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Steroid-resistant nephrotic syndrome in children: Evaluation and management

Steroid-resistant nephrotic syndrome in children: Evaluation and management
Authors:
Patrick Niaudet, MD
Olivia Gillion Boyer, MD, PhD
Section Editor:
Tej K Mattoo, MD, DCH, FRCP
Deputy Editor:
Jessica Kremen, MD
Literature review current through: Apr 2025. | This topic last updated: Mar 05, 2025.

INTRODUCTION — 

Most children with idiopathic nephrotic syndrome (NS) have minimal change disease, which is generally responsive to glucocorticoid therapy (eg, treatment with prednisone, also referred to as steroid therapy.) As a result, children with NS are usually empirically started on glucocorticoids. 80 to 90 percent of patients respond to this treatment. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial therapy'.)

Steroid-resistant NS (SRNS) describes the cases that do not respond to initial glucocorticoid therapy. Approximately one-third of these cases are monogenic (caused by pathogenic variants in a single gene), and disease progression is rapid. [1,2]. Therapeutic decisions in children with SRNS are partially determined by the underlying etiology.

The evaluation and management of children with SRNS will be reviewed here. Related information is available in the following topic reviews:

●(See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)

●(See "Treatment of idiopathic nephrotic syndrome in children".)

●(See "Complications of nephrotic syndrome in children".)

DEFINITIONS — 

For the purposes of this topic, we will use the following definitions:

●Steroid-resistant nephrotic syndrome (SRNS) – We define SRNS as persistent proteinuria (urine protein-to-creatinine ratio [UPCR] ≥20 mg/mmol [0.2 mg protein/mg creatinine]) demonstrated by first morning void (or 24-hour urine collection or urine dipstick with more than trace proteinuria) after four weeks of daily prednisone therapy at a dose of 60 mg/m2/day (maximum daily dose 60 mg/day) followed by two weeks of further interventions, as discussed below.

For patients in whom proteinuria persists after four weeks of daily prednisone therapy at a dose of 60 mg/m2/day (maximum daily dose 60mg/day), SRNS is likely [3,4].

For such patients, the subsequent two weeks is known as the "confirmation period," definitively establishing the diagnosis of SRNS. The confirmation period is used to determine their response to further interventions, such as continuation of oral prednisone and/or adding three pulses of intravenous methylprednisolone and renin-angiotensin-aldosterone system (RAAS) inhibitors such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) [5].

●Slow responders – Patients in whom proteinuria resolves only after the confirmation period are considered slow responders, whereas those in whom proteinuria persists have confirmed SRNS.

●Remission and partial remission – Remission is defined by a UPCR ≤20 mg/mmol (0.2 mg protein/mg creatinine) on first morning void or urine dipstick with trace or no proteinuria.

Partial remission is defined by a UPCR on first morning void that is decreased from baseline but is >20 mg/mmol (>0.2 mg protein/mg creatinine) or more than trace on urine dipstick. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial steroid course' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Next steps'.)

EVALUATION FOR ETIOLOGY

Possible etiologies — While etiology is not identified in most children with SRNS, approximately one-third of cases are due to single gene variants that affect glomerular podocyte structure and/or function (table 1 and table 2) [6]. The remainder are due to unknown mechanisms. Some monogenic forms of SRNS are poorly responsive to immunosuppressive therapy, and disease progression is rapid. Thus, therapeutic decisions in children with SRNS depend in part on the underlying etiology.

History and physical examination — The primary aim of the diagnostic evaluation is to identify a specific cause of SRNS to guide treatment.

A complete history and physical examination should be focused on the following:

●Potential infectious causes of SRNS based on known exposures and other symptoms. Possible infections are discussed below. (See 'Screening for infection' below.)

●Features suggestive of an underlying monogenic etiology of SRNS including:

•History of family members with NS or unexplained proteinuria/hematuria.

•History of consanguinity.

•Presentation prior to age three months (concerning for congenital NS).

•History/physical examination demonstrating extrarenal findings associated with known monogenic causes of SRNS (table 1 and table 2).

Screening for infection — Although uncommