Childhood steroid-sensitive nephrotic syndrome: Does the histology matter?

Childhood Steroid-Sensitive Nephrotic Syndrome: Does the Histology Matter? Nicholas J.A. Webb, BMedSci, MRCP, Malcolm A. Lewis, MRCP, Javed Iqbal, MRCP, Peter J. Smart, FRCPath, Mehroo Lendon, PhD, FRCPath, and Robert J. Postlethwaite, FRCP 0 Renal biopsy specimens from 51 children with steroid-sensitive nephrotic syndrome who were following a frequently relapsing or steroid-dependent course were reviewed by two histopathologists. In all cases the biopsy was performed prior to the commencement of an 8-week course of cyclophosphamide. The clinical courses of these patients both prebiopsy and for a minimum of 2 years after completion of cyclophosphamide therapy were analyzed using retrospective case note analyses. The distribution of histologic diagnoses differed significantly from that reported by the International Study of Kidney Disease in Children in their study of children who underwent biopsy at the time of presentation, there being an excess of focal segmental glomerulosclerosis and mild mesangial hypercellularity in this series. The prebiopsy clinical course did not predict for histologic diagnosis, and there was no correlation between prebiopsy course or histology and postcyclophosphamide course. The findings of this study support the clinical impression that steroid sensitivity rather than histology is the major determinant of prognosis in childhood nephrotic syndrome and that frequency of relapse alone is not an indication for biopsy. 0 1996 by the National Kidney Foundation, Inc. INDEX

WORDS:

Steroid-sensitive

nephrotic

syndrome;

childhood;

E

ARLY publications by the International Study of Kidney Disease in Children (ISKDC) reported that the majority of children with nephrotic syndrome had minimal-change disease (MCD).’ Almost all these children demonstrated a response to corticosteroids with disappearance of proteinuria,’ and for some time steroid responsiveness has been taken as the hallmark of benign disease. Routine biopsy at the onset of the disease was therefore abandoned and the procedure reserved for those who demonstrated frequent relapses (FR), steroid dependence (SD), or either primary or secondary steroid resistance. Long-term follow-up of patients with biopsy proven MCD has shown the prognosis to be good. In a cohort of 63 patients followed at this institution for between 10 and 21 years, none developed hypertension or renal failure,’ despite the fact that two thirds of this cohort had FRs or SD requiring one or more courses of alkylating agents. The abandonment of biopsy at presentation, From the Departments of Nephrology and Pathology, The Royal Manchester Children’s Hospital, Manchester, United Kingdom. Received March 30, 1995; accepted in revised form November 14, 1995. Address reprint requests to Malcolm A. Lewis, Department of Nephrology, The Royal Manchester Children’s Hospital, Hospital Rd, Pendlebury, Manchester, M27 4HA, United Kingdom. 0 1996 by the National Kidney Foundation, Inc. 0272~6386/96/2704-0003$3.00/O 484

American

Journal

renal

biopsy;

renal

histology;

cyclophosphamide.

however, does mean that the histology of patients with FRs or SD is not known. Siegel et al4 found that 11 of 38 patients with FRs or SD had focal segmental glomerulosclerosis (FSGS) on biopsy, while Trachtman et aL5 studying a predominantly black and Hispanic population, found immunoglobulin M nephropathy (IgMN) to be the most common histologic finding. On the basis of these studies, some investigators have recommended that all children with FRs or SD undergo renal biopsy to identify histologies associated with an unfavorable prognosis. Moreover, Bems et al,6 in a long-term follow-up study that included 20 children who received at least one course of cyclophosphamide, found that the clinical course following cyclophosphamide therapy was strongly dependent on the biopsy findings, relapses occurring much less frequently in those with MCD than in those with focal glomerulosclerosis or a mesangioproliferative lesion. These studies raise the following questions: 1. What is the histologic pattern of disease seen in children with FRs or SD and how does it compare with the pattern of disease described at presentation by the ISKDC7? 2. What is the relationship between histologic appearance and clinical course in children with FRs or SD? To answer these questions we undertook a retrospective analysis of the clinical courses and reviewed the renal biopsies of all patients with FRs or SD who underwent renal biopsy prior to treatment with cyclophosphamide at this institution between January 1981 and December 1989, when routine biopsy was abandoned on the of Kidney

Diseases,

Vol 27, No 4 (April),

1996:

pp 484-488

STEROID-SENSITIVE

NEPHROTIC Table

Histology

This Series

MCNS FSGS DMH Other

SYNDROME

1. Distribution

485 of Histologic

(n = 51)

ISKDC? (n = 368)

80.4% 13.7% 5.9% 0.0%

Abbreviations: MCNS, mesangial hypercellularity.

