Consensus guidelines on management of steroid resistant nephrotic syndrome

Anil Vasudevan; Ranjeet Thergaonkar; Mukta Mantan; Jyoti Sharma; Priyanka Khandelwal; Pankaj Hari; Aditi Sinha; Arvind Bagga

doi:10.4103/ajpn.ajpn_35_21

CLINICAL PRACTICE GUIDELINES

Year : 2021 | Volume : 4 | Issue : 2 | Page : 67-81

Consensus guidelines on management of steroid resistant nephrotic syndrome

Anil Vasudevan¹, Ranjeet Thergaonkar², Mukta Mantan³, Jyoti Sharma⁴, Priyanka Khandelwal⁵, Pankaj Hari⁵, Aditi Sinha⁵, Arvind Bagga⁵
¹ Department of Pediatric Nephrology, St. John's Medical College Hospital, Bengaluru, India
² Department of Pediatrics, INHS Asvini, Mumbai, India
³ Department of Pediatrics, Maulana Azad Medical College, New Delhi, India
⁴ Department of Pediatrics, Pediatric Nephrology Service, King Edward Memorial Hospital, Pune, India
⁵ Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission	10-Sep-2021
Date of Decision	10-Sep-2021
Date of Acceptance	13-Oct-2021
Date of Web Publication	28-Dec-2021

Correspondence Address:
Arvind Bagga
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi - 110 029
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajpn.ajpn_35_21

Abstract

Justification: The management of steroid-resistant nephrotic syndrome (SRNS) is challenging. These guidelines update existing 2009 Indian Society of Pediatric Nephrology recommendations on its management. Objective: To frame revised guidelines on diagnosis and evaluation, treatment and follow-up, and supportive care of patients with the illness. Process: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by systematic review of literature, evaluation of evidence by experts, and two face-to-face meetings. Recommendations: Patients with SRNS should be managed under supervision of a pediatric nephrologist. Fourteen statements provide updated advice for defining steroid resistance, and underscore the importance of estimating proteinuria and baseline kidney function and the need for kidney biopsy and genetic screening. Calcineurin inhibitors are recommended as most effective in inducing remission of proteinuria, the chief factor associated with long-term renal survival. Advice on managing allograft recurrence, congenital nephrotic syndrome, and monitoring and supportive care, including the transition of care is described. This revised practice guideline is intended to improve management and patient outcomes and provide direction for future research.

Keywords: Calcineurin inhibitors, congenital nephrotic syndrome, focal segmental glomerulosclerosis, minimal change disease

How to cite this article:
Vasudevan A, Thergaonkar R, Mantan M, Sharma J, Khandelwal P, Hari P, Sinha A, Bagga A. Consensus guidelines on management of steroid resistant nephrotic syndrome. Asian J Pediatr Nephrol 2021;4:67-81

How to cite this URL:
Vasudevan A, Thergaonkar R, Mantan M, Sharma J, Khandelwal P, Hari P, Sinha A, Bagga A. Consensus guidelines on management of steroid resistant nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2021 [cited 2023 May 27];4:67-81. Available from: https://www.ajpn-online.org/text.asp?2021/4/2/67/334037

Introduction

The prevalence of idiopathic nephrotic syndrome, characterized by proteinuria, hypoalbuminemia, and edema, varies from 12 to 16 per 100,000 children.^[1] The majority of patients achieve remission of proteinuria following 4–6 weeks of therapy with prednisolone. However, 10%–15% of patients do not achieve complete remission and are termed steroid-resistant nephrotic syndrome (SRNS).^[2] Renal histology shows focal segmental glomerulosclerosis (FSGS), minimal change disease, and mesangioproliferative glomerulonephritis. Other patterns, including C3 glomerulopathy, membranous nephropathy and IgA nephropathy, and secondary causes of nephrotic syndrome are uncommon. The management of patients with SRNS is challenging. The illness is associated with unsatisfactory patient-reported quality of life, morbidity due to infectious and noninfectious illnesses, and side effects of therapy.^[2],[3] Patients with persistent proteinuria are at risk for progressive kidney failure.^[4]

Guidelines from the Indian Society of Pediatric Nephrology (ISPN) were first published in 2009.^[5] In view of recent evidence, the ISPN has proposed revision of these recommendations. The revised guidelines refer to patients with SRNS due to minimal change disease, mesangioproliferative glomerulonephritis, and FSGS. These guidelines also address management of patients with posttransplant recurrence of FSGS and congenital nephrotic syndrome. Clinical practice recommendations, from the International Pediatric Nephrology Association (IPNA), on the illness were published recently.^[6]

Process

Three workgroups were constituted to evaluate evidence on (i) diagnosis and evaluation, (ii) treatment and follow-up, and (iii) supportive care of patients with SRNS. The groups developed key questions and reviewed and analyzed published studies. Quality of evidence was assessed and rated from A-D following the GRADE model.^[7] Each statement was assigned one of the two levels of guidance: recommendation or suggestion, indicating strength of the advice [Supplementary Table 1]. Ungraded statements (X) are like practice points, not supported by sufficient evidence. The workgroups discussed the evidence, through alternating breakout and plenary sessions, in New Delhi on April 5, 2019. Draft guidelines were discussed with members of the ISPN in Pune on December 21, 2019.

Guidelines

[Table 1] compares the current and previous guidelines^[5] and recent recommendations from the IPNA.^[6] Given the challenges in management, we advise that a pediatric nephrologist be responsible for the diagnosis and management of children with SRNS.

