Three work-groups 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], and is provided with each guideline. Each statement was assigned one of the two levels of guidance, recommen-dation or suggestion, indicating strength of the advice (Web Table I). Ungraded statements (X) are like practice points, not supported by sufficient evidence.The work-groups discussed the evidence, through alternating break-out and plenary sessions, in New Delhi on 5 April 2019. Draft guidelines were discussed with members of the ISPN in Pune on 21 December 2019.

Approximately 85-90% patients with idiopathic nephrotic syndrome respond to treatment with prednisolone, with complete remission of proteinuria and normalization of serum albumin [1]. There is 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-weeks daily treatment and the rest during 4-weeks’ alternate-day therapy [8]. Others found that 4-weeks and 6-8 weeks initial therapy results in remission in 90-92% and 87-93% patients, respectively [9-12]. While few experts suggest additional therapy with 3-doses of IV methyl pre-dnisolone before labeling steroid-resistance, this is not uniformly practiced [6,13,14].

We recommend the following in all patients with SRNS: Quantitation of proteinuria; serum creatinine; estimated glomerular filtration rate (eGFR); and kidney biopsy (Box II). (1A)

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

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

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 year and 13-18 years, respectively [26]. Syndromic forms of the illness may be associated with specific mutations and characteristic phenotype (Web Table II). 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.

Causal variants in ~90 genes are associated with monogenic SRNS (Web Table II). 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 sequen-cing. 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 (OMIM) database, facili-tates 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 context of extrarenal features or positive family history with 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].

Therapy aims to induce complete or partial remission, while avoiding medication-related toxicity. Long-term renal outcome in patients who achieve remission is significantly better when compared to non-responders [17-19,41]. 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-months [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 [44-46], better outcomes in the latter have been reported [18]. The efficacy of tacrolimus and cyclosporin 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 II and Web Table IV). Low levels are associated with non-response 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]. Fig. 1 provides an outline of the approach to management of SRNS.

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

Most patients who respond to CNI do so within the first 6-months of treatment [44,45,47,51]. Non-response to CNI is therefore considered in patients who continue to show nephrotic-range proteinuria, hypoalbuminemia or edema despite 6-months therapy. Patients showing non-response 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 [6,44-46]. Following CNI-induced remission, ~60% 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-months’ therapy [6,16]. An RCT comparing continued therapy with tacrolimus vs switching to mycophenolate mofetil (MMF) at 6-months, found the former twice as effective in maintaining remission (90% vs 45%) [45]. In a retrospective study on 23 patients, therapy with cyclosporine for mean duration of 1.7 years could be successfully switched to MMF in 79% 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 (Fig. 1), ensuring adequate dose and trough levels [49,51].

About 10-25% patients receiving prolonged CNI treatment are at risk of nephrotoxicity [53]. Risk factors for nephrotoxicity include presence of initial resistance, dose of CNI used, duration of heavy proteinuria, and hyper-tension during therapy [48,53]. In order to balance the benefits and toxicity of CNI, we suggest individualizing therapy in children with partial or complete response at 24-months. Options include: i) discontinue therapy if 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 or steroid-sensitive relapses.

In patients with non-genetic forms of SRNS and non-response to therapy with CNI, we suggest additional treatment with either IV rituximab or oral MMF (Fig. 1). (2C)

Approximately 25-35% patients with non-genetic forms of SRNS do not show complete or partial remission following 6-months’ therapy with CNI [43]. The management of patients with non-response to CNI therapy is difficult, since they are at high risk of kidney failure [17-19]. 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 immuno-suppressive 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. 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-resistance (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 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 do not recommend that patients with monogenic disease receive therapy with calcineurin inhibitors or other immunosuppressive agents. (1B)

Patients with SRNS with pathogenic or likely pathogenic variations (monogenic disease, Box I) usually do not show complete or partial remission following therapy with CNI. Analysis of pooled data (Web Table III; n=867) shows that compared to non-genetic disease, those with genetic forms of SRNS are not likely to respond to CNI (RR 4.00; 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 non-genetic illness (RR 2.87; 95% CI 2.22-3.72).

The recent IPNA guidelines do not recommend that patients with monogenic disease receive immuno-suppressive 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) vs risks (therapy-related toxicity, infec-tions) and cost of therapy. Targeted therapy is possible for specific mutations, e.g., coenzyme Q10 for defect(s) in CoQ10 pathway, eplerenone for ARHGDIA, and cortico-steroids for mutations in genes of Rho/Rac/Cdc42 network [31,32].

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

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

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

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 risk of AKI [79]. Non-pharmacological 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 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 pre-dictable pharmacokinetics and is associated with the risk of adverse effects (thrombocytopenia, anaphylaxis and osteoporosis) [80]. 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 (INR) for prothrombin time is targeted between 2.0 and 3.0. Children with recurrent throm-botic events require long-term anticoagulation [77,80].

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

Steroid resistance is associated with multiple cardio-vascular 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 BMI <85th centile for age, non-exposure to tobacco, and achieving target levels of lipids, fasting glucose (<100 mg/dL) and HbA1c (<　5.7%) [82].

Hypertension: Blood pressure should be measured at each visit. A study on Indian children with frequently relapsing disease showed clinic hypertension in 64%, ambulatory hypertension in 33%, white coat hypertension in 30% and increased left ventricular mass in 21% [83]. Systolic and diastolic blood pressures are targeted between 50-75th 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 additional benefit of reducing proteinuria (Table III).

Dyslipidemia: Children with nephrotic syndrome show high blood levels of cholesterol, triglycerides, apoB-containing lipoproteins (LDL, VLDL, IDL) 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 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-fats 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 restricting 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-hr/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.

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

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 hypothalamo-pituitary axis (HPA) [86]. The duration of HPA suppression might last up to two years, and vary with dose and duration of treatment [87].

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

Kidney transplantation is the definitive option for patients with SRNS and stage 5 CKD. Careful pre-transplant 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 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% patients, especially in 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%) [18,97-100]. 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 trans-plantation is therefore the first choice, except in patients with moderate to high risk of recurrence.

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 upto 18 years [108]. Parallel to the change in medical caregiver, patients need to transition from care by parents to self-care. Transition should occur smoothly, without affecting patient health. Institution-specific protocols for transition of care should be based on standard guidelines [109].

Patients with congenital nephrotic syndrome present at birth or in first 3-months 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% 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 (Web Table II) is recommended. Results of screening have implications for genetic counseling. Rarely, the condition is secondary to intrauterine infec-tions 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.

Evaluation aims to confirm the diagnosis and identify complications, including poor growth, hypothyroidism, systemic infections and thromboembolism (Web Box II) [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 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 patient has features of hypovolemia. Monitoring of fluid status, creatinine, electrolytes and blood pressure are necessary during diuretic therapy [111].

After 4-weeks of life, judicious use of ACE inhibitors (Table III) 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 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.

Recommendations on 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 better understanding regarding the genetic basis and management, important clinical issues require to be examined (Box III). 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.

Note: Supplementary material related to this study is available with the online version at www.indianpediatrics.net

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.

Funding: 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.

Competing interests: None stated.

Kamran Afzal, Aligarh; Indira Agarwal, Vellore; Vinay Agarwal, New Delhi; Kanav Anand, New Delhi; M Ashraf, Srinagar; Arvind Bagga, New Delhi; Sushmita Banerjee, Kolkata; Girish C Bhatt, Bhopal; Sudha Ekambaram, Chennai; Arpita Gogoi, Dibrugarh; Sanjeev Gulati, New Delhi; Pankaj Hari, New Delhi; Suprita Kalra, New Delhi; Kanika Kapoor, New Delhi; Priyanka Khandelwal, New Delhi; Sriram Krishnamurthy, Puducherry; Manish Kumar, New Delhi; Mukta Mantan, New Delhi; Jitendra K Meena, New Delhi; Kirtisudha Mishra, New Delhi; Amarjeet Mehta, Jaipur; OP Mishra, Varanasi; Aliza Mittal, Jodhpur; Saroj K Patnaik, New Delhi; Subal Pradhan, Cuttack; PK Pruthi, New Delhi; Sumantra Raut, Kolkata; Abhijeet Saha, New Delhi; Manisha Sahay, Hyderabad; Jyoti Sharma, Pune; Shobha Sharma; New Delhi; Jyoti Singhal, Pune; Aditi Sinha, New Delhi; Rajiv Sinha, Kolkata; Ranjeet Thergaonkar, Mumbai; Karalanglin Tiewsoh, Chandigarh; Susan Uthup, Thiruvananthapuram; Anand S Vasudev, New Delhi; Anil Vasudevan, Bengaluru.

Experts: Uma Ali, Mumbai; Amit K Dinda, New Delhi; Mohammed Faruq, New Delhi; Madhuri Kanitkar, New Delhi; Kumud Mehta, Mumbai; BR Nammalwar, Chennai; Kishore D Phadke, Bengaluru; Geetika Singh, New Delhi; RN Srivastava, New Delhi.

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