Evolving Consensus on Management of Nephrotic Syndrome in Childhood: Focus on KDIGO Guidelines 2025

Long-term alternate-day (AD) prednisone

Guidelines from the KDIGO, IPNA, and ISPN recommend 6-12 months of therapy with AD prednisone for frequent relapsers without features of steroid toxicity, although the doses differ [Table 1].^4,6,8 Since children with frequent relapses are expected to have a long disease course and most medications do not have a legacy effect, the initial use of long-term AD prednisone is rational since it may postpone or avoid the need for additional medications in a fraction of children.

Upper respiratory tract viral infections are the trigger for ∼50% relapses of nephrotic syndrome. Contrary to data from three studies that found reduced frequency of relapses in patients on AD prednisolone who received daily steroid therapy for 5-7 days during upper respiratory infections,^16-18 a large placebo-controlled RCT (PREDNOS-2) did not show similar benefits.¹⁹ The inconsistent results might reflect differences in eligibility criteria, disease severity, ethnicity, and concurrent therapy with other medications. Based on the findings of PREDNOS-2, the KDIGO advises that administration of daily prednisone during infections be limited to patients with previous infection-associated relapses [Table 1].⁸ This advice is at variance from that of ISPN, which routinely recommends 5-7 days of prednisone therapy during upper respiratory infections.⁴

Steroid-sparing medications

All guidelines recommend the use of steroid-sparing agents in patients with frequent relapses or steroid dependence [Table 1].^4,6,8 While the guidelines differ in therapeutic choices, it is important to note that few studies have prospectively compared various interventions for comparative efficacy and safety. Hence, the choice of therapy is dictated by relative efficacy, toxicity, costs, and physician preference. Figure 1 summarizes the choice of steroid-sparing medications, determined by the pattern of relapses, patient age, presence of steroid toxicity, and physician and patient preference. Table 2 summarizes the dosage and practical considerations in their prescription.^4-8

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Figure 1:

Summarizes the choice of steroid-sparing medications, determined by the pattern of relapses, patient age, presence of steroid toxicity, and physician and patient preference.

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Steroid-resistant nephrotic syndrome

The ISPN defines steroid-resistance as a lack of complete remission following 6 weeks’ therapy with prednisone that aligns with the duration of daily corticosteroid therapy for the initial episode.⁵ The IPNA and KDIGO define steroid-resistance differently, using the terms ‘confirmation period’ and ‘late responder’, which are not evidence-based, confusing, and do not significantly affect management.^7,8 Patients with steroid-resistance require quantification of proteinuria, eGFR, and a kidney biopsy. While KDIGO (and IPNA) advise genetic testing for all patients with infantile onset and steroid-resistant disease,^7,8 the cost of testing and limited access to interpretation of results preclude its application across India. We advise that all infants with congenital nephrotic syndrome should undergo genetic studies. Beyond infancy, the likelihood of detecting monogenic disease in initial steroid-resistance is ∼20%, and ISPN guidelines limit genetic testing to disorders with a high likelihood of detecting a monogenic disease [Table 1].⁵

The management of patients with steroid-resistance is challenging because of variable response to immunosuppression, high incidence of therapy- and disease-related adverse effects, and risk of progression to kidney failure.^2,3 Across guidelines, treatment with calcineurin inhibitors (CNI), either cyclosporine or tacrolimus, titrated to their trough levels is recommended, since they induce complete or partial remission of proteinuria in 60-70% patients by 6 months of therapy.^5,7,8 Management choices for patients who are refractory to CNI are limited, empirical, and lack evidence-base. Guidelines suggest the use of rituximab or MMF as add-on therapies in such a context.^5,7,8 Although KDIGO guidelines advise the use of MMF if the eGFR is <30 mL/min/1.73 m², the ISPN has not advised the use of immunosuppression in CKD stage 4-5.^5,7,8 While recognizing that patients with monogenic steroid-resistance may occasionally show partial remission following CNI therapy, expert guidelines do not recommend their use.^5,7,8

All these guidelines advise regarding management of complications and supportive care, summarized in Supplementary Table S1.^5,7,8 Use of an inhibitor of the renin-angiotensin-aldosterone system is recommended to reduce proteinuria and manage hypertension. Patients with steroid-resistance with non-response to CNI and/or monogenic disease are at risk of progression to kidney failure. More than half the cases with non-genetic disease that undergo kidney transplantation show recurrent disease that requires specialized management.^5,7

Review of KDIGO guidelines in the context of IPNA and ISPN guidelines shows reasonable consensus on the management of steroid-sensitive and steroid-resistant nephrotic syndrome in children. Minor differences reflect practice patterns and physician preferences rather than ethnic differences in therapeutic response.

In the Indian context, key considerations include the use of optional vaccines not included in the regular national immunization schedule to reduce infection-related morbidity, and individualized therapeutic decision-making based on age, cumulative steroid exposure, cost, and resource availability. Access to generic second-line immunosuppressive agents through schemes such as the Pradhan Mantri Bharatiya Janaushadhi Kendras facilitates sustained therapy. Caregiver education should focus on infection prevention, home urine protein monitoring to detect early relapses, and lifestyle measures to mitigate steroid-related metabolic and psychosocial complications. Planned transition to adult services is important for adolescents with persistent or relapsing disease. The KDIGO advice is broadly in agreement with ISPN guidance on childhood nephrotic syndrome, with recommendations that are largely applicable across the subcontinent.