KDOQI US Commentary on the KDIGO 2025 Clinical Practice Guideline for the Management of Nephrotic Syndrome in Children

Abstract

The Kidney Disease Outcomes Quality Initiative (KDOQI) convened a work group to review the 2025 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Management of Nephrotic Syndrome in Children. The KDOQI work group reviewed the KDIGO guideline statements and practice points and provided perspective for implementation within the context of clinical practice in the United States. The updated guidelines reflect contemporary US practice and offer highly relevant guidance that is harmonized with the International Pediatric Nephrology Association’s guidelines published in 2020 and 2022. A focus on close monitoring and characterization of the disease status for children with nephrotic syndrome remains central to treatment and management decisions, noting that the lack of insurance coverage for urine dipsticks in the United States is a significant barrier to optimal disease management. As more treatment options become available to children with nephrotic syndrome, the detailed practice points are a sound tool to help providers engage patients and their families in joint decision making. The clinical utility of the guidelines would be enhanced by inclusion of practice points on the incorporation of genetic testing results into treatment decisions, as well as factors to consider when treating and managing patients at high risk for progression to end-stage kidney disease—those with secondary steroid-resistant nephrotic syndrome and those with the chronic kidney disease high-risk APOL1 genotype. The research needs detailed in the updated guidelines reflect the exciting direction of the practice landscape to provide patient-centered, precision-based care.

Introduction

In children, primary nephrotic syndrome (NS) is the most common glomerular disease and a leading cause of end-stage kidney disease (ESKD) in the United States. ^1,2 Efforts to effectively treat and manage NS in children led to the formation of the first international collaborative and randomized clinical trial in nephrology, the International Study of Kidney Disease in Children (ISKDC) in 1966. ³ The ISKDC established the importance of detailed characterization of the patient’s disease activity and treatment response for prognosis while the cause of the disease is unknown and forms the foundation of current standards for management. Today, the underlying pathogenesis of NS for most children remains elusive, but ongoing multicentered collaboratives have also revealed the importance of genetic factors, treatment response, and disease activity with agents other than corticosteroids in patient outcomes. ^4–7 The observational studies offer critical real-world data and informed relevant clinical definitions, practice points, and implementation considerations incorporated in the Kidney Disease Outcomes Quality Initiative (KDOQI) 2025 guidelines for the management of NS in children. Importantly, the 2025 KDIGO guidelines incorporated results from 21 additional randomized clinical trials published since the 2021 guidelines, and these have informed guideline revisions pertaining to NS treatment. Although there has been a growth in the number of clinical trials in childhood NS, the data are insufficient to generate guidance for all aspects of treatment and management decisions faced by practitioners, and the strength of the recommendations remains limited. This highlights the need for additional research and well-designed studies, as summarized in the guidelines and with additional suggestions offered in this commentary.

Management of NS is significantly impacted by available resources, as is evident in disparities in outcomes experienced by patients due to social, economic, and environmental disadvantages. ^8–10 The feasibility of implementing evidence-based guidelines can differ by context of care. In the United States, though many of the newer therapeutic agents are available to prescribe, challenges remain due to a lack of universal access, affecting disease monitoring, treatment, and effective management. To address regional differences, KDOQI convened a work group to review the new “KDIGO 2025 Clinical Practice Guideline for the Management of Nephrotic Syndrome in Children.” ¹¹ This commentary is the product of the KDOQI work group and presents the recommendations and practice points from the KDIGO guideline. Each recommendation is followed by commentary and brief notes on clinical utility, implementation, and challenges pertinent to the United States.

Review and Approval Process for This Commentary

The KDOQI Steering Committee selected members of the KDOQI work group based on their clinical and research expertise as well as interest in the guideline process and experience taking care of children with NS.

KDOQI work group members worked in groups of 2 to 3 to review recent literature and provide commentary on the KDIGO guideline recommendations. The work group discussed the guideline via teleconference, and all work group members and KDOQI leadership reviewed and approved the commentary. This review and commentary follow the same order and numbering scheme used in the KDIGO guideline. All KDIGO guideline practice points and recommendations are reproduced. The KDOQI workgroup agrees with the practice points and recommendations for which they have provided no commentary. For those guideline recommendations that may have implications for clinical care in the United States, we present comments and discuss their clinical utility and implementation. All material is reproduced with the permission of KDIGO.

Diagnosis, Prognosis, Treatment, and Special Situations

Diagnosis

Practice Point 1.1.1: The clinical characteristics of and definitions for nephrotic syndrome in children are outlined in Figure 1.

Commentary

In contemporary clinical practice, response to corticosteroids is regarded as the most important prognostic factor in childhood NS; children who are responsive to corticosteroids and other forms of immunomodulating agents are expected to have excellent long-term outcomes, and they are unlikely to develop ESKD requiring dialysis and or kidney transplantation. ¹² Therefore, the initial response to a corticosteroid is typically used in classifying children with NS. The KDIGO 2025 guideline’s proposed clinical classification of NS (Figure 1; Box 1 in this commentary) is based on corticosteroid response. In addition, the guidelines proposed definitions that characterize disease activity with respect to relapse frequency as well as response to corticosteroid-sparing agents. ¹¹ The inclusion of these definitions reflects the contemporary practice landscape wherein clinicians and patients have therapeutic options beyond corticosteroids and need to delineate disease outcomes beyond initial response to corticosteroids. Furthermore, the definitions are harmonized with the International Pediatric Nephrology Association (IPNA) guidelines on the management of NS in children, ^13,14 establishing a shared language among medical professionals that is fundamental to the promotion of evidence-based practice.

Clinical Utility

The definitions provide detailed characterization of disease activity and treatment response, including outcomes such as partial remission, steroid-sensitive nephrotic syndrome (SSNS) late responder, secondary steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitor responsive and resistant SRNS, and multidrug resistant SRNS. This provides clinicians with consistent and relevant terminology to inform treatment and monitoring needs, as relapse frequency and treatment response patterns beyond complete response to corticosteroids have prognostic importance for long-term kidney function and morbidity from active disease or treatment side effects. ²

The provision of definitions using spot urine and urine dipstick readings is also useful because 24-hour urine collection is impractical, laborious, and inaccurate in children. ¹⁵ The inclusion of a 24-hour urine collection definition is probably unnecessary because practitioners do not typically rely on 24-hour urine collection to define nephrotic range proteinuria. Measurement of urinary protein-creatinine ratio (UPCR) is routine in the United States and in research studies on outcomes of NS. The upper limit of UPCR of <2 g/g to define partial remission is controversial, and it is not supported by data to show differences in outcomes in those with UPCR ≥ 2 g/g. A review of recent literature seems to suggest that a UPCR < 1.5 g/g or 40% reduction in proteinuria from the baseline is associated with improved kidney survival.⁷

Implementation and Challenges

In the United States, urine dipsticks are frequently recommended for home urine protein monitoring. Regular home monitoring allows for (1) early detection and treatment of disease relapses in order to prevent complications of NS (eg, anasarca, acute kidney injury [AKI]), (2) prompt recognition that a child has achieved remission so corticosteroid tapering may begin in a timely manner in order to minimize corticosteroid exposure and toxicity, and (3) detailed tracking of disease activity to inform overall treatment and monitoring plan. As above, practitioners in the United States rely on urine dipstick results to characterize a child’s disease. Unfortunately, urine dipsticks are not typically covered by insurance policies in the United States. The lack of this important resource for patients who cannot afford the out-of-pocket cost of dipsticks hampers the ability to closely monitor and manage children living with NS.

Prognosis

Practice Point 1.2.1: The prognosis for children with nephrotic syndrome is best predicted by the patient’s response to the initial treatment and frequency of relapse during the first year after treatment. Therefore, a kidney biopsy is not usually needed at initial presentation and is instead reserved for children with resistance to therapy or an atypical clinical course.

Commentary

The landmark ISKDC study established that the single most important prognostic factor in NS is the response to corticosteroid therapy. ^16,17 Children with SSNS have long-term normal kidney function if they remain therapy responsive whereas children with SRNS will develop progressive kidney damage leading to ESKD within 5 to 10 years of diagnosis. This clinical course is irrespective of kidney biopsy findings, and it is this study that informs the current practice of treating all children with typical presentation of NS with corticosteroids first before subjecting them to kidney biopsy. The ISKDC findings have since been reproduced in multiple studies. However, a small percentage of children who are initially steroid sensitive but later become steroid resistant (secondary SRNS) have high risk of rapidly progressive kidney disease leading to ESKD. ¹⁸ Patients with secondary SRNS may represent the group of children with diseases due to circulating factors because >80% of them will have recurrence of NS following kidney transplantation compared to ∼40% in all patients with NS and 0–5% in patients with genetic NS. ^19,20

The KDIGO 2025 guideline recommended that kidney biopsy should be performed only in children with SRNS and children with atypical clinical features such as macroscopic hematuria, low C3 levels, AKI not related to hypovolemia, sustained hypertension, arthritis, and/or rash. In addition, in patients who are likely to have genetic (monogenic) NS, biopsy is indicated, especially in parts of the world where genetic testing is not accessible. Furthermore, children with more than 2 years of exposure to calcineurin inhibitors (CNIs) should have surveillance kidney biopsy to assess the nephrotoxicity of CNI and need for therapy modifications.

Clinical Utility and Implementation

The clinical indications for kidney biopsy described in the guideline are appropriate and are the standard of practice in most centers in the United States, avoiding the risk of kidney biopsy in situations where the histologic findings are unlikely to add to prognosis or management. We also agree with the recommendation to consider kidney biopsy in patients with a family history of NS or with syndromic features. With increasing availability and adoption of genetic testing in childhood NS, correlating the genetic testing results with histologic findings will build our understanding of the phenotypic expression and severity of gene variants and help differentiate between causative and benign variants. Thus, it is important to point out that kidney biopsy should not be used as a substitute for genetic testing. A clearer recommendation addressing this point would be to state that one should consider performing a kidney biopsy with genetic testing for children with family history of NS or with syndromic features.

The comment that SSNS tends to resolve spontaneously following puberty in 75% to 85% of patients could create the impression that follow-up may not be indicated in adulthood. Although the frequency of relapses decreases with age and the maturation of the immune system, lifelong follow-up is recommended.

Treatment

Initial Treatment of NS in Children

Recommendation 1.3.1.1: We recommend that oral glucocorticoids be given for 8 weeks (4 weeks of daily glucocorticoids followed by 4 weeks of alternate-day glucocorticoids) or 12 weeks (6 weeks of daily glucocorticoids followed by 6 weeks of alternate-day glucocorticoids) (1B).

