Childhood Steroid-resistant Nephrotic Syndrome: Long-term Outcomes from a Tertiary Care Center

Introduction

Nephrotic syndrome is a chronic disorder in children characterized by edema, nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia. The annual incidence of the condition is 2–7 in 100,000 in children under 15 years of age with a prevalence of 16 in 100,000; the Asian population appears to have a higher prevalence.[12] While most children respond to daily prednisolone therapy, failure to respond after 4 weeks of compliant steroid therapy indicates steroid-resistant nephrotic syndrome (SRNS) seen in about 10% to 20% of all children with the condition.[3] There is variability in the prevalence of SRNS depending on the ethnicity with a prevalence of about 20% among European children to 27% to 54% among Asians.[45]

Patients with steroid-resistant disease pose the most difficult therapeutic challenge. These children are at risk for complications of unremitting nephrotic syndrome and developing end-stage kidney disease (ESKD) in the long term. Medications like cyclosporine, tacrolimus, intravenous cyclophosphamide, intravenous steroids, and most recently rituximab are used for inducing and maintaining remission in these patients; these drugs cause intense immunosuppression.

The largest data till date reported outcomes of SRNS from the PodoNet registry, which primarily had European children of Caucasian ancestry (90.3%). The same publication also showed 10-year ESKD-free survival rates of 43%, 94%, and 72% in children with nonresponse (NR), complete remission (CR), and partial remission (PR), respectively, with 79% and 52% in children with biopsy findings of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS).[67] Non-responders are at high risk of developing chronic kidney disease (CKD) with a prevalence of up to 50%.[8] While the information on long-term outcomes of SRNS is available for Caucasian and African American children, studies from India have looked mostly at the short-term outcomes after the administration of different immunosuppressive agents.[910] Ethnicity appears to influence the outcomes, and as most children with SRNS receive calcineurin inhibitors (CNIs), the long-term outcome is also dependent on the response to these agents and their inherent nephrotoxicity.[89] This retrospective study was done to determine the clinicopathological profile and long-term outcomes of Indian children with SRNS.

Methods

This study was done in the department of pediatrics of a tertiary care teaching hospital located in the northern part of India. The records of all children with SRNS (initial and late resistance) with biopsy findings of MCD, FSGS, or mesangioproliferative glomerulonephritis (MesPGN), who were treated and were in follow-up in pediatric nephrology clinic during the period 2007–2018 were retrieved. Patients with a minimum follow-up of 12 months and complete records were included for the study analysis; children with congenital and secondary nephrotic syndrome were excluded. The study protocol was approved by the institute's ethical committee.

A study pro forma was filled for each patient that included information related to demographics, onset of nephrotic syndrome, histopathological features, therapy details, and outcomes.

Results

During the study period of 12 years, 135 children were treated as SRNS; 91 (72 boys) were finally included in the study after excluding two children with congenital nephrotic syndrome, 18 with secondary nephrotic syndrome, and 24 with nonavailability of complete data. The median (IQR) age at the onset of illness was 48 (24–87) months. While 31.9% had initial resistance, the remaining (68.1%) developed resistance after the initial response (late resistance) after a median (IQR) period of 12 (6.5–33) months. None of the patients had any family history of nephrotic syndrome. The demographic and clinical features of the study population are provided in Table 1.

Long-term course

Eighty-three patients had a follow-up of more than 2 years, and 66 (79.5%) of them were in CR, nine (10.8%) had PR, and eight (6.8%) had NR. Of those who achieved CR, 46/63 (73%) subsequently had IFRNS, whereas 14 (22.2%) had FRNS and three (4.8%) had SDNS. Forty-seven patients had a follow-up of more than 5 years and 27 (57.4%) were in CR, while four (8.5%) and 16 (37%) had PR and NR, respectively.