Table 1: Guidelines on Steroid-Resistant Nephrotic Syndrome: Current Indian Society of Pediatric Nephrology, Indian Society of Pediatric Nephrology 2009 and International pediatric Nephrology Association 2020

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Guideline 1: Diagnosis of steroid-resistant nephrotic syndrome

We recommend that steroid resistance be defined in patients not showing complete remission of proteinuria, despite 6-week daily treatment with prednisolone (1B)
We suggest similar definitions for initial and late (secondary) steroid resistance (X).

Rationale

Approximately 85%–90% of patients with idiopathic nephrotic syndrome respond to treatment with prednisolone, with complete remission of proteinuria and normalization of serum albumin.^[1] There is a lack of consensus regarding the minimum duration of daily prednisolone treatment before defining steroid resistance. The International Study of Kidney Disease in Children (ISKDC) reported that, of patients who achieved remission, 94% did so within 4-week daily treatment and the rest during 4-week alternate-day therapy.^[8] Others found that 4-week and 6–8 weeks initial therapy results in remission in 90%–92% and 87%–93% patients, respectively.^{[9],[10],[11],[12]} While few experts suggest additional therapy with 3 doses of IV methylprednisolone before labeling steroid resistance, this is not uniformly practiced.^{[6],[13],[14]}

The previous version of this guideline defined SRNS as lack of complete remission despite 4-week therapy with prednisolone at a daily dose of 60 mg/m².^[5] The ISKDC and Kidney Disease: Improving Global Outcomes (KDIGO) proposed that steroid resistance be defined following 8-week therapy.^[8],[15] Recent IPNA and KDIGO guidelines propose confirming steroid resistance following 4–6-week therapy with predniso (lo) ne, with or without additional therapy with 3-doses of IV methylprednisolone.^[6],[16]

In order to balance the benefits of extending therapy with steroid adverse effects, we recommend defining SRNS in patients who fail to show complete remission of proteinuria despite 6-week therapy with prednisolone at daily dose of 60 mg/m². Patients with steroid adverse effects may receive daily prednisolone for 4-week, followed by alternate-day therapy for the next 2-week. We do not advise therapy with IV methylprednisolone before making the diagnosis of SRNS.

We suggest similar definitions for initial (primary) and late (secondary) steroid resistance [Box 1]. Initial resistance is a lack of remission at the first episode of nephrotic syndrome. Patients who are steroid-sensitive initially but show steroid resistance during subsequent relapse have late resistance. Systemic infections may be associated with persistent proteinuria and should be treated appropriately.

Guideline 2: Evaluation of patients

We recommend the following in all patients with SRNS: Quantitation of proteinuria; serum creatinine; Estimatedglomerular filtration rate; and kidney biopsy [Box 2] (1A).

Rationale

Nephrotic syndrome is characterized by nephrotic range proteinuria: >3+ by dipstick, proteinuria >40 mg/m²/hr (>1000 mg/m²/day), urine protein to creatinine ratio (Up/Uc) ≥2 mg/mg; hypoalbuminemia (<3 g/dL); and edema.^[6] All patients should be evaluated appropriately [Box 2]. Estimation of proteinuria, by Up/Uc in morning specimen or 24-hr protein excretion, at diagnosis and 6-monthly follow-up, helps determine response to therapy. Since 24-hr collection of urine is difficult to implement, Up/Uc is preferred. Parents are counseled regarding the importance of urinary dipstick analysis for home monitoring of proteinuria.

Response of proteinuria to therapy is an important determinant of renal survival.^{[4],[17],[18]} Data from the PodoNet Registry on 1354 patients with SRNS shows that 10-year renal survival was highest (94%) in complete remission, 72% with partial remission, and 43% with nonresponse.^[19] The assessment of creatinine and eGFR at baseline and follow-up identifies acute kidney injury (AKI) secondary to hypovolemia, fluid loss, infections and drug toxicity, and chronic kidney disease (CKD).^[20],[21]

History and examination might help identify genetic and secondary forms of SRNS. History of deafness, developmental delay, seizures, family history of similar disorder and consanguinity, and syndromic features or extrarenal anomaly (e.g., genitourinary abnormality, microcoria, dystrophic nails, and microcephaly) suggest a genetic etiology. History of joint pain, weight loss, alopecia, jaundice, rash, or palpable purpura indicates a secondary cause.

All patients with SRNS should undergo a kidney biopsy before instituting specific treatment. Biopsies are examined by light, immunofluorescence, and electron microscopy. An adequate biopsy should include the corticomedullary junction and have ~20 glomeruli to identify a focal pathology like FSGS.^[22] A biopsy is useful for: (i) Identifying pathology, extent of interstitial fibrosis, and glomerulosclerosis for diagnosis and prognosis; and (ii) excluding differential diagnosis and secondary causes of nephrotic syndrome. Repeat biopsy is required to assess calcineurin inhibitor (CNI) toxicity, progression of disease, or change in pathology.

Chief histological diagnoses in children with SRNS include FSGS (40%–50%), minimal change disease (25%–40%), and mesangioproliferative glomerulonephritis (5%–8%).^[23] Histology suggestive of FSGS is considered a risk factor for progression to CKD.^{[15],[16],[17],[24]} Around 10%–15% of patients show membranous nephropathy, IgA nephropathy, or proliferative glomerulonephritis, which requires additional evaluation. A kidney biopsy is not necessary in patients with a well-described monogenic form of SRNS, known to be unresponsive to immunosuppression, for example, congenital nephrotic syndrome, familial disease, or if known genetic cause is already identified.

