosphamide should not be taken as a recommendation for the use of this drug in all such patients. It is possible that continued administration of prednisone might eventually induce a remission, as suggested by the course of Case 9. Moreover, it is well established that cyclophosphamide can have irreversible toxic effects on the gonads) ~, ~3 even in prepubertal children, z', ~5 It is obvious, however, that in the individual case the risks of cyclophosphamide administration must be weighed, on the one hand, against the benefit which may accrUe from this treatment, and, on the other hand, against the risks of either long-term steroid therapy a n d / o r persistent active disease. That such risks are real is clear since in our series five patients had serious complications (including cellulitis, peritonitis, sepsis, cerebrovascular thrombosis, and hypertension) due either to steroids or to the nephrotic state itself, and one patient
The Journal of Pediatrics October 1975
died from septicemia. It is in such patients that cyclophosphamide therapy may be of considerable value. Moreover, it has been suggested recently that gonadal damage does not occur if the daily dosage of cyclophosphamide is kept below 2.5 mg/kg and the drug is given for no more than 60 days. ~6 In conclusion, on the basis of our experience, it is likely that children with the nephrotic syndrome who become late nonresponders during the first few years of the disease have "minimal legions" and their long-term prognosis is good. If such a patient becomes steroid toxic or demonstrates serious complications as a result of the nephrotic state, a course Of cyclophosphamide, which probably should not exceed 60 days, ~6 can be expected either to induce a long-lasting remission or at least restore steroid responsiveness. In patients with an uncomplicated course, cyclophosphamide should probably not be administered; however, there is, at present, insufficient data on which to base a more definite recommendation. It remains entirely unclear why a particular patient with "minimal lesions" suddenly becomes steroid resistant and how this state is reversed by cyclophosphamide.
REFERENCES 1. Churg J, Habib R, and White RHR: Pathology of the nephrotic syndrome in children. A report for the International Study of Kidney Disease in Children, Lancet 1:1299, 1970. 2. White RHR, Glasgow EF, and Mills RJ: Clinicopathological study of nephrotic syndrome in childhood, Lancet 1:1153, 1970. 3. Siegel NJ, Goldberg B, Krassner LS, and Hayslett JP: Long-term follow-up of children with steroid-responsive nephrotic syndrome, J PEDIAXR81:251, 1972. 4. Chin J, and Drummond KN: Long-term follow-up ofcyclophosphamide therapy in frequently relapsing minimallesion nephrotic syndrome, J PEDIATR84:825, 1974. 5. 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, 6. Makker SP, and Heymann W: The idiopathic nephrotic syndrome of childhood. A clinical reevaluation of 148 cases, Am J Dis Child 127:830, 1974. 7. McCrory WW, Rapoport M, and Fleisher DS: Estimation of severity of the nephrotic syndrome in childhood as a guide to therapy and prognosis, Pediatrics 23:861, 1959. 8. Cornfeld D, and Schwartz MW: Nephrosis--a long-term study of children treated with corticosteroids, J P~DIAXR 68:507, 1)68. 9. Scharer K, and Minges U: Long-term prognosis of the nephrotic syndrome in childhood, Clin Nephrol 1:182, 1973. 10. Hopper J Jr, Ryan P, Lee JC, and Rosenau W: Lipoid nephrosis in 31 adult patients. Renal biopsy study by light, electron and fluorescence microscopy with experience in treatment, Medicine 49:32t, 1970.