Final Outcome: After a median (IQR) follow-up of 5 (3–7) years, 63 (69.2%) of the patients had become infrequently relapsing, nine (9.9%) remained FRNS whereas four (4.4%) were SDNS; overall 83.5% patients had a favorable course. Seven (7.7%) children had a partial response to the therapy, whereas eight (8.8%) children remained nonresponsive, and of them, four developed CKD; five (5.5%) children died (three with ESKD and two with sepsis). There was an improvement in the height standard deviation score (SDS) from −1.65 at initial presentation to −1.3 at the last follow-up, whereas the weight SDS declined from −0.6 to −0.9.

About 46 (50.5%) patients required modification of immunosuppressive therapy during the follow-up period. The indications for use of MMF, rituximab, or another CNI were primarily NR in 19 (31.9%), PR in nine (12.7%), and FRNS or SDNS course after becoming steroid sensitive in 17 (27.6%) and CNI toxicity in one child. A comparison of clinical and biopsy features in children with CR or PR with NR is provided in Table 2. Use of CNIs was significantly associated with CR/PR (P < 0.0001). Biopsy findings were not significantly different between CR/PR and NR (P = 0.33), but when compared between CR and non-CR (PR/NR), MCD on biopsy was significantly associated with CR (P = 0.001). Also, the age of onset was significantly higher in the CR/PR group compared with the NR group. There was no significant association of gender and type of resistance with the remission rate. There was no significant difference in the response rates of cyclosporine and tacrolimus (odds ratio [OR]; 95% confidence interval [CI] = 0.34; 0.08–1.4; P = 0.14). A regression analysis with CR as the dependent variable showed the R² value as 0.298 and the biopsy findings of MCD and use of CNI predicted CR significantly unlike other factors [Table 3]. KM analysis was performed for survival times of CR (event) for the groups based on initial or late resistance and use of CNI or alternative agents. The mean survival time was compared using log-rank test. Figure 1 shows the KM curve for the type of resistance where the mean (95% CI) time period for CR with initial resistance was 6.43 (5.42, 7.43) and 6.61 (4.75, 8.47) years for late resistance; P = 0.76. The survival curves showed much better chances of CR in patients receiving CNI as first-line agents compared with those receiving other alternative agents [Figure 2], the mean (95% CI) time period for CR being 12.08 (9.02, 15.15) years for CNI and 5.79 (4.95, 6.63) years with other agents; P < 0.001.

Table 2 Comparison of patients achieving CR and PR/NR

Parameter	CR/PR (n=72)	NR (n=19)	OR (95%CI)	P
Gender
Male	55 (76.4%)	17 (89.5%)	0.38 (0.07-1.8)	0.22
Female	17 (23.6%)	2 (10.5%)
Age of onset of NS (years)	4 (2.2, 8)	2.5 (1.5, 4)		<0.001#
Median (Q1, Q3)
Age of onset of SRNS (Years)	6 (3.7, 9)	3.5 (2, 4.5)		<0.001#
Median (Q1, Q3)
Type of resistance
Initial resistance	23 (31.9%)	6 (31.6%)	1.01 (0.34-3.0)	0.97
Late resistance	49 (68.1%)	13 (68.4%)
Biopsy findings*
MCD	43 (59.8%)	9 (47.4%)	1.6 (0.59-4.55)	0.33
FSGS	27 (37.5%)	6 (31.5%)
MesPGN	2 (2.7%)	4 (21.1%)
Immunosuppressants**
Tacrolimus	15 (20.8%)	4 (21.1%)	38 (7.3-206)	<0.0001
Cyclosporine	55 (76.4%)	5 (26.3%)
IV Cyclophosphamide	2 (2.7%)	10 (52.6%)

*Odds ratio were calculated for MCD and non-MCD. **Odds ratio were calculated for Cylcosporine/tacrolimus and IV Cyclophosphamide. ^#Mann–Whitney U test. CR=complete remission, PR=partial remission, NR=nonresponse, OR=odds ratio; CI=confidence interval; NS=nephrotuc syndrome; Q=quartile; MCD=minimal change disease, FSGS: focal segmental glomerulosclerosis, MesPGN: mesangioproliferative glomerulonephritis

Table 3 Logistic regression for the predictors of complete remission (n=91)

Variable	OR	95% CI	P
Gender (male)	0.79	0.19-3.3	0.75
Age at onset	1.07	0.89-1.3	0.46
Type of resistance (initial)	0.38	0.1-1.4	0.15
Biopsy (MCD)	6.16	1.6-23.3	0.007*
Use of CNIs	15.5	2.07-116.4	0.008*
Duration of therapy	1.68	0.94-2.99	0.08

*P<0.05 OR=odds ratio; CI=confidence interval; MCD=minimal change disease, CN=: calcineurin inhibitor

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Figure 1

Kaplan–Meier survival curve showing the chances of complete remission (CR) in follow-up (in years) in patients with initial resistance (IR) and late resistance (LR)

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Figure 2

Kaplan–Meier survival curve showing the chances of complete remission (CR) in follow-up (in years) in patients having received calcineurin inhibitors or other agents

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Discussion

While various studies have reported the response rates with the use of CNI in children with SRNS, the information on long-term outcomes from India is lacking.[71213] Most guidelines recommend treatment of SRNS with CNIs for a duration lasting 2 to 3 years.[1114] Treatment often changes the disease course, and the long-term renal outcomes are dependent on the achievement of prolonged remission and appearance of drug toxicity with prolonged use of CNIs. Ethnicity and genetics of SRNS too influence the long-term outcomes.[45]

The median (Q1, Q3) age of onset of nephrotic syndrome in our study was 48 (24, 87) months and 79.1% were boys; earlier studies too have shown similar results.[715] Most (68.1%) patients had late resistance and developed resistance after a median (Q1, Q3) period of 12 (6.5, 33) months; other studies have shown a higher proportion of initial resistance, and time to develop late resistance has not been described previously.[715] Underlying histopathology usually affects the clinical presentation and also the outcomes of children with SRNS; a higher proportion of MCD (57.1%) compared with 36.3% FSGS could have contributed to a lower prevalence of initial resistance in this study. Srivastava et al.[16] reported the incidence of MCD and FSGS as 52.7% and 23%, respectively, in a cohort of children biopsied between 1984 and 1995. Later, Banaszak et al.[17] compared the histopathology of childhood nephrotic syndrome over two consecutive decades (1985–1995 and 1996–2005) and reported a tendency toward increasing proportional incidence of FSGS and fall in the incidence of MCD. They also reported a simultaneous significant increase in steroid resistance, which they attributed partially to the rising incidence of FSGS. In 2005, an Indian study reported FSGS to be the most common histopathological finding in children with SRNS accounting for 59% of the total cases.[15] A higher incidence of FSGS was further reported in later studies. A randomized controlled trial (RCT) from India reported the incidence of FSGS and MCD as 69% and 31%, respectively.[9] A higher incidence of FSGS was also reported by the PodoNet registry (primarily European countries) data that looked at SRNS in children (n = 1,368) and documented a higher proportion of FSGS (56%) compared with MCD (21.1%).[7] Almost 50.9% of children in their cohort had an onset of nephrotic syndrome between 1 and 5 years of age. The lower incidence of FSGS in our study could be due to the lower median age of the study population and were similar to one by Inaba et al.,[18] where the median age of onset was 3.2 years and also due to a higher proportion of late resistance. Besides the difference in the histopathology in our study may also be attributable to genetic and ethnic factors.[4]

Overall, 69.2% of patients attained CR with CNIs within a median period of 3 months in our patient cohort. Children who achieved CR/PR were older than the children who did not achieve any response. This finding is in contrast with Trautmann et al.,[6] who did not find any significant difference in the age of onset of the children achieving CR, PR, or NR. Inaba et al.[18] also showed that higher age of onset of SRNS (>11 years) was an independent risk factor for progression to ESKD. Genetic diagnoses were identified in 23.6% of the children with SRNS in the PodoNet registry, and chances of detecting a genetic etiology reduced with increasing age (35.6% in children 3–12 months of age compared with 15.6% in children 6–11 years of age). Only 10.4% of these children responded to immunosuppressive therapy.[7] It is possible that in our study, some of the children with NR had underlying genetic etiology, although this could not be ascertained. RCTs and cohort studies show that therapy with cyclosporine or tacrolimus results in CR in 30% to 40% and CR or PR in 60% to 80% of patients.[1920] A higher proportion of CR in our study population could be due to a larger number of children having late resistance and MCD on biopsy. Other studies too have shown better response in patients with MCD.[2122]

Attaining PR is an important predictor for a good outcome in children with SRNS; the risk of ESKD decreases by 85% to 90% if CR was achieved and by 50% for those with PR. Ten-year renal survival rates were 94% and 72%, respectively, for those with CR and PR, and only 43% for those with NR to immunosuppression in one cohort.[6] After a median follow-up of 5 years, 83.5% of our patients had a favorable course (69.2% had IFRNS and 14.3% had FRNS/SDNS); four (4.4%) developed CKD, and the mortality was 5.5%, which was contributed by ESKD and complications of SRNS course. The better outcomes observed in the present study appear to be due to a higher proportion of late resistance, MCD on biopsy, and the treatment with CNIs as first line in 86.8% of children. The PodoNet registry reported 33% CR and 22.5% PR after a median follow-up of 3.7 years among SRNS children, and 78.5% of patients had received CNI.[7]

Similar efficacy of cyclosporine and tacrolimus in inducing remission was observed in the present study (median time 3 months) consistent with the findings of a previous study.[18] Büscher et al.[23] also reported a good response with cyclosporine in nongenetic forms of SRNS (78% by 2.5 months), whereas the response was poor in the genetic form of SRNS (CR only in 3%). The side effects observed during therapy were comparable between the two CNIs although the incidence of hypertrichosis in 40% was exclusively among children on cyclosporine. Repeat biopsies for CNI toxicity were done in seven patients who required CNI for more than 3 years, and four (57.1%) of them showed features of CNI toxicity; a previous study on Indian children showed toxicity in 25% of biopsies after a median (Q1, Q3) duration of 30 (26, 35) months.[24] The difference may be due to the very small number of biopsies performed in our study. Cyclophosphamide was used less commonly and accounted for only 12% of the immunosuppressive regimen; response rates were low (8.3%) consistent with the earlier report of >80% failure rate with these regimens.[25]

The infection rates observed over a 5-year period were about 10 per year, and 72.5% of infections were spontaneous bacterial peritonitis, and 4.4% of children were treated for tuberculosis during the follow-up period. Also, the incidence of venous thrombosis was 2.2%. A previous RCT on comparison of tacrolimus and intravenous cyclophosphamide too observed a higher number (45%) of peritonitis episodes over a 12-month observation period.[15] An incidence of 3.8% for thrombosis has been described in children with SRNS from Bulgaria.[26]

A major limitation of the present study is its retrospective nature, and a significant number of patients had to be excluded due to incomplete records. Also, we were not able to do the genetics for patients with initial resistance (31.9%) due to nonavailability and financial constraints, although none of the patients had any family history of nephrotic syndrome or other renal diseases. However, considering the fact that SRNS is a rare disease in childhood and patient attrition is expected in long-term follow-up and this being a single-center study, these limitations are not completely unavoidable.

Conclusions

Based on the results of this study, we conclude that Indian children with SRNS, especially those with late resistance and MCD on biopsy, are more likely to respond to CNIs and have good long-term outcomes. There appears to be a higher occurrence of late resistance and MCD in this part of the world and with the early use of CNIs, the chances of complications decrease, and the overall growth parameters too improve.