minimal-change

AND

nephrotic

syndrome;

METHODS

Between 1981 and 1989, 51 children with FRs or SD underwent renal biopsy prior to the commencement of cyclophosphamide therapy. Cases were identified from records in the Department of Pathology. Case notes were retrospectively analyzed, recording sex, age at diagnosis, age at biopsy, number and frequency of relapses prior to biopsy, duration of remission following completion of cyclophosphamide therapy, and number and frequency of relapses in the first 2 years after completion of cyclophosphamide therapy. Patients were classified according to standard ISKDC criteria’ as being FRs or SD in the prebiopsy period and were then reclassified using the same criteria for the 2-year follow-up period following completion of cyclophosphamide therapy. Classification was made easier by the use of rigid and uniform treatment protocols. Patients were treated at initial presentation and at each subsequent relapse with prednisolone 60 mg/m2/d in divided doses until the first-morning urine showed zero or trace proteinuria on Albustix (Bayer Diagnostics, Basingstoke, Hants, United Kingdom) for 3 consecutive days. At this point patients were given 40 mg/m’ prednisolone as a single morning dose on alternate days for a total of 14 doses. Therapy was then abruptly stopped. Cyclophosphamide was given as a single daily dose of 2.5 mg/kg for 8 weeks. The first 4 weeks were accompanied by prednisolone in a dosage of 40 mg/m* as a single morning dose on alternate days. This was then reduced to 20 mg/m’ for the second

Table MCNS

2. Distribution Subgroup

MMH FTC MMT FGO Nil

of Minimal-Change This Series

58.9% 7.3% 9.8% 9.8% 14.6%

in This

(n = 41)

and

Other

Series

Siegel et aI4 (n = 38)

91.8% 4.6% 1.4% 2.2%

grounds of a clinical impression that management was not influenced by the biopsy findings. PATIENTS

Diagnoses

Trachtman

47.4% 28.9% 23.7% 0.0% FSGS,

focal

et al5 (n = 16)

25.0% 12.5% 18.8% 43.8%

segmental

glomerulosclerosis;

DMH,

diffuse

month of cyclophosphamide therapy, the steroids and cyclophosphamide both being stopped abruptly at the end of the g-week period. Renal biopsy specimens were examined independently by two experienced histopathologists, one of whom (M.L.) had been involved in the original ISKDC studies. They were blinded to both the clinical histories and the original biopsy reports. Light microscopy, immunofluorescence, and electron microscopy results were available for all specimens. Biopsy findings were classified according to ISKDC criteria as MCD, diffuse mesangial hypercellularity, FSGS, and other diagnoses. Biopsy specimens classified as MCD were subgrouped according to ISKDC criteria6 into mild mesangial hypercellularity, focal tubular change, mild mesangial thickening, focal glomerular obsolescence, and nil disease. Statistical analysis was performed using correlation coefficients, Fisher’s exact test, and the Chi-squared test as appropriate.

RESULTS

The study group of 51 children had a skewed age distribution at presentation, with a median age of 2.3 years (age range, 1.3 to 8.5 years). The female to male ratio was 1.2: 1. Forty children were white, 10 were Asian of Indian subcontinental origin, and one was black. Biopsies were performed a median of 8 months (range, 2.5 to 10.5 months) after presentation.

Subgroups ISKDC9 (n = 346)

6.6% 6.9% 4.3% 24.0% 58.2%

Abbreviations: MCNS, minimal-change nephrotic syndrome; MMH, mild mesangial hypercellularity; FTC, focal tubular changes; MMT, mild mesangial thickening; FGO, focal glomerular obsolescence.

Table 3. Histologic in the 41 Children

Picture and Prebiopsy Category With Complete Follow-up Data

Histology

MCNS FSGS DMH Other

FRs

6 1 1 0

(14.6%) (2.4%) (2.4%) (0.0%)

SD

27 4 2 0

(65.9%) (9.8%) (4.9%) (0.0%)

Abbreviations: MCNS, minimal-change nephrotic drome; FSGS, focal segmental glomerulosclerosis; diffuse mesangial hypercellularity.

synDMH,

486

WEBB Table

4. Histologic Picture in the 41 Children

and With

Postcyclophosphamide Complete Follow-up Lenqth

Histology

o-13

MCNS FSGS DMH

8 (19.5%) 1 (2.4%) 2 (4.9%)

Abbreviations: MCNS, mesangial hypercellularity.

minimal-change

14-26

syndrome;

FSGS,

and Postcyclophosphamide Complete Follow-up Length

FRs SD

2 (4.9%) 9 (22.0%)

14-26

0 (0.0%) 7 (17.1%)

segmental

glomerulosclerosis;