Volume 87 Number 4
11. White RHR, Glasgow EF, and Mills RJ: Focal glomerulosclerosis in childhood, in Kincaid-Smith P J, editor: Glomerulonephritis-morphology, natural history and treatment, New York~ 1973, John Wiley & Sons, Inc, pp 231-248. 12. Habib R, and Gubler M-C: Focal sclerosing glomerulonephritis, in Kincaid-Smith PJ, editor: Glomerulonephritis-morphology, natural history and treatment, New York, 1973, John Wiley & Sons, Inc, pp 263-278. 13. Rich AR: A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis, Bull Johns Hopkins Hosp 100:173, 1957. 14. Hayslett JP, Krassner LS, Bensch KG, Kashgarian M, and Epstein FH: Progression of lipoid nephrosis to renal insufficiency, N Engl J Med 281:181, 1969. 15. Hyman LR, and Burkholder PM: Focal sclerosing glomerulonephropathy with hyalinosis, J PEDIATR70:758, 1974. 16. McGovern VJ: Persistent nephrotic syndrome-a renal biopsy study, Aust Ann Med 13:306, 1964. 17. Olbing H, Nash MA, Bernstein J, Bennett B, Spitzer A, and Greifer I: Prognosis of glomerular focal sclerosis in children, Pediatr Res 8:459, 1974. 18. Prospective controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome. Report of the International Study of Kidney Disease in Children, Lancet 2:423, 1974. 19. Moncrieff MW, White RHR, Ogg CS, and Cameron JS:
Nonresponsiveness to steroids
20.
21.
22.
23.
24.
25.
26.
523
Cyclophosphamide therapy in the nephrotic syndrome in childhood, Br Med J 1:666, 1969. Etteldorf JN, Shane R III, Summitt RL, Sweeny M J, Wall HP, and Barton WM; Cyclophosphamide in the treatment of idiopathic lipoid nephrosis, J Pediatr 70:758, 1967. Siegel NJ, Kashgarian M, Spargo BH, and Hayslett JP: Minimal changes and focal sclerotic lesions in lipoid nephrosis, Nephron 13:306, 1974. Fairley KF, Barrie JU, and Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy, Lancet 1:568, 1972. Kumar R, Biggart JD, McEvoy J, and McGeown MG: Cyclophosphamide and reproductive function, Lancet 1:1212, 1972. Penso J, Lippe B, Ehrlich R, and Smith F Jr: Testicular function in prepubertal and pubertal males treated with cyclophosphamide for nephrotic syndrome. J PEDIATR 84:831, 1974. Pennisi AJ, Grushkin CM, and Lieberman E: Gonadal function in children with nephrosis treated with cyclophosphamide, Am J Dis Child 129:315, 1975. Etteldorf JN, West C, Pitcock J, and Williams D: Gonadal function, testicular histology and meiosis in patients with preadolescent nephrotic syndrome treated with cyclophosphamide, Abstracts, Third International Symposium on Pediatric Nephrology, Washington, DC, 1974, p 23.
The Journal o f P E D I A T R I C S
519
Late nonresponsiveness to steroids in children with the nephrotic syndrome Among 195 nephrotic children, ten developed resistance to prednisone therapy after responding to this drug on one or more occasions (late nonresponders). All were found to have "minimal lesions'on renal biopsy. Nine o f these patients went into remission: one responded to further prednisone therapy, one went into remission while receiving azathioprine, and the remaining seven children responded to cyclophosphamide. Five of these seven patients subsequently relapsed; three of them have continued to respond to prednisone. The other two eventually became steroid resistant a second time, but in both instances a second course of cyclophosphamide again induced a remission. These nine patients have been followed for periods ranging from 6 months to 9.5 years (median = 53 months)," all are doing well and have normal renal function. The tenth patient died from sepsis four months after the onset o f steroid resistance.
Eugene B. Trainin, M.D., Hayim Boichis, M.D., Adrian Spitzer, M.D., Chester M. Edelmann, Jr., M.D., and Ira Greifer, M.D.,* Bronx, N. Y.
CHILDREN with the nephrotic syndrome can be divided into two groups according to their response or lack of response to prednisone therapy. In general, those who respond have "minimal lesions ''1 on renal biopsy, whereas those who remain proteinuric have some form of glomerulopathy? Many patients with "minimal lesions" have a relapsing course, but as a rule they continue to respond to prednisone? There are, however, patients who after having responded to prednisone on one or more occasions become resistant to this agent (late nonresponders). This group has only occasionally been referred to in the literature, 3-~ and the underlying histology, clinical course, and prognosis of these patients is unclear. We have reviewed the records of 195 children with the From the Department of Pediatrics, Hospital o f the Albert Einstein College of Medicine, and Division o f Pediatric Nephrology, Albert Einstein College o f Medicine and Rose F Kennedy Center. Supported in part by Public Health Service Program Project Grant A M 14877, The Kidney Disease Institute of the State of New York, The Kidney Foundation of New York, and the Rath Foundation. *Reprint address: Department of Pediatrics, Hospital of the Albert Einstein College of Medicine, 1825 Eastehester Rd, Bronx, N. Y. 10461.
nephrotic syndrome seen at our center in the past ten years and have found among them ten late nonresponders. The histology in all cases was that of "minimal lesions." Nine of these patients eventually went into remission, seven of them following treatment with cyclophosphamide. The tenth patient died of septicemia. Five of the patients treated with cyclophosphamide subsequently relapsed but they all responded again to prednisone therapy. Abbreviation used FSS: focal segmental glomerular sclerosis
I
MATERIAL AND METHODS Definitions. The following definitions were arbitrarily chosen for the purpose of this study: 1. Nephrotic syndrome: proteinuria of more than 40 mg per hour per square meter body surface area and a serum albumin value of less than 2.5 gm/dl. 2. Remission: demonstration of a "protein-free" urine on three consecutive examinations of the first morning specimen. 3. Relapse: the presence of at least 2 + proteinuria in a first morning specimen on three consecutive days in a patie'~t previously in remission.
Vol. 87, No. 4, pp. 519-523
520
Trainin et al.
The Journal of Pediatrics October 1975
Table I. Clinical course and treatment with cytotoxic drugs Treatment with cytotoxic drugs and subsequent course
i Case No. Sex
tge at onset (mo)
Interval between clinical onset and No. resisof tance relapses* (mo)
Interval between clinical onset and biopsy (mo)
1
F
64
4
24
26
2
F
18
7
12
3
M
25
3
5
4 16 7
4
M
24
3
6
1
5
F
45
4
5
6
6
F
23
1
4
8
7
F
37
1
2
1
8
M
20
3
4
3
9 10
F M
32 19
1 1
3 4
5 4
Drug
6-Thioguanine Azathioprine Cyclophosphamide Azathioprine Cyclophosphamide Azathioprine Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide Cyclophosphamide
Dosage (mg/kg/ day)
Duration of treatment (wk)
Interval from onset of treatment to "emission (wk)
1.0 1.5 3.0
4 64 12
-36 8
9 54
5 0
54 56
2.0 3.0
6 16
24
30
1
60
2.0 3.0
6 12
3
12
6
25
3.0
6
3
2
3
27
3.0
12
2
13
5
25
3.0
12
3
20
5
33
2.5
6
1
24
0
24
2.0
7
11
24
0
27
2.5
6
2
9
3
15
t t
Duration of remission (mo)
No. oJ relapses
Length of observation (mo)~.
-
Died of septicemia
*Number includes the relapse during which the patients failed to respond. tThese patients were treated only with prednisone (see text). ~Refers to the period from the beginning of cytotoxic therapy to the present. (In Cases 4 and 6 the first number refers to the period from the first course of cytotoxic therapy to the second steroid-resistant relapse.) 4. Late nonresponder: a patient who went into remission after steroid therapy on one or more occasions but who fails to remit after four weeks of daily therapy with prednisone, 60 mg per square meter body surface area in divided doses given for a subsequent relapse. Patient material. During~a 10-year period (1964 to 1974), 195 patients with the nephrotic syndrome have been studied at our center and ten have been identified as late nonresponders. Only two o f them were seen by us from the clinical onset of their disease. N o n e o f the patients had a history or signs suggesting a specific etiology for their disease. All had normal antistreptolysin-O titers and negative LE cell preparations or antinuclear antibody titers. Serum c o m p l e m e n t levels were found tO be normal in all patients on at least one occasion. The urine o f all patients was tested daily for protein by semiquantitative methods; quantitative deter-
mination of urine protein, Addis counts, blood chemistries, and renal clearances of urea and creatinine were performed at intervals of three to six months.
RESULTS The clinical features of the ten patients are presented in Table I. The age at onset of the nephrotic syndrome ranged from 19 to 64 months with a m e a n o f 30 months. F o u r o f the patients were male and six were female. Percutaneous renal biopsies were p e r f o r m e d in all patients; one patient (Case 2) had a repeat biopsy. Seven of the biopsies were performed at the time the patients became steroid resistant, and four were p e r f o r m e d earlier in the course of the disease. In all cases, renal biopsy revealed "minimal lesions." Steroid resistance appeared three months to two years
Volume 87 Number 4
after the clinical onset of the nephrotic syndrome with a mean interval of 7.4 months. Three patients (Cases 7, 9, and 10) became late nonresponders at the first relapse, three patients (Cases 3, 4, and 8) at the third, two patients (Cases 1 and 5) at the fourth, and one patient (Case 2) at the seventh relapse. Since eight of the ten patients were referred to us, there was some variation in treatment regimens. However, all were treated daily with prednisone (60 mg per square meter in divided doses) for at least one month before a diagnosis of steroid resistance was made. In addition, four patients (Cases 1, 3, 7, and 10) were treated with daily or intermittent prednisone for one more month, three patients (Cases 2, 4, and 6) for two more months, and one patient (Case 9) for three more months. There was no clinical evidence in any patient of any acute or chronic infection at the time the diagnosis of steroid resistance was made. Eight of the ten patients were given cytotoxic drugs for the treatment of steroid-resistance. Case 1 remained proteinuric after four weeks of 6-thioguanine administration and went into remission only after 36 weeks o f treatment with azathioprine. Azathioprine was given for six weeks without success to two other patients (Cases 3 and 4). Nine courses of cyc!ophosphamide were given to seven patients (Cases 2 to 8) for periods ranging from 6 to 16 weeks. On seven occasions a remission occurred during the administration of the drug, whereas in two instances (Cases 3 and 7) a remission occurred eight and four weeks, respectively, after the cessation of treatment. The remissions lasted for two and nine months, respectively, in two instances (Cases 4 and 8) and ranged from 13 months to more than four years after the other seven courses of therapy. Relapses occurred subsequent to treatment with cyclophosphamide in five patients. In two instances (Cases 4 and 6) steroid resistance eventually recurred. In both o f these patients a second course of cyclophosphamide induced a remission again; in one patient (Case 6) there have been no further relapses; the other one (Case 4) has had several relapses, each responding to prednisone therapy. Case 9 was not treated with cytotoxic drugs. Instead, following one month of daily prednisone therapy, she was continued on intermittent ]~rednisone therapy; went into remission after two weeks of this treatment. She has since had two more relapses, each responding to prednisone given for less than one month. Case 10 died of septicemia four months after the onset of a steroid-resistant relapse. He was treated with prednisone for one month daily and for three months intermittently but no remission occurred. The consent needed for
Nonresponsiveness to steroids
521
administering cyclophosphamide was not obtained for this patient because both the family and the private physician were concerned about the possibility of gonadal damage. The nine surviving patients have been followed for periods of 6 months to 9.5 years (median = 53 months) after the clinical onset of the nephrotic syndrome, and they continue to do well and have normal renal function. Five patients (Cases l, 2, 3, 6, a n d 7) have been in remission for more than two years. DISCUSSION It is common knowledge that the nephrotic syndrome is associated with various histologic lesions and that the most benign of these is that termed "minimal lesions." The reason for the over-all good prognosis in children with the nephrotic syndrome 3, 7-9 is the frequency of "minimal lesions" in this age group: it accounts for approximately 80% of affected children, 9 whereas this diagnosis is made in only about 25% of affected adults/~ It is also known that patients who respond to steroids have a better long-term prognosis than those who do not~; this is also due to the high frequency of"minimal lesions" in the former group. ~ What, then, is the prognosis of the patient who initially responds to steroid treatment but subsequently becomes steroid resistant? More specifically, what is the histologic lesion associated with such a course? One of the lesions which should be considered in this context is focal segmental glomerular sclerosis. This is both because FSS is the most common lesion associated with steroid resistance ~n children 11 and because Habib and Gubler ~2 reported that late nonresponsiveness to steroids occurred in three of their 98 patients with FSS. All ten of our patients had "minimal lesions" on renal biopsy despite their becoming steroid resistant. It may be argued that because of its focal nature and its tendency to begin in the juxtamedullary glomeruli? 3 FSS may easily be missed, especially early in the course of the disease, if the biopsy specimen is too superficial; indeed, all but two o f the biopsies in our patients were performed in the first year of illness, and only one patient had a repeat biopsy. In addition, several authors 14-1~ have described, and we have also observed, patients in whom an initial biopsy showed no apparent changes on light microscopy whereas a subsequent biopsy revealed histologic features typical of FSS. There are several reasons, however, why we can be reasonably certain that our patients have "minimal lesions" rather than FSS. First, as defined here, late nonresponsiveness to steroids is most unusual in patients with FSS since almost all, in our experience, are nonre-
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Trainin et al.
sponders from the outset. Thus of 21 children with FSS identified and studied at our center, 20 were nonresponders from the onset and only one responded repeatedly to steroid treatment? 7 Second, a remission occurred in all o f our patients who were treated with cyclophosphamide, and in all but one patient this remission lasted for nine months or longer; moreover, two patients responded to this drug on two separate occasions. This response to cyclophosphamide is highly unusual in patients with FSSll, 15 but has been frequently reported to occur in those with "minimal lesions."', 16-20 Third, the five patients who relapsed following cyclophosphamide treatment regained responsiveness to steroids. Such a course has been described in patients with "minimal lesions ''~ but to our knowledge not in patients with FSS. Finally, our patients have been followed for a median period of 53 months, all but one have done well, and none has shown evidence of functional deterioration. One patient has died; however, his death was secondary to sepsis and his renal function remained normal until that time. Siegel and associates~ described six patients with the nephrotic syndrome and a relapsing course who developed resistance to steroids. However, they became resistant after a long period of responsiveness (4 to 15 years as compared to less than two years in our series) and, unlike our patients, developed renal insufficiency. In a subsequent report by these authors, ~1 three such patients were biopsied and were found to have focal, segmental, sclerotic lesions. These reports are of considerable interest since they suggest that the clinical and pathologic features of FSS may develop after many years in patients who, by all accepted criteria, seem to have followed an initial course typical of "minimal lesions." Such a course of events has not been reported previously and we have not seen it among our patients. The response of our patients to cyclophosphamide should not be taken as a recommendation for the use of this drug in all such patients. It is possible that continued administration of prednisone might eventually induce a remission, as suggested by the course of Case 9. Moreover, it is well established that cyclophosphamide can have irreversible toxic effects on the gonads) ~, ~3 even in prepubertal children, z', ~5 It is obvious, however, that in the individual case the risks of cyclophosphamide administration must be weighed, on the one hand, against the benefit which may accrUe from this treatment, and, on the other hand, against the risks of either long-term steroid therapy a n d / o r persistent active disease. That such risks are real is clear since in our series five patients had serious complications (including cellulitis, peritonitis, sepsis, cerebrovascular thrombosis, and hypertension) due either to steroids or to the nephrotic state itself, and one patient
The Journal of Pediatrics October 1975
died from septicemia. It is in such patients that cyclophosphamide therapy may be of considerable value. Moreover, it has been suggested recently that gonadal damage does not occur if the daily dosage of cyclophosphamide is kept below 2.5 mg/kg and the drug is given for no more than 60 days. ~6 In conclusion, on the basis of our experience, it is likely that children with the nephrotic syndrome who become late nonresponders during the first few years of the disease have "minimal legions" and their long-term prognosis is good. If such a patient becomes steroid toxic or demonstrates serious complications as a result of the nephrotic state, a course Of cyclophosphamide, which probably should not exceed 60 days, ~6 can be expected either to induce a long-lasting remission or at least restore steroid responsiveness. In patients with an uncomplicated course, cyclophosphamide should probably not be administered; however, there is, at present, insufficient data on which to base a more definite recommendation. It remains entirely unclear why a particular patient with "minimal lesions" suddenly becomes steroid resistant and how this state is reversed by cyclophosphamide.
REFERENCES 1. Churg J, Habib R, and White RHR: Pathology of the nephrotic syndrome in children. A report for the International Study of Kidney Disease in Children, Lancet 1:1299, 1970. 2. White RHR, Glasgow EF, and Mills RJ: Clinicopathological study of nephrotic syndrome in childhood, Lancet 1:1153, 1970. 3. Siegel NJ, Goldberg B, Krassner LS, and Hayslett JP: Long-term follow-up of children with steroid-responsive nephrotic syndrome, J PEDIAXR81:251, 1972. 4. Chin J, and Drummond KN: Long-term follow-up ofcyclophosphamide therapy in frequently relapsing minimallesion nephrotic syndrome, J PEDIATR84:825, 1974. 5. 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, 6. Makker SP, and Heymann W: The idiopathic nephrotic syndrome of childhood. A clinical reevaluation of 148 cases, Am J Dis Child 127:830, 1974. 7. McCrory WW, Rapoport M, and Fleisher DS: Estimation of severity of the nephrotic syndrome in childhood as a guide to therapy and prognosis, Pediatrics 23:861, 1959. 8. Cornfeld D, and Schwartz MW: Nephrosis--a long-term study of children treated with corticosteroids, J P~DIAXR 68:507, 1)68. 9. Scharer K, and Minges U: Long-term prognosis of the nephrotic syndrome in childhood, Clin Nephrol 1:182, 1973. 10. Hopper J Jr, Ryan P, Lee JC, and Rosenau W: Lipoid nephrosis in 31 adult patients. Renal biopsy study by light, electron and fluorescence microscopy with experience in treatment, Medicine 49:32t, 1970.
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11. White RHR, Glasgow EF, and Mills RJ: Focal glomerulosclerosis in childhood, in Kincaid-Smith P J, editor: Glomerulonephritis-morphology, natural history and treatment, New York~ 1973, John Wiley & Sons, Inc, pp 231-248. 12. Habib R, and Gubler M-C: Focal sclerosing glomerulonephritis, in Kincaid-Smith PJ, editor: Glomerulonephritis-morphology, natural history and treatment, New York, 1973, John Wiley & Sons, Inc, pp 263-278. 13. Rich AR: A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis, Bull Johns Hopkins Hosp 100:173, 1957. 14. Hayslett JP, Krassner LS, Bensch KG, Kashgarian M, and Epstein FH: Progression of lipoid nephrosis to renal insufficiency, N Engl J Med 281:181, 1969. 15. Hyman LR, and Burkholder PM: Focal sclerosing glomerulonephropathy with hyalinosis, J PEDIATR70:758, 1974. 16. McGovern VJ: Persistent nephrotic syndrome-a renal biopsy study, Aust Ann Med 13:306, 1964. 17. Olbing H, Nash MA, Bernstein J, Bennett B, Spitzer A, and Greifer I: Prognosis of glomerular focal sclerosis in children, Pediatr Res 8:459, 1974. 18. Prospective controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome. Report of the International Study of Kidney Disease in Children, Lancet 2:423, 1974. 19. Moncrieff MW, White RHR, Ogg CS, and Cameron JS:
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Cyclophosphamide therapy in the nephrotic syndrome in childhood, Br Med J 1:666, 1969. Etteldorf JN, Shane R III, Summitt RL, Sweeny M J, Wall HP, and Barton WM; Cyclophosphamide in the treatment of idiopathic lipoid nephrosis, J Pediatr 70:758, 1967. Siegel NJ, Kashgarian M, Spargo BH, and Hayslett JP: Minimal changes and focal sclerotic lesions in lipoid nephrosis, Nephron 13:306, 1974. Fairley KF, Barrie JU, and Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy, Lancet 1:568, 1972. Kumar R, Biggart JD, McEvoy J, and McGeown MG: Cyclophosphamide and reproductive function, Lancet 1:1212, 1972. Penso J, Lippe B, Ehrlich R, and Smith F Jr: Testicular function in prepubertal and pubertal males treated with cyclophosphamide for nephrotic syndrome. J PEDIATR 84:831, 1974. Pennisi AJ, Grushkin CM, and Lieberman E: Gonadal function in children with nephrosis treated with cyclophosphamide, Am J Dis Child 129:315, 1975. Etteldorf JN, West C, Pitcock J, and Williams D: Gonadal function, testicular histology and meiosis in patients with preadolescent nephrotic syndrome treated with cyclophosphamide, Abstracts, Third International Symposium on Pediatric Nephrology, Washington, DC, 1974, p 23.