Screening for viral infections

Patients should be evaluated for hepatitis B and C and HIV infections. Collapsing FSGS may be associated with HIV or parvovirus infection.^[25] Those with positive serology are evaluated for viral load and extent of disease. Active infection may require the use of appropriate antiviral therapy.

Guideline 3: Indications for genetic studies

We recommend genetic studies in the following patients: congenital nephrotic syndrome; initial resistance during infancy; nephrotic syndrome with extrarenal features; familial steroid-resistance; nonresponse to therapy with CNI; and prior to transplantation (1B).

Rationale

Approximately 20%–30% of patients with SRNS have pathogenic variations in genes encoding proteins of podocyte structure and function [Supplementary Table 2].^[2] Mutations in NPHS1, NPHS2, WT1, COQ2, PLCE1, and LAMB2 account for 50%–60% of monogenic disease in children.^{[26],[27],[28]} Genetic testing is useful as follows:

Identification of causal variant enables diagnosis of monogenic disorders and occasional phenocopies (e.g., Alport syndrome, Dent disease, cystinosis). Specific diagnosis allows counseling regarding the progression of kidney disease and monitoring for extrarenal complications, for example, patients with WT1, LMX1B, WDR73, and SMARCAL1 mutations^[29]
Patients with monogenic etiology have 4-fold risk of nonresponse to therapy with CNI (odds ratio [OR] 4.00; 95% confidence interval [CI] 2.52–6.51) and 3-fold risk of kidney failure (OR 2.87; 95% CI 2.22–3.72) [Supplementary Table 3]^{[18],[26],[28],[29],[30]}
Certain mutations respond to targeted therapy, for example, coenzyme Q10 for defects in CoQ pathway and eplerenone for ARHGDIA mutations^[31],[32]
Compared to patients with no identifiable genetic cause, those with monogenic etiology have significantly lower risk for allograft recurrence^{[18],[27],[33]}
Diagnosis of a monogenic etiology assists in counseling for future pregnancies and antenatal diagnosis and facilitates screening of live-related renal transplant donors.^{[34],[35],[36]}

While IPNA guidelines suggest comprehensive genetic evaluation in all children with initial steroid resistance,^[6] we suggest a focused approach. The likelihood of detecting a genetic cause is inversely related to age at onset of the illness. A monogenic etiology was seen in 69%, 50%, 25%, 18%, and 11% with disease presenting during the first 3 months, 4–12 months, 1–6 years, 7–12 years, and 13–18 years, respectively.^[26] Syndromic forms of the illness may be associated with specific mutations and characteristic phenotype [Supplementary Table 2]. Family history of similar illness or consanguinity suggests a genetic cause in ~50%–70% cases.^[26],[27] Although patients with an underlying genetic etiology are less likely to respond to therapy with CNI, few patients may occasionally show partial remission.^[37]

Siblings of patients with a monogenic cause may be screened for proteinuria by dipstick. There is no role for genetic screening in healthy children with family history of the disease. Since pathogenic mutations are not identified in patients with late steroid resistance, genetic testing in these children is also not indicated.^[18],[27]

The precise prevalence of monogenic variations in Indian patients with SRNS is unclear as studies are limited to small cohorts.^[38],[39] A nationwide study is in progress to determine the genetic basis of SRNS, and indications for testing may be revised in future.

Method of Genetic Testing

Causal variants in ~90 genes are associated with monogenic SRNS [Supplementary Table 2]. Most genes do not show a clear phenotype-genotype correlation. Next-generation sequencing (NGS) panels, incorporating multiple genes relevant to the phenotype, are feasible and less expensive, and provide higher diagnostic yield than Sanger sequencing. These panels include genes associated with other renal diseases that may have phenotype similar to SRNS. Clinical exome sequencing (Mendeliome gene panel), which includes all exons of genes listed in Online Mendelian Inheritance of Man database facilitates targeted gene analysis. In case a causative variant is not identified in the gene panel, search for variants may be extended to remaining genes in the clinical exome. Whole-exome sequencing might be considered for novel disease-causing genes. Sanger sequencing is preferred if a disease-causing mutation is highly likely in a specific gene, in the context of extrarenal features or positive family history with a known genetic cause. Sanger sequencing is essential to confirm variants detected on NGS, to screen parents to confirm segregation and for antenatal counseling.

Parents should be advised regarding risks and benefits of NGS, including limitation of insurance cover. Referral to genetic counselors might be necessary. Testing must be performed by certified and experienced laboratories, and pathogenicity of variants determined based on criteria proposed by the American College of Medical Genetics and Genomics.^[40]

Guideline 4: Therapy of patients with steroid-resistant nephrotic syndrome

We recommend CNI as first-line therapy for patients with initial or late steroid resistance (1A)
We suggest continuing therapy with CNI for at least 24-month if partial or complete remission is achieved (2C)
We suggest that CNI therapy should be withheld or discontinued for patients with AKI Stage 2–3 or estimated glomerular function rate (eGFR) persistently below 60 ml/min/1.73 m² (2C).