10 (24.4%) 1 (2.4%) 1 (2.4%) DMH,

diffuse

We have demonstrated that the histologic pattern of disease in children with FRs or SD who underwent biopsy prior to treatment with cyclophosphamide is significantly different from that described by the ISKDC in their study of histology at presentation.2z9 The proportion of patients with FSGS is higher in those with FRs or SD, and among those with true MCD, most have mild mesangial hypercellularity rather than nil disease. Despite these differences, the histologic distri-

Complete 2-year follow-up data regarding relapse frequency were available for 41 of the 5 1

5. Prebiopsy Clinical Category in the 41 Children With

focal

5 (12.2%) 1 (2.4%) 0 (0.0%)

>104

DISCUSSION

Clinical Course

o-13

53-l 04

children, the other 10 resuming care in their districts of origin with instructions to local pediatricians that re-referral would be necessary if FRs occurred. The characteristics of these 10 were not different from the whole group with regard to age, sex, prebiopsy relapse frequency, and histology. There was no relationship between prebiopsy clinical course and histology, nor was there any relationship between either of these and clinical course following cyclophosphamide (Tables 3 to 7). At their most recent clinic visits, 4 to 13 years after biopsy, all patients were normotensive, had no hematuria or proteinuria, and had normal renal function.

Consistent with the findings of others, the distribution of the major histologic groups (Table 1) was significantly different from the steroidsensitive group of the ISKDC study (P < 0.0001, U&squared test), the proportion of patients with FSGS being higher in this series (P = 0.023, Fisher’s exact test). The proportion of patients with FSGS, however, was smaller than that described by Siegel et a1,4 although this difference failed to reach statistical significance (P = 0.052, Fisher’s exact test). The distribution of histologic groups was significantly different from that reported by Trachtman et al5 (P < 0.0001, Chisquared test) because of the paucity of minimal change in their series and the absence of IgMN in ours. Contrary to the findings of the ISKDC, who reported no difference between the histologic subgroups with regard to the development of a frequently relapsing course,’ we found a marked overrepresentation of mild mesangial hypercellularity in this series (P < 0.0001) (Table 2). The diagnoses made by the two histopathologists did not differ on any occasion.

Patients

(wk)

4 (9.8%) 1 (2.4%) 0 (0.0%)

Histology

Table

Remission Data

27-52

6 (14.6%) 1 (2.4%) 0 (0.0%) nephrotic

of Remission

ET AL

of Remission 27-52

0 (0.0%) 5 (12.2%)

Remission Data

(wk) 53-l 04

1 (2.4%) 4 (9.8%)

>104

5 (12.2%) 8 (19.5%)

STEROID-SENSITIVE

NEPHROTIC

SYNDROME

467

Table 6. Prebiopsy Histology and Relapse Frequency in the First and Second Years After Cyclophosphamide First-Year Histology

<4

MCNS FSGS DMH

25 (61 .O%) 4 (9.8%) 1 (2.4%)

Relapses 24

8 (19.5%) 1 (2.4%) 2 (4.9%)

Second-Year

Relapses

<4

25 (61 .O%) 4 (9.8%) 1 (2.4%)

24

8 (19.5%) 1 (2.4%) 2 (4.9%)

Abbreviations: MCNS, minimal-change nephrotic drome; FSGS, focal segmental glomerulosclerosis; diffuse mesangial hypercellularity.

synDMH,

bution that we have demonstrated is dissimilar from those described by both Siegel et al4 and Trachtman et al.’ Siegel et al’s study indicated a higher incidence of FSGS than ours. One explanation for this is that if patients who have nephrotic syndrome with FSGS histology are more likely to have a frequently relapsing or steroiddependent course, the increased incidence of FSGS reported by Siegel et al could be due to the selected referral of difficult patients with FRs to their center. The timing of renal biopsy also may be of importance; children underwent biopsies at a much later stage in Siegel et al’s study compared with ours (6 years v 8 months, respectively). Tejani proposed that morphologic transformation from MCD to FSGS occurs with increasing time from diagnosis,” which may be a further explanation for the observed differences. The largest single histologic subgroup in Trachtman et al’s study was IgMN. This was not seen in our series despite that fact that immunofluorescence was available for all biopsy specimens. This could again be explained by morphologic transformation,” the mean disease duration prior to biopsy in Trachtman et al’s study being 4.85 years, or could represent differences in the population being studied. The populations are certainly different, as our study group consisted almost entirely of white and Asian patients, whereas the group studied by Trachtman et al contained a high percentage of patients of black and Hispanic origin. As the long-term outcome both in this report and in the larger long-term follow-up study of patients with MCD at this institution3 was excellent, and as morphologic transformation is associated with a poor longterm outcome (25% of Tejani’s patients suffered

“renal death”“), it seems very likely that these histologic differences reflect observations on two different patient populations. We found the underlying histology in this group of children with FRs or SD to be totally unrelated to the relapse frequency prior to biopsy and the subsequent relapse frequency after cyclophosphamide. This finding is in accordance with those of Mattoo,” who reported a small series of children with selected histologies, and Schulman et al,‘* who studied 92 patients, 41 of whom had primary steroid resistance. Both reports state that response to cytotoxic therapy correlated better with initial steroid sensitivity than histology. We have taken this one step further and shown that within a moderately large, exclusively steroidsensitive group, no correlation exists between histology and clinical course. Our results differ significantly from those of Bems et al,6 who found that the response to cyclophosphamide was strongly dependent on the histologic lesion, children with FSGS or mesangioproliferative lesions being much less likely to maintain permanent disease remission, and Tejani et al,” who reported a worse outcome in children with IgMN and FSGS. These differences are again likely to reflect the different populations being studied. Ninety percent of children with MCD in the study of Bems et al6 had no further relapses following cyclophosphamide therapy, which was commenced on average 6.8 years after disease onset. It is possible that this success rate, which is in excess of those in most published series, can be accounted for by natural disease remission, which is known to occur with increasing age. These findings support the clinical impression held by many pediatric nephrologists that renal biopsy is not required in FRs or SD. It gives no prognostic information, and steroid sensitivity is the major determinant of prognosis. Fears about poor prognosis in children with FRs or SD are Table

7. Prebiopsy Clinical Category and Relapse Frequency in the First and Second Years After Cyclophosphamide First-Year

Patients FRs SD

Relapses

Second-Year

Relapses

<4

24

<4

24

7 (17.1%) 23 (56.1%)

I (2.4%) IO (24.4%)

7 (17.1%) 23 (56.1%)

1 (2.4%) IO (24.4%)

WEBB

unfounded in the white and Asian populations, who comprise the majority of patients in the United Kingdom. REFERENCES 1. International Study of Kidney Disease in Children: Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at the time of diagnosis. Kidney Int 13:159-165, 1978 2. International Study of Kidney Disease in Children: The primary nephrotic syndrome in children. Identification of patients with minimal change from initial response to prednisolone. J Pediatr 98561-564, 1981 3. Lewis MA, Baildom EM, Davis N, Houston IB, Postlethwaite RT: Nephrotic syndrome: From toddlers to twenties. Lancet 1:255-259, 1989 4. Siegel NJ, Gaudio KM, Krassner LS, McDonald BM, Anderson FP, Kashgarian M: Steroid-dependent nephrotic syndrome in children: Histopathology and relapses after cyclophosphamide therapy. Kidney Int 19:454-459, 1981 5. Trachtman H, Carroll F, Phadke K, Khawar M, Nicastri A, Chen CK, Tejani A: Paucity of minimal-change lesion in children with early frequently relapsing steroid-responsive nephrotic syndrome. Am J Nephrol 7:13-17, 1987 6. Bems JS, Gaudio KM, Krassner LS, Anderson FP, Durante D, McDonald BM, Siegel N: Steroid-responsive nephrotic syndrome of childhood: A long-term study of clinical

ET AL

course, histopathology, efficacy of cyclophosphamide therapy and effects on growth. Am J Kidney Dis 92: 108-l 14, 1987 7. Churg J, Habib R, White RHR: Pathology of the nephrotic syndrome in childhood. A report for the International Study of Kidney Disease in Childhood. Lancet 1:1299-1302, 1970 8. International Study of Kidney Disease in Childhood: Early identification of frequent relapsers among children with minimal change nephrotic syndrome. J Paediatr 101:514-518, 1982 9. International study of Kidney Disease in Childhood: Primary nephrotic syndrome in children: Clinical significance of histological variants of minimal change and of diffuse mesangial hypercellularity. Kidney Int 20:765-771, 1981 10. Tejani A: Morphological transformation in minimal change nephrotic syndrome. Nephron 39:157-159, 1985 11. Mattoo TK: Kidney biopsy prior to cyclophosphamide therapy in primary nephrotic syndrome. Pediatr Nephrol 5:617-619, 1991 12. Schulman SL, Kaiser BA, Polinsky MS, Srinivasan R, Baluarte HJ: Predicting the response to cytotoxic therapy for childhood nepbrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns. J Pediatr 113:996-1001, 1988 13. Tejani A, Phadke K, Nicastri A, Adamson 0, Chen CK, Trachtman H, Tejani C: Efficacy of cyclophosphamide in steroid sensitive childhood nepbrotic syndrome with different morphological lesions. Nephron 41 2:170-173, 1985