Practice Point 1.3.1.1: The standard dosing regimen for the initial treatment of nephrotic syndrome is daily oral prednisone/prednisolone 60 mg/m² per day or 2 mg/kg per day (maximum 60 mg/d) for 4 weeks followed by alternate-day prednisone/prednisolone 40 mg/m² or 1.5 mg/kg (maximum 40 mg) for another 4 weeks or prednisone/ prednisolone 60 mg/m² per day or 2 mg/kg per day (maximum 60 mg/d) for 6 weeks followed by alternate-day prednisone/prednisolone 40 mg/m² or 1.5 mg/kg (maximum 40 mg) for another 6 weeks.

Commentary.

Glucocorticoid is the first-line treatment of NS, and 80% of children will achieve remission with this treatment. However, approximately half the children will have frequently relapsing or steroid-dependent courses that will warrant frequent exposure to steroids, thereby increasing the risk of major steroid side effects such as growth failure, cataracts, diabetes, and increased risk of infection.²

The KDIGO 2025 guidelines discussed the optimal duration of steroid therapy at the initial presentation of NS and its association with risk of relapse. The recommendations placed a higher value on the moderate certainty of evidence of clinical outcome of frequent relapse and favorable safety profile of 8 to 12 weeks of steroid therapy versus higher certainty of evidence of higher risk of steroid toxicity with treatment > 12 weeks. The guideline evaluated 4 randomized controlled clinical trials published since the publication of the 2012 guideline. Three studies compared 8- or 12-weeks’ duration with 6 months, and 1 study compared 8 weeks versus 4 months. All 4 studies showed that prolonged treatment may delay the time to first relapse but does not have an impact on subsequent development of frequently relapsing or steroid-dependent course. Pooled analysis and Cochrane review confirmed the findings in these studies and also showed that prolonged treatment, while not more effective in preventing frequent relapse, is also not associated with more side effects compared with short course. The guideline noted, however, that prolonged steroid therapy in other conditions is associated with major glucocorticoid toxicity. Thus, because the short course is not associated with higher risk of frequent relapse and it mitigates the risk of steroid toxicity, the overall balance of evidence is that 8 to 12 weeks of steroid is optimal for the treatment of first presentation of NS.

There are few studies comparing 8 versus 12 weeks, with 1 recent individual patient data meta-analysis of randomized controlled trials finding that the 8-week regimen may not be equally effective as the 12-week regimen. ²¹ The KDIGO guideline therefore left this decision to local preferences of physicians, and parental choice. We agree that there is a need for studies comparing 8 versus 12 weeks of treatment.

Clinical Utility and Implementation.

Although there is no strong evidence to support making a recommendation for 8 versus 12 weeks of corticosteroid treatment, it is unclear why a provider would consider choosing a longer course of treatment if a shorter course could be sufficient. The KDIGO guidelines would benefit from practical points provided on the factors providers may consider and discuss with patients and their families when considering an 8- or 12-week course of treatment.

Recommendation 1.3.1.1 for an 8- to 12-week course of steroid for the first presentation of NS is consistent with practice in most US centers. It is also consistent with the IPNA ¹⁴ recommendations for the treatment of the initial presentation of NS with corticosteroid, which indicate:

• 4 weeks at 60 mg/m² or 2 mg/kg (maximum dose 60 mg/day), followed by alternate day at 40 mg/m² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 4 weeks

or

• 6 weeks at 60 mg/m² or 2 mg/kg (maximum dose 60 mg/day), followed by alternate day at 40 mg/m² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 6 weeks (Grade A, strong recommendation).

Prevention of Relapses of Nephrotic Syndrome in Children

Recommendation 1.3.2.1: For children with frequently relapsing and steroid-dependent nephrotic syndrome, we recommend that daily glucocorticoids not be routinely given during episodes of upper respiratory tract and other infections to reduce the risk of relapse (1C).

Practice Point 1.3.2.1: A short course (i.e., 3 extra doses) of low-dose (0.5 mg/kg per day), daily prednisone or prednisolone at the onset of an upper respiratory tract infection can be considered in children with frequently relapsing and steroid-dependent nephrotic syndrome who are already taking low-dose, alternate-day prednisolone and have a history of repeated infection-associated relapses or significant prednisone- or prednisolone-related morbidity.

Commentary.

The 2 most important goals in the management of SSNS in children with frequent relapsing and steroid-dependent courses are (1) achieving sustained and durable remission and (2) limiting steroid exposure to prevent steroid toxicity. Up to 60% of children with SSNS will have frequent relapsing/steroid-dependent courses. ² In some of these children, infection, especially upper respiratory infection (URI), is usually the trigger for relapses.² Studies carried out in Europe and Asia suggest giving a short course of low-dose prednisolone: ∼0.5 mg/kg can prevent full relapse during an episode of URI and therefore minimize exposure to steroid.^22–24

Most of these studies were single-center studies with limited sample size, with a recent large multicenter study from the United Kingdom (PREDNOS) showing that short-course prednisolone did not prevent relapse of NS in children with URI. This study reported no increased side effects in the prednisolone group and showed that short-course prednisolone has the potential to reduce healthcare costs and improve quality of life compared with placebo. ^25,26

The advantage of the PREDNOS study is that it is a large multicenter study; however, unlike the earlier studies that focused mainly on children who were already on alternate-day prednisolone, the study population in the PREDNOS study was composed of patients who were off steroid or on low-dose prednisone. Thus, we agree with the practice point that a short course of low-dose corticosteroids may be considered in children already taking low-dose, alternate-day prednisone with a history of infection-associated relapses.

Clinical Utility and Implementation.

In the United States, the feasibility of implementing short-course, low-dose corticosteroids to prevent relapses is unclear. The onset of URI symptoms is often unclear, and caregivers are frequently uncertain of when to initiate corticosteroids. Young children may experience URIs as frequently as 11 to 12 times a year, and it is unclear whether one should give a short course for each and every one of the infections or base the dosing on infection severity. Monitoring each additional treatment course added to the ongoing maintenance corticosteroids compounds the burden on the caregivers and providers, and it may not reduce the total cumulative exposure in patients. Additional studies to understand the role of short-course prednisolone in preventing relapse of NS in children with URI are needed.

The IPNA does not recommend the routine use of a short course of low-dose daily prednisolone at the onset of an upper respiratory tract infection for prevention of relapses of NS (Grade B, moderate recommendation) ¹⁴ but suggests considering a short course of low-dose daily prednisolone at the onset of URI in children who are already taking low-dose alternate-day prednisolone and have a history of repeated infection-associated relapses (Grade D, weak recommendation).

Treatment and Prevention of Subsequent Relapses of Nephrotic Syndrome in Children

Practice Point 1.3.3.1: The initial approach to relapse should include oral prednisone or prednisolone as a single daily dose of 60 mg/m² per day or 2 mg/kg per day (maximum 60 mg/d) until the child remits completely for ≥3 days.

Practice Point 1.3.3.2: After achieving complete remission in patients with steroid-sensitive nephrotic syndrome treated for relapse, reduce oral prednisone/prednisolone to 40 mg/m² or 1.5 mg/kg (maximum 40 mg) on alternate days for 4 weeks.

Practice Point 1.3.3.3: For children with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome without glucocorticoid toxicity, the same glucocorticoid regimen may be employed in subsequent relapses, while a shorter taper and/or more robust steroid-sparing approaches should be considered in children with signs of glucocorticoid toxicity.

Practice Point 1.3.3.4: For children with frequently relapsing nephrotic syndrome without serious glucocorticoid-related adverse effects, low-dose, alternate-day oral prednisone/prednisolone (optimally ≤0.5 mg/kg per dose) can be prescribed to prevent relapse.

Practice Point 1.3.3.5: Patients should ideally be in remission with glucocorticoids prior to the initiation of glucocorticoid-sparing agents such as oral calcineurin inhibitors (CNIs), cyclophosphamide, levamisole, mycophenolate mofetil (MMF), and rituximab. Co-administration of glucocorticoids is recommended for ≥2 weeks following the initiation of glucocorticoid-sparing treatment.

Practice Point 1.3.3.6: Choosing the most appropriate glucocorticoid-sparing agent from among oral CNIs, cyclophosphamide, levamisole, MMF, and rituximab (listed here in an unbiased order) is a decision that requires careful consideration of specific patient-related issues such as resources, adherence, adverse effects, and patient preferences. Oral cyclophosphamide and levamisole may be preferable for glucocorticoid-sparing therapies in frequently relapsing nephrotic syndrome. MMF, rituximab, CNIs, and, to a lesser extent, oral cyclophosphamide may be preferable glucocorticoid-sparing therapies in children with steroid-dependent nephrotic syndrome.

Recommendation 1.3.3.1: For children with frequently relapsing nephrotic syndrome who develop serious glucocorticoid-related adverse effects and for all children with steroid-dependent nephrotic syndrome, we recommend that glucocorticoid-sparing agents be prescribed to prevent relapses, rather than no treatment or continuation with glucocorticoid treatment alone (1B).

Commentary.

Relapse is common in children with NS: about 80% of children will have at least 1 relapse within the first year of diagnosis. ^2,12 The goal of treating relapse is to induce remission rapidly and to taper the dose of steroid to minimize exposure to steroid, thereby avoiding major steroid side effects. We agree with Practice Points 1.3.3.1 and 1.3.3.2. We also agree with Practice Point 1.3.3.3 that the same glucocorticoid regimen may be used in subsequent relapses; however, we believe that there is insufficient evidence to support a taper of shorter than 4 weeks without a second agent. The recommendation would be strengthened by explicitly describing “robust” steroid-sparing approaches that would allow a safe, shorter glucocorticoid taper.

Practice Point 1.3.3.4 states that in children with frequently relapsing NS without serious glucocorticoid-related adverse effects, low-dose, alternate-day oral steroid can be prescribed to prevent relapse. This approach, while common among practitioners in the United States and other parts of the world, does not have robust evidence. ^27,28 A recent open-label study showed greater efficacy in preventing relapses with daily ∼0.25 mg/kg prednisolone with fewer side effects. ²⁹ Although this study has the limitation of small sample size, it directly challenges the benefits of alternate-day dosing and emphasizes the need for shared decision making between physicians and caregivers, particularly with respect to the feasibility of administering medications on a daily versus alternate-day basis.

There is a need for comparative effectiveness studies of daily versus alternate-day corticosteroid to prevent relapses of SSNS. We agree with Practice Point 1.3.3.5 to initiate glucocorticoid-sparing agents when in remission and provide a period of coadministration with glucocorticoids, when possible. We appreciate the emphasis in Practice Point 1.3.3.6 that the most appropriate glucocorticoid-sparing agent is dependent on careful consideration of multiple factors beyond efficacy.

Clinical Utility.

In the United States and many parts of the world, corticosteroids are affordable and easily accessible, making it a useful and important relapse treatment. As described above, clinical utility would be improved with more in-depth descriptions of alternative approaches for corticosteroid tapering in combination with other agents when children develop intolerable corticosteroid toxicity.

Figure 3 of the KDIGO guideline (Table 1 in this commentary) lists in an unbiased order glucocorticoid-sparing therapies in children with SSNS. This figure includes clinical tips for providers and families to consider when selecting an agent, which is a helpful tool for engaging patients and families in shared decision making. Within Table 1, rituximab is discussed as an option for patients who continue to have frequent relapses despite optimal combinations of prednisone and other agents. This suggests a bias against selecting rituximab as a first-line glucocorticoid-sparing agent. Recently, autoantibodies against podocyte proteins, including antinephrin, have been found to play a role in the pathogenesis of childhood NS in as many as two-thirds of patients, ³⁰ raising the role of B-cell–directed therapies like rituximab in childhood NS treatment. The use of rituximab and other B-cell–directed therapies has risen in recent years, reflecting these advances in understanding; reserving rituximab only for when other agents fail to achieve adequate disease control may overlook its potential benefit as a first-line agent in selected patients.

Table 1.

Glucocorticoid-sparing Therapies in Children With Steroid-Sensitive Nephrotic Syndrome, Listed in an Unbiased Order

Treatment	Dose and Duration	Clinical Tips
Calcineurin inhibitorsa		CNI should be continued for at least 12 months as most children will relapse upon discontinuation. Monitor CNI levels during therapy to limit toxicity
Cyclosporine	4 to 5 mg/kg/d (starting dose) in two divided doses	Cyclosporine may be preferable in patients at risk for diabetic complications. Target 12-hour trough level of 60–150 ng/mL [50–125 nmol/L] aiming for lowest levels to maintain remission and avoid toxicity
Tacrolimus	0.1 mg/kg/d (starting dose) given in two divided doses	Tacrolimus may be preferred over cyclosporine in patients for whom the cosmetic side effects of cyclosporine are unacceptable. Target 12-hour trough level of 5–10 ng/mL (6–12 nmol/L) aiming for lowest levels to maintain remission and avoid toxicity
Oral cyclophosphamide	2 mg/kg/d for 12 weeks (maximum cumulative dose 168 mg/kg)	Cyclophosphamide should not be started until the child has achieved remission with glucocorticoids. Moreover, second courses of alkylating agents should not be given. Weekly CBCs are recommended during the treatment course to assess for severe leukopenia or overall bone marrow suppression prompting dose reduction or treatment cessation
Oral levamisole	2.5 mg/kg on alternate days, with a maximum dose of 150 mg	Monitor CBC every 2–3 months and alanine and aspartate aminotransferases every 3–6 months during therapy with levamisole. Check ANCA titers every 6 months, if possible, and interrupt treatment in case of ANCA positivity, skin rash, or agranulocytosis. Maintaining low-dose alternate-day glucocorticoid dosing on the days not taking levamisole may be effective in some children. Levamisole should be continued for at least 12 months
Mycophenolate mofetil	Starting dose of 1200 mg/m2/d (given in two divided doses)	Target area under the curve >50 μg • h/mL. 41 Mycophenolate mofetil should be continued for at least 12 months, as most children will relapse when it is stopped. In children experiencing significant abdominal pain on mycophenolate mofetil, other mycophenolic acid analogs (MPAAs), such as sodium mycophenolate, may be employed at equivalent doses (360 mg of sodium mycophenolate corresponds to 500 mg of mycophenolate mofetil)
Rituximab	375 mg/m2 i.v. × 1–4 doses	Rituximab may be used as a treatment for steroid-sensitive nephrotic syndrome in children who have continuing frequent relapses despite optimal combinations of prednisone and glucocorticoid-sparing oral agents, and/or who have serious adverse effects of therapy. Current trials report 1 to 4 doses of rituximab. There are insufficient data to make a recommendation for specific number of needed doses. Where available, CD20 levels should be monitored. In children with complicated forms of FRNS or SDNS, the use of mycophenolate mofetil after rituximab can decrease the risk of treatment failure. Hepatitis B surface antigen, hepatitis B core antibody, and a QuantiFERON test for tuberculosis must be checked prior to rituximab administration. Monitoring IgG levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement

Abbreviations: ANCA, antineutrophil cytoplasmic antibody; CBC, complete blood count; FRNS, frequently relapsing nephrotic syndrome; i.v., intravenous; SDNS, steroid-dependent nephrotic syndrome.

^aThe calcineurin inhibitor (CNI), while often used twice daily, may be dosed once a day, depending on individual formulations. In younger children (<6 years of age), the daily dose of cyclosporine can be divided into 3 doses (every 8 hours) to obtain steady hematic levels. Blood levels of CNIs do not provide information on intracellular levels. The target ranges for CNIs have been based on the transplant literature. The Work Group acknowledges that target ranges for nephrotic syndrome are not known. Most clinicians check these levels to verify adherence and avoid CNI toxicity. At present, the most reasonable dosing of a CNI may be to titrate in the individual patient to achieve the desired effect on proteinuria, balancing dose escalation against serum creatinine and reducing the dose if serum creatinine increases but does not plateau or increases over 30% of baseline. If the serum creatinine level does not fall after dose reduction, the CNI should be discontinued.

Research into duration of treatment with maintenance medications is needed. Practice points on factors to consider for stopping maintenance treatment would be of high relevance to clinical practice and should be emphasized.

Implementation and Challenges.

That urine dipsticks are not typically covered by insurance is an important barrier in the United States for relapse treatment. Restricted access to this important, noninvasive home-monitoring tool hinders the ability to initiate relapse treatment in a timely manner before complications occur and delays the ability to initiate corticosteroid tapers to minimize corticosteroid toxicity.

In the United States, levamisole is currently approved for use only in veterinary medicine and not for treatment of human diseases, so it is not one of the medications available for glucocorticoid-sparing therapies.

Many characteristics of the medications can make it difficult for patients and families to adhere to treatment, such as complicated dosing schedule, taste and size of the medicines, and side effects, thereby risking suboptimal disease control and patient outcomes. ³¹ The alternate-day tapering may be difficult for families to remember and carry out. Each of the glucocorticoid-sparing agents has unique monitoring needs, side-effect profiles, route of administration, and frequency of administration. To ensure the selection of the treatment reflects patient priorities and preferences and to facilitate adherence, providers need to clearly communicate the rationale for medication initiation, switch, and termination and give the instructions in a clear manner. Additional research and quality improvement efforts to support NS management are important and need to consider impacts such as provider-burden and resource constraints.

Steroid-Resistant Nephrotic Syndrome in Children Treatment

Recommendation 1.4.1.1: We recommend using cyclosporine or tacrolimus as initial second-line therapy for children with steroid-resistant nephrotic syndrome (1C).

Commentary.

Among children with primary NS, steroid-resistance makes up 5% to 20% of the cases and is a significant risk factor for progression to ESKD. ² The risk is further increased in children who fail to respond to second-line agents beyond corticosteroids, for example, CNI-resistant SRNS and multidrug-resistant SNRS. ^4,6 Though renal prognosis is poor among treatment-resistant patients, due to the condition’s rarity robust prospective trials are difficult to conduct, and thus the evidence is limited.

We agree with the recommendation to use cyclosporine or tacrolimus as initial second-line therapy based on current available evidence. In particular, this recommendation aligns with the IPNA clinical practice recommendations published in 2020.¹³ Harmonization of treatment recommendations based on best-available evidence is important to allow for assessment of real-world effectiveness using observational data, where controlled trials have been difficult to conduct. ³² For patients with SRNS who are resistant to CNIs, the current guidelines promote the consideration of clinical trial entry, which is critically important to generate strong evidence of effective treatments for this vulnerable subset of children with NS.

Clinical Utility.

The recent discovery of antinephrin autoantibodies in children with NS, including those with SRNS, raises the exciting prospect of a biomarker that can be used to predict treatment response and guide treatment selection. ^33,34 Currently in clinical practice, 3 factors are key in SRNS treatment decisions. First, observational cohort studies have established that patients with monogenic forms of SRNS are generally unlikely to respond to immunosuppression, though exceptions exist. ^4,13 The ability to achieve even partial response with CNI treatment at 6 months has been associated with a lower risk of progression to kidney failure and slower rate of progression. ³⁵ The KDIGO guideline would benefit from practice points that provide guidance on how to incorporate genetic testing results into treatment considerations, in particular, initiation and treatment length for use of CNIs, given positive genetic testing results. Given the limited evidence, practice points on how to weigh the pros and cons of CNI treatment in genetic forms of SRNS and how to engage patients and their families in shared decision making would be helpful.

Second, two high-risk alleles of the gene APOL1 confer high risk for treatment resistance and progression to ESKD. ^36,37 In the CureGN observational trial network of 68 centers in North America and 3 centers in Europe, 18% of the focal segmental glomerulosclerosis study participants carry 2 risk alleles, indicating that this genetic factor impacts a significant proportion of patients with NS and SRNS. Many commercially available genetic panels for SRNS include testing for the chronic kidney disease (CKD) risk alleles (G1 and G2) in the APOL1 gene. Given the consistent recommendation from both IPNA and KDIGO guidelines to perform genetic testing in patients with SRNS, clinical utility would be further enhanced by guidance to providers on how to incorporate information about APOL1 risk alleles into practice. Much less is known about response to CNIs among patients with high-risk APOL1 genotypes (G1/G1, G1/G2, G2/G2), though CNI treatment appears to be protective against CKD progression. ³⁸ Practice points helping providers to offer prognostic information and discuss uncertainties surrounding treatment response would further support shared decision making between clinicians, patients, and families. Targeted drug therapies against APOL1-mediated kidney diseases are currently in clinical trial, including inaxaplin (NCT05312879), baricitinib (NCT05237388), and anti-sense oligonucleotide (ASO) against APOL1 (NCT06824987).

Finally, an analysis of the United Kingdom National Registry of Rare Kidney Disease (RaDar) cohort found differential response to treatment between patients with SRNS diagnosed following the first course of corticosteroid treatment versus those with secondary SRNS (a patient with SSNS who fails to achieve remission within 4 weeks of corticosteroid treatment at a subsequent relapse). ⁴ Patients with secondary SRNS are more likely to achieve complete response to rituximab treatment compared to those with primary SRNS (64% achieved complete response vs 26%), presumably because secondary SRNS is more likely to have an immunologic basis of disease.

Because patients with secondary SRNS face a high risk of progression to ESKD as well as a strikingly high risk of disease recurrence after transplant, achieving disease remission is particularly important. ¹⁹ Practice points addressing treatment considerations of this particularly vulnerable group who may benefit from anti–B-cell therapy would be helpful.

Implementation and Challenges.

The recommendation includes the use of 2 efficacious CNI agents with significantly different side-effect profiles. This offers important flexibility in clinical practice to tailor the treatment to the patient’s individual health needs and preferences and is an opportunity to engage patient and families in shared decision making to optimize patient outcomes.

The detailed clinical tips included for each agent offer practical considerations for selecting between cyclosporine and tacrolimus. Nonetheless, both cyclosporine and tacrolimus have significant needs for monitoring therapeutic target trough levels and screening for and managing side effects. The twice-a-day dosing regimen may be difficult for some families, in addition to the side effects of the medications. These barriers may negatively impact adherence and lead to treatment nonresponse. ³¹ For patients with CKD progression or those with high risk for AKI due to intravascular volume depletion from severe hypoalbuminemia, it may be particularly hard to tolerate CNIs, and close laboratory monitoring would be needed.

Engaging patients and families in shared decision making, inviting the patient and caregivers to participate with treatment selection, clearly communicating the expected clinical response and potential side effects, gathering the patient’s and family’s values and preferences, and regularly evaluating the treatment outcomes help promote adherence by ensuring that the selected treatment is patient centered.³⁹

Special Situations

Practice Point 1.5.1: Figure 5 outlines the general principles for children with nephrotic syndrome.

Commentary and Clinical Utility

We agree with the general principles outlined in this practice point. Provision of additional recommendations or practice points on universal management needs as well as the highest factors impacting morbidity would be helpful, as would guidance on acute complications such as hypovolemia and AKI prevention, thrombosis prevention and/or treatment, edema management, and infection prevention and vaccination. Consider guidance on long-term monitoring needs and transition of care to adult practices, including growth and nutrition, body mass index, cardiovascular disease and hypertension, mineral bone disease, fertility, and ocular complications.²

Implementation and Challenges

The principles listed in Figure 5 of the guideline (Table 2 in this commentary) are generally well-accepted and align with practice in the United States. Genetic testing is becoming widely available for children with NS. The current barrier to practice is now related to the interpretations of the results, incorporation of the findings into treatment, and providing accurate and helpful counseling to families.

Table 2.

General Principles for Children With Nephrotic Syndrome

Indication for kidney biopsy	• Children presenting with nephrotic syndrome ≥ 12 years of age • Steroid-resistant nephrotic syndrome or subsequent failure to respond to glucocorticoids in steroid-sensitive nephrotic syndrome (secondary steroid-sensitive nephrotic syndrome) • A high index of suspicion for a different underlying pathology (macroscopic hematuria, systemic symptoms of vasculitis, hypocomplementemia, etc.) • At onset, kidney failure not related to hypovolemia. Subsequently, decreasing kidney function in children receiving calcineurin inhibitors or prolonged exposure to calcineurin inhibitors (2 to 3 years)
Genetic testing	• Steroid-resistant nephrotic syndrome • Congenital and infantile forms of nephrotic syndrome (<1 year of age) • Nephrotic syndrome associated with syndromic features • Family history of steroid-resistant nephrotic syndrome or focal segmental glomerulosclerosis
Vitamin D/calcium	In patients with steroid-sensitive nephrotic syndrome and normal vitamin D levels, supplementation is not required. However, in frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome in children or in the presence of a known vitamin D deficiency, a reduction in bone mineral content can be prevented by oral supplementation with oral calcium and vitamin D.42,43
Gastroprotection	There is insufficient evidence of benefit to recommend prophylactic use of proton-pump inhibitors in children with nephrotic syndrome in the absence of risk factors for gastrotoxicity or of gastric symptoms

Research Recommendations

RCTs are needed to:

• Compare 8 versus 12 weeks of oral prednisone/prednisolone for initial therapy and explore further shortening of the initial glucocorticoid regimen and assess combination therapy with a glucocorticoid-sparing agent at disease onset.

• Optimize subsequent treatment of SSNS after relapse in different forms of disease.

• Optimize the dosing regimen for glucocorticoid treatment at the onset of an infection.

• Define the optimal dosing and choice of glucocorticoid-sparing agents in frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS).

• Evaluate the optimal duration of glucocorticoid treatment in SRNS, in particular when CNIs are initiated, and stratify patients based on the identification of podocytopathy-related genetic mutations.

• Determine the mode of action of glucocorticoids and other immunosuppressive medications in SSNS, determine the potential role of pharmacogenomics in treatment, and identify biomarkers or genetic risk haplotypes to stratify disease subgroups.

• Determine the long-term safety of therapies that deplete B cells.

• Include quality-of-life measures as end points in clinical trials assessing the treatment of children with both SSNS and SRNS.

• Evaluate antinephrin and antislit diaphragm antibodies as biomarkers as well as predictors of response to treatment and outcome of NS in children.

Commentary

We suggest the following additional recommendations based on the commentaries we have provided:

• A survey of US pediatric nephrologists and patients and families to gather perspectives on the feasibility of using short-course, low-dose prednisolone in preventing full relapse of NS in children with URI.

• Comparative effectiveness trial of different durations of oral prednisone/prednisolone for initial therapy.

• Management support for patients with the need for frequent monitoring and medication administration.

• Characterization of responses to treatment for patients with CKD high-risk APOL1 genotype.

• Comparative effectiveness trial of B-cell–directed therapeutic agents versus CNIs for secondary SRNS treatment.

• Shared decision making approaches for medication selection and clinical trial participation.

Conclusions

Tremendous advancements have been made in recent years on the understanding of childhood NS pathogenesis, and many therapeutic agents targeting the biologic underpinnings of disease onset and progression are currently being tested. The rapid pace of discoveries offers great hope for our ability to dramatically improve patient outcomes. The KDIGO guidelines offer providers important evidence-based guidelines that keep pace with research advancements, with important questions outlined that need to be addressed to continuously improve the care we provide to patients and their families. This commentary provides practical considerations when applying the KDIGO guidelines in the US clinical setting in order to promote adoption of evidence-based guidelines.

Box 1.

Clinical Characteristics of and Definitions for Nephrotic Syndrome (NS) in Children Aged 1–18 Years

• Nephrotic-range proteinuria: Urinary protein-to-creatinine ratio (uPCR) ≥200 mg/mmol (2 g/g) in a spot urine, or proteinuria ≥1000 mg/m2 per day in a 24-h urine sample corresponding to 3+ (300–1000 mg/dL) or 4+ (≥1000 mg/dL) by urine dipstick

• NS: Nephrotic-range proteinuria and either hypoalbuminemia (serum albumin <30 g/L (3 g/dL) or edema when albumin level is not available

• Complete remission: First morning urine or a24-h uPCR ≤200 mg/g (0.2 g/g or 20 mg/mmol or negative or trace dipstick or <100 mg/m2 per day) on three or more consecutive days

• Partial remission: First morning urine or a24-h uPCR >200 mg/g (0.2 g/g) but <2 g/g (or >20 and <200 mg/mmol) and, if available, serum albumin ≥30 g/L (3 g/dL)

• Relapse: Recurrence of nephrotic-range proteinuria in a child who had previously achieved complete remission. In children, relapse is commonly assessed by urine dipstick and is thus defined as dipstick ≥3+ for 3 consecutive days. Typical dipstick results are expressed semiquantitatively as follows,b or as stated by manufacturer:

◇ Negative: 0 to <15 mg/dL

◇ Trace: 15 to <30 mg/dL

◇ 1+: 30 to <100 mg/dL

◇ 2+: 100 to <300 mg/dL

◇ 3+: 300 to <1000 mg/dL

◇ 4+: ≥ 1000 mg/dL

• SSNS: Complete remission within 4 weeks of prednisone or prednisolone at standard dose

• Infrequently relapsing NS: <2 relapses in the 6 months following remission of the initial episode or <3 relapses in any subsequent 12-month period

• Frequently relapsing NS: >2 relapses in the first 6 months following remissions of the initial episode or ≥ 3 relapses per 12 months in any subsequent 12-month period

• Steroid-dependent NS: 2 consecutive relapses during recommended prednisone or prednisolone therapy for first presentation or relapse (either at full-dose or during tapering) or within 14 days of prednisone or prednisolone discontinuation

• SRNS: Lack of complete remission within 4 weeks of therapy with daily prednisone or prednisolone at standard dose

• Confirmation period: Time period between 4 and 6 weeks from prednisone or prednisolone initiation during which response to further oral prednisone or prednisolone and/or pulses of i.v. methylprednisolone and RAS inhibitor are ascertained in patients achieving only partial remission at 4 weeks. A patient achieving complete remission at 6 weeks is defined as a late responder. A patient not achieving complete remission at 6 weeks, although he had achieved partial remission at 4 weeks, is defined as SRNSc

• SSNS late responder: A patient with new-onset NS achieving complete remission during the confirmation period (i.e., between 4 and 6 weeks of prednisone or prednisolone therapy)

• Calcineurin inhibitor-responsive SRNS: Partial remission with 6 months of treatment and/or complete remission with 12 months of treatment with a calcineurin inhibitor at adequate doses and/or levels

• Calcineurin inhibitor-resistant SRNS: Absence of partial remission with at least 6 months of treatment with a calcineurin inhibitor at adequate doses and/or levels

• Multi-drug resistant SRNS: Absence of complete remission with 12 months of treatment with 2 mechanistically distinct glucocorticoid-sparing agents at standard doses (see below)

• Secondary SRNS: A SSNS patient at disease onset who at a subsequent relapse fails to achieve remission within 4 weeks of therapy with daily prednisone or prednisolone at standard dose

Abbreviations: i.v., intravenous; RAS, renin-angiotensin system; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome.

^aTo rule out orthostatic proteinuria, the first morning urine should be collected separately for assessment.

^bVan der Watt et al.⁴⁰

^cInternational Pediatric Nephrology Association 2020. ^13,14

Because they are designed to reflect the views and recommendations of the responsible KDOQI Commentary work group and they are reviewed and approved by KDOQI and NKF leadership, KDOQI Commentaries are not peer reviewed by AJKD. This article was prepared by a KDOQI Commentary work group composed of the authors. It was reviewed and approved by the NKF Scientific Advisory Board and the KDOQI.