Rationale

Therapy aims to induce complete or partial remission while avoiding medication-related toxicity. The long-term renal outcome in patients who achieve remission is significantly better when compared to nonresponders.^{[17],[18],[19],[41]} Randomized controlled trials (RCT) and case series show that therapy with CNI (cyclosporine, tacrolimus) results in complete remission in 30%–40% and complete or partial remission in 60%–80% patients.^{[2],[3],[18],[41],[42]} A Cochrane meta-analysis that compared cyclosporine to no treatment showed increased likelihood of complete or partial remission with the former (2 RCT; relative risk [RR] 3.50; 95% CI 1.04–9.57) at 6-month.^[43] Similarly, therapy with CNI, compared to IV cyclophosphamide, was associated with higher rates of complete or partial remission (3 RCT; RR 1.98; 95% CI 1.25–3.13).^[43] While most reports do not show different outcomes between initial and late steroid resistance,^{[44],[45],[46]} better outcomes in the latter have been reported.^[18] The efficacy of tacrolimus and cyclosporine is comparable (2 RCT; RR 1.05; 95% CI 0.87–1.25), with no difference in nephrotoxicity or hypertension.^[43],[47]

Similar to the IPNA and KDIGO guidelines, we recommend first-line use of CNI for patients with SRNS.^[6],[16] Tacrolimus is preferred to cyclosporine except in children who are unable to swallow tablets (cyclosporine is available as suspension) and patients with seizures or at risk for diabetes. Doses of tacrolimus and cyclosporine are titrated to achieve recommended trough levels, keeping in mind interaction with other medications [Table 2] and [Supplementary Table 4]. Low levels are associated with nonresponse and relapse, while high levels increase the risk for nephrotoxicity.^[48] Lower levels may be targeted once sustained remission is achieved for 6–9 months.^[49],[50] [Figure 1] provides an outline of the approach to the management of SRNS.

Table 2: Dosing and monitoring of immunosuppressive therapy

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Figure 1: Management of steroid-resistant nephrotic syndrome. Kidney biopsy is necessary, except in patients where genetic testing may obviate the need for biopsy [Box 2]. Patients with monogenic cause for steroid-resistance should not receive immunosuppression and are managed with angiotensin converting enzyme inhibitors and supportive therapy. Patients with likely nongenetic disease are initiated on therapy with a calcineurin inhibitor along with supportive care. Lack of remission despite adequate therapy with calcineurin inhibitor for 6-months is an indication for genetic screening, if not performed earlier. Patients with calcineurin inhibitor-resistant disease who do not show a monogenic defect may be treated with IV rituximab or combined therapy of calcineurin inhibitor and mycophenolate mofetil. Immunosuppression is withdrawn in patients with continued nonresponse.

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Most patients who respond to CNI do so within the first 6-month of treatment.^{[44],[45],[47],[51]} Nonresponse to CNI is therefore considered in patients who continue to show nephrotic-range proteinuria, hypoalbuminemia or edema despite 6-month therapy. Patients showing nonresponse should be screened for significant genetic variations (see above) and considered for alternate management (Guideline 6).

Therapy with CNI is initially combined with prednisolone, administered at a dose of 1–1.5 mg/kg on alternate days for 4–6 weeks, and tapered over 6–9 months.^{[6],[44],[45],[46]} Following CNI-induced remission, ~60% of patients may have steroid-sensitive relapses.^{[44],[45],[52]} Relapses are treated with prednisolone (2 mg/kg/day until remission; tapered on alternate-days). Stoppage of steroid therapy might not be possible in patients with multiple relapses.

The duration of treatment with CNI for patients with partial or complete remission is not clear, with guidelines recommending minimum 12-month's therapy.^[6],[16] An RCT comparing continued therapy with tacrolimus versus switching to mycophenolate mofetil (MMF) at 6-month, found the former twice as effective in maintaining remission (90% vs. 45%).^[45] In a retrospective study on 23 patients, therapy with cyclosporine for a mean duration of 1.7 years could be successfully switched to MMF in 79% of cases.^[52] In view of the risk of relapse with early cessation of therapy, we suggest continuing therapy with CNI for 24 months or longer [Figure 1], ensuring adequate dose and trough levels.^[49],[51]

About 10%–25% of patients receiving prolonged CNI treatment are at risk of nephrotoxicity.^[53] Risk factors for nephrotoxicity include the presence of initial resistance, dose of CNI used, duration of heavy proteinuria, and hypertension during therapy.^[48],[53] In order to balance the benefits and toxicity of CNI, we suggest individualizing therapy in children with a partial or complete response at 24-months. Options include: (i) Discontinue therapy if the patient has been in sustained remission; (ii) continue CNI therapy; perform kidney biopsy if treatment is prolonged beyond 30–36 months, or if restarting treatment; (iii) switch to IV rituximab or oral MMF in patients with CNI or steroid toxicity with steroid-sensitive relapses.

Risk factors for AKI in nephrotic syndrome include volume depletion, infections, nephrotoxic injury, and steroid resistance.^{[21],[54],[55]} We suggest withholding CNI during AKI;^{[16],[55],[56]} treatment is restarted following recovery of kidney function. Therapy with CNI is avoided if eGFR is persistently <60 mL/min/1.73 m².

Guideline 5: Alternate immunosuppressive therapy

We suggest treatment with IV cyclophosphamide in patients with nonavailability of CNI, either due to its cost or adverse effects (2B)
We do not suggest the use of oral cyclophosphamide for therapy of patients with steroid resistance (2A).

Rationale

Studies utilizing IV cyclophosphamide (every month for 6-month) and tapering prednisolone show complete or partial remission in 10%–50%, but with significant adverse effects.^{[46],[57],[58]} Compared to CNI, IV cyclophosphamide is associated with lower rates of sustained remission (RR 0.50; 95% CI 0.37–0.68) at 6-months.^[43] A multicenter study compared the efficacy of cyclosporine (150 mg/m²/day) for 48-weeks with IV cyclophosphamide (500 mg/m²; 7-doses over 36 weeks) in patients with SRNS. While complete remission was low, 47% of patients treated with cyclosporine and 6% with IV cyclophosphamide had a partial response.^[57] Another multicenter trial on 131 patients showed 6-month complete remission rates of 14.8% and partial remission rates of 31.1% with IV cyclophosphamide, as against 52.4% and 30.1%, respectively, with tacrolimus.^[44]

Two RCT showed similar efficacy and safety of oral and IV cyclophosphamide in 61 children with steroid resistance (RR 1.58; 95% CI 0.65–3.85).^[58],[59] However, two other RCT found no difference in rates of remission in patients receiving oral cyclophosphamide with prednisone compared to prednisone (n = 84; RR 1.06, 95% CI 0.61–1.87).^[60],[61] Based on the above, we do not advise the use of oral cyclophosphamide in patients with SRNS.

Guideline 6: Treatment of calcineurin inhibitor-resistant nephrotic syndrome

In patients with nongenetic forms of SRNS and nonresponse to therapy with CNI, we suggest additional treatment with either IV rituximab or oral MMF [Figure 1] (2C).

Rationale

Approximately 20%–40% of patients with nongenetic forms of SRNS do not show complete or partial remission following 6-months therapy with CNI.^[43] The management of patients with nonresponse to CNI therapy is difficult, since they are at high risk of kidney failure.^{[17],[18],[19]} Patients with initial steroid and CNI resistance should be screened for an underlying monogenic disorder. Those with no pathogenic or likely pathogenic variants in podocyte genes may be considered for additional immunosuppressive therapy, administered under close supervision.

While rituximab has shown promising results in patients with steroid-sensitive nephrotic syndrome, its efficacy in CNI-resistant SRNS is less satisfactory. In a systematic review (7 case series, one RCT; n = 226) on efficacy of rituximab in steroid and CNI-resistant nephrotic syndrome, the mean number of rituximab doses was 3.1 ± 1.1. Complete or partial remission was observed in 46.4%, with better response in minimal change disease (63.2%) than in FSGS (39.2%) and late (52.8%) compared to initial-resistance (40.8%).^[62] Similar findings of satisfactory response to rituximab in patients with late resistance are reported in a series from the United Kingdom^[18] and in a systematic review.^[63] While less favorable outcomes were reported in a study from India, with remission in 29.3% of 58 patients with CNI-resistance, there was trend for better response in minimal change disease and late-resistance.^[64]

We suggest administering 2-doses of IV rituximab at a dose of 375 mg/m² at weekly interval, targeting CD19 count <5/μl or <1% of lymphocyte count. If CD19 target is not met, 1–2 additional doses may be repeated at weekly interval (maximum 4 doses). In patients achieving complete or partial remission, repeat dose (s) of rituximab may be given following B-cell reconstitution, which typically occurs after 6–9 months. There is limited guidance regarding redosing with rituximab, and benefits should be balanced by the risk of side effects, including infusion reactions, serum sickness, neutropenia and hypogammaglobulinemia. Therapy with rituximab may be associated with reactivation of hepatitis B, Pneumocystis jirovecii pneumonia, severe lung injury and rarely, progressive multifocal leukoencephalopathy.^[65]

The efficacy of MMF in patients with SRNS is less satisfactory than in steroid-sensitive disease. In the PODONET cohort, monotherapy with this medication was not effective in 83% of patients.^[19] The efficacy of combination of CNI and MMF (600–1000 mg/m²/day) has been reported in patients with CNI-resistant disease. Three case-series (n = 168) on combined therapy for 6–12 months show complete remission, partial remission and nonresponse in 11.8%–47.7%, 8.7%–38.2% and 43.5%–58.8%, respectively.^{[66],[67],[68]} There is limited data on the efficacy of treatment with adalimumab, abatacept, ofatumumab, and adrenocorticotrophic hormone, oral galactose and low density lipoprotein (LDL) apheresis in patients with CNI-resistant SRNS. These therapies should only be used in the context of clinical trials.^{[69],[70],[71]}

Intense immunosuppression is associated with the risk of systemic infections. Patients receiving combined therapy with CNI and either rituximab or MMF should receive prophylaxis with cotrimoxazole (5 mg/kg trimethoprim on alternate days) for 3–6 months. [Table 2] summarizes dosing, side effects, and monitoring of children receiving immunosuppressive agents.

Guideline 7: Immunosuppressive therapy with pathogenic or likely pathogenic variants

We do not recommend that patients with monogenic disease receive therapy with CNIs or other immunosuppressive agents (1B).

Rationale

Patients with SRNS with pathogenic or likely pathogenic variations [monogenic disease, [Box 1]] usually do not show complete or partial remission following therapy with CNI. Analysis of pooled data [Supplementary Table 3]; n = 867) shows that compared to nongenetic disease, those with genetic forms of SRNS are not likely to respond to CNI (RR 4.0; 95% CI 2.52–6.51). Patients with monogenic forms of SRNS, irrespective of response are more likely to progress to kidney failure than those with nongenetic illness (RR 2.87; 95% CI 2.22–3.72).

The recent IPNA guidelines do not recommend that patients with monogenic disease receive immunosuppressive medications.^[6] However, some patients with a genetic cause for steroid resistance, especially those with WT1 variants, might show partial remission following treatment with CNI.^[37] The decision to continue therapy in such patients should follow counseling of parents regarding anticipated benefits (relief of edema, higher blood albumin) versus risks (therapy-related toxicity, infections) and cost of therapy. Targeted therapy is possible for specific mutations, for example, coenzyme Q10 for defect (s) in CoQ10 pathway, eplerenone for ARHGDIA, and corticosteroids for mutations in genes of Rho/Rac/Cdc42 network.^[31],[32]

Guideline 8: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

We recommend that all patients with SRNS should receive therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) [Table 3] (1B).

Table 3: Antihypertensive and anti-proteinuric medications

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Rationale

Since proteinuria is a risk factor for progressive kidney disease, its reduction is important for renoprotection.^[72] The use of ACE inhibitors is associated with 30%–40% reduction in proteinuria in a dose- and time-dependent manner.^[16],[43] ARB may be used as effectively [Table 3].^[73] Dual blockade with ACE inhibitors and ARB further reduces proteinuria but is associated with side effects such as hypotension, AKI, and hyperkalemia, and is not recommended.^[74] ACE inhibitors or ARB are avoided in patients with eGFR <25 mL/min/1.73 m², and discontinued during vomiting, diarrhea, or reduced oral intake. In patients with FSGS, sparsentan, that combines endothelin receptor Type A and angiotensin II receptor blockade, reduces proteinuria and hypertension more effectively than irbesartan.^[75] We do not advise therapy with other medications that target the renin-angiotensin axis, including aliskiren, eplerenone, and Vitamin D analogs.

Supportive Care and Monitoring

Important aspects of supportive care are summarized in [Table 4]. Principles of management of edema, systemic infections, and immunization are discussed in the revised ISPN guidelines on steroid-sensitive nephrotic syndrome, published recently.^[76]

Table 4: Supportive care of children with steroid-resistant nephrotic syndrome

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Guideline 9: Thrombotic complications

We do not recommend routine thromboprophylaxis in children with SRNS (1C).

Rationale

The risk of thromboembolic complications in nephrotic syndrome is ~3% in children, compared to 25% in adults, with most events within the first 3-months of illness.^[77] Risk factors for thrombosis include congenital nephrotic syndrome, heavy proteinuria, membranous nephropathy, central venous catheters, and coexisting heart disease.^[77] Sites of thrombosis include the deep veins, cerebral sinus (es), renal veins, and occasionally, arteries.^[78]

Routine use of prophylactic anticoagulants is not recommended.^[77] Aspirin is less effective and is associated with the risk of AKI.^[79] Nonpharmacological measures such as ambulation, hydration, and use of compression stockings are encouraged; central venous catheters and arterial punctures should be avoided.^[79],[80]

Therapy aims to prevent the extension of thrombi and reduce the risk of embolism. Thrombolysis followed by anticoagulation is considered in patients with life or limb-threatening thrombosis. While anticoagulation may be initiated with unfractionated heparin, this requires IV access and close laboratory monitoring has less predictable pharmacokinetics and is associated with the risk of adverse effects (thrombocytopenia, anaphylaxis and osteoporosis).^[80] The use of low-molecular-weight heparin is preferred.^[79],[81] Therapy is initiated with enoxaparin at a dose of 1.5 mg/kg/dose (<2-months age) or 1 mg/kg/dose (>2-months) subcutaneously, every 12-hr.^[81] Long-term therapy may continue either with enoxaparin or warfarin (0.2 mg/kg/dose started concurrently with enoxaparin) for 3-months or until remission.^[80] For warfarin, the international normalized ratio for prothrombin time is targeted between 2.0 and 3.0. Children with recurrent thrombotic events require long-term anticoagulation.^[77],[80]

Guideline 10: Cardiovascular morbidity

We recommend strategies to minimize cardiovascular risk in patients with SRNS (X).

Rationale

Steroid resistance is associated with multiple cardiovascular risks, including hypertension, dyslipidemia, hypoalbuminemia, hypercoagulable state, and steroid-induced obesity. Strategies to reduce this risk include minimizing residual proteinuria, managing hypertension, weight reduction to achieve body mass index <85^th centile for age, nonexposure to tobacco, and achieving target levels of lipids, fasting glucose (<100 mg/dL), and HbA1c (<6%).^[82]

Hypertension

Blood pressure should be measured at each visit. A study on Indian children with the frequently relapsing disease showed clinic hypertension in 64%, ambulatory hypertension in 33%, and white coat hypertension in 30%, and increased left ventricular mass in 21%.^[83] Systolic and diastolic blood pressures are targeted between 50 and 75^th percentile for age and sex.^[84] Lifestyle changes include increased intake of vegetables, fresh fruits, low-fat milk, legumes and nuts, and reduced salt and sweets. Pharmacotherapy is initiated with ACE inhibitor or ARB, in view of the additional benefit of reducing proteinuria [Table 3].

Dyslipidemia

Children with nephrotic syndrome show high blood levels of cholesterol, triglycerides, apoB-containing lipoproteins (LDL, very-LDL [VLDL], intermediate-density lipoprotein), and lipoprotein (a). While abnormalities resolve during remission, these might persist in patients with SRNS. Dyslipidemia aggravates glomerulosclerosis and proximal tubular damage and is associated with the progression of CKD. Screening for dyslipidemia is advised in patients with SRNS and those with steroid-sensitive disease and cardiovascular risk factors.^[82],[85]

We advise reduced intake of trans-or saturated fats and sugar and increased consumption of fruits, vegetables, legumes, and whole-grain cereals.^[85] The CHILD-1 diet is the first step in children with dyslipidemia or risk factors for cardiovascular disease and includes restricted intake of saturated fat and cholesterol to <10% of daily calories and 300 mg, respectively. In case this is not effective, the respective restrictions are enhanced to 7% and 200 mg in the CHILD-2 diet.^[82],[85] Limiting leisure screen time to <2-h/day, ensuring moderate physical activity for 1-hr/day, and vigorous physical activity at least 3 days a week are advised.^[85]

If lifestyle measures fail to correct dyslipidemia, therapy with statins is advised, especially if associated with risk factors for cardiovascular disease.^[85] Therapy in children 8-year or older may begin with atorvastatin at 10 mg/day, with monitoring for adverse effects.

Guideline 11: Stress dosing of glucocorticoids

We recommend that patients, who have received oral corticosteroids for more than 2-week within the past 1-year, should receive additional steroid dosing during conditions associated with physiological stress (1D).

Rationale

Therapy for nephrotic syndrome involves high-dose prednisolone for 12-weeks for the first episode, 5–6 weeks for relapse, and prolonged alternate-day for frequent relapses and steroid resistance. A systematic review reported that 269 of 487 (55.2%) children receiving corticosteroids for varied indications for more than 14-days had biochemical evidence of suppressed hypothalamic-pituitary axis (HPA).^[86] The duration of HPA suppression might last up to 2 years and vary with dose and duration of treatment.^[87]

We recommend additional steroids in situations where physiological stress is expected (fever ≥38°C, inadequate oral intake, lethargy, dehydration, invasive surgery, dental surgery, trauma, and large burns). Conditions such as uncomplicated viral infections, acute otitis media, and fever postimmunization do not require stress dosing. In case of critical illness or surgery, hydrocortisone is administered parenterally at 100 mg/m², initially or preoperatively followed by 25 mg/m² every 6-hr. With less serious illness, hydrocortisone 30–50 mg/m²/day or prednisolone 0.3–1.0 mg/kg in a single daily dose is given during stress and tapered thereafter.^[88]

Guideline 12: Monitoring of patients

Children with SRNS are at risk for progression to stage 5 CKD, complications of the disease, and adverse effects of medications.^{[89],[90],[91]} Managing immunosuppressive therapies is a challenge due to the risk of infections, noncompliance, and presence of comorbidities. Patients require regular monitoring and careful follow-up, and counseling regarding the need for compliance with medications [Table 5].

Table 5: Monitoring of patients with steroid-resistant nephrotic syndrome

Click here to view

Guideline 13: Transplantation

We recommend that kidney transplant be considered in all patients with SRNS and stage 5 CKD (1B)
We recommend that genetic testing be performed before transplant to assist in donor selection and predict the risk of recurrence in allograft (1B)
In a patient with prior allograft recurrence, the decision for retransplantation should be taken after discussing the risks and benefits with treating physicians, patient, and family (2C)
In patients with allograft recurrence, we suggest initiation of plasma exchanges, increasing the dose of CNI, with or without additional use of rituximab (2B).

Rationale

Kidney transplantation is the definitive option for patients with SRNS and Stage 5 CKD. Careful pretransplant evaluation of recipient and donor is required. Genetic screening of the recipient is necessary, particularly if there is initial resistance or equivocal course of the illness since it stratifies the risk for allograft recurrence and helps in donor screening. If inheritance pattern is autosomal recessive, a heterozygous carrier (parent) may be accepted as a donor with negligible risk of recurrence, except Afro-Caribbean donors with APOL1 risk variant or heterozygous R229Q variants in NPHS2.^[35],[92] Heterozygous carriers of pathogenic variants in COL4A3 and COL4A4 and women with variants in COL4A5 should not be accepted as donors since they are at risk of kidney failure.^[93] For autosomal dominant inheritance, individuals with the same variant are not accepted as donors since they might show variable penetrance with late onset of disease.

FSGS recurs in the allograft in ~30% (range 6%–50%) patients.^[94],[95] Recurrence is associated with allograft dysfunction and its loss in 40%–60% of patients, especially those with persistent nephrotic range proteinuria.^[33],[96] Recurrence risk is highest in patients with late steroid resistance or recurrent nephrotic syndrome in a prior transplant (~80%), moderate with initial resistance and no identified genetic cause (~50%), and lowest with confirmed genetic mutation underlying SRNS (<5%).^{[18],[97],[98],[99],[100]} Patients with FSGS and kidney failure should be counseled about these risks.

Living-related transplantation is associated with better graft survival and is preferred for children in our country. While the risk of recurrence is minimally higher in children receiving live-related grafts, this is balanced by reduced risk of rejection and lower need for immunosuppression.^[100],[101] Live-related transplantation is therefore the first choice, except in patients with moderate to high risk of recurrence.

Nephrotic syndrome might recur within hours to days after transplant and is characterized by nephrotic range proteinuria and progressive hypoalbuminemia. Patients are monitored for recurrence by screening for proteinuria (Up/Uc ratio), initially daily and then with reduced frequency [Supplementary Box 1]. Recurrence is considered in patients with proteinuria and Up/Uc ≥1 mg/mg if anuric prior to transplant or increase of ratio by ≥1 in those with proteinuria at transplantation.^[6] Early-onset graft dysfunction may be a feature of recurrent FSGS. Where feasible, an allograft biopsy is recommended to detect podocyte foot process effacement or segmental sclerosis that supports the diagnosis of recurrence. A biopsy may also help exclude other diagnoses in patients with lower degree of late-onset proteinuria or allograft dysfunction.

Multiple therapies have been used to prevent recurrence of nephrotic syndrome, including pretransplant plasma exchanges, rituximab and lipoprotein apheresis. There is limited evidence that any of these strategies prevent allograft recurrence in the first kidney transplant.^[102],[103] Strategies for managing patients with allograft recurrence include a combination of plasma exchanges with high-dose CNI and corticosteroids, with or without cyclophosphamide^{[104],[105],[106],[107]} [Supplementary Box 1]. Multiple reports show benefit from additional therapy with rituximab (2–4 doses of 375 mg/m², administered once every 1–2 weeks).^[65],[104] Using these strategies, 60%–70% of patients with recurrent FSGS show complete or partial remission.

Guideline 14: Transition of care

A significant proportion of patients continue to have active disease into adulthood.^[89] These children will need to be cared for by 'adult' physicians and nephrologists, keeping with the policy of the Indian Academy of Pediatrics of caring for children up to 18 years.^[108] Parallel to the change in medical caregiver, patients need to transition from care by parents to self-care. The transition should occur smoothly without affecting patient health. Institution-specific protocols for transition of care should be based on standard guidelines.^[109]

Congenital Nephrotic Syndrome

Patients with congenital nephrotic syndrome present at birth or in first 3-month of life. Infants are born prematurely with large placenta and show massive proteinuria, hypoalbuminemia, and anasarca. Antenatal ultrasonography may show hyperechoic kidneys; amniocentesis reveals high alpha-fetoprotein. There may be dysmorphic features or comorbidities. Most patients develop kidney failure by the age of 2–8 years. Recommendations on genetic aspects and management were published recently.^[110],[111]

Almost 70%–80% of patients with congenital nephrotic syndrome have a genetic cause; mutations in NPHS1, NPHS2, WT1, LAMB2, and PLCE1 account for ~90% cases.^[110],[112] Exome sequencing using an extended SRNS gene panel [Supplementary Table 2] is recommended. Results of screening have implications for genetic counseling. Rarely, the condition is secondary to intrauterine infections with cytomegalovirus, rubella, toxoplasma, and syphilis.^[111] The role of kidney biopsy is limited and may be considered if a genetic diagnosis is not established.

The evaluation aims to confirm the diagnosis and identify complications, including poor growth, hypothyroidism, systemic infections and thromboembolism [Supplementary Box 2].^[111] Infants with WT1 variants are monitored by ultrasonography for Wilms tumor every 3–6 months.

Management includes maintaining euvolemia, optimizing nutrition, and therapy of complications. Patients should receive high energy (110–120 Cal/kg) and protein (3–3.5 g/kg/d) diet, orally or by feeding gastrostomy. Supplements of thyroxine, vitamin D, and calcium are required. Albumin infusions (0.5–1.0 g/kg) are advised in the presence of hypovolemia (oliguria, prolonged capillary refill, tachycardia) or anasarca. IV furosemide (0.5–2 mg/kg) is given at the end of infusion unless the patient has features of hypovolemia. Monitoring of fluid status, creatinine, electrolytes, and blood pressure are necessary during diuretic therapy.^[111]

After 4-week of life, judicious use of ACE inhibitors [Table 3] with or without prostaglandin inhibitors (indomethacin, celecoxib) is effective in reducing the severity of proteinuria. Therapy with these agents and diuretics should be withheld during episodes of hypovolemia. Since infections are the chief cause of death, infants should receive all primary immunization, and bacterial infections are treated promptly. Therapy with anticoagulants is considered in patients with a history of thrombosis.

Unilateral or bilateral nephrectomies are not proposed routinely and may be considered in patients with repeated episodes of hypovolemia or refractory edema, thrombosis, and malnutrition.^[112] Bilateral nephrectomy is advised, prior to kidney transplantation, in patients with WT1 mutations or persistent nephrotic range proteinuria. Kidney transplantation is the definitive treatment but has ethical, technical, and immunologic challenges.

Conclusions

Recommendations on the management of SRNS, first proposed by the ISPN in 2009, have been revised based on systematic reviews, published studies, and expert opinion. While there is a better understanding regarding the genetic basis and management, important clinical issues require to be examined [Box 3]. The management of the disease continues to be challenging, and patients not responsive to treatment with CNI are at risk of progressive kidney disease. We hope that the present guidelines will standardize therapies and improve the quality of care for these patients.

Contributors

All authors involved in review of literature and preparation of background document; AV, RT, MM, JS, AS, and AB drafted the manuscript; AB conceived the idea and critically revised the manuscript. All authors approved the final version of the manuscript.

Acknowledgement

This article is reprinted with permission from Vasudevan A, Thergaonkar R, Mantan M, Sharma J, Khandelwal P, Hari P, Sinha A, Bagga A; Expert Group of The Indian Society of Pediatric Nephrology. Consensus Guidelines on Management of Steroid-Resistant Nephrotic Syndrome. Indian Pediatr 2021;58: 650-666.

Financial support and sponsorship

The Indian Council of Medical Research; Advanced Centre for Research in Pediatric Kidney Diseases; 5/7/1090/2013-RHN; Department of Biotechnology, Government of India; BT/PR11030/MED/30/1644/2016.

Conflicts of interest

There are no conflicts of interest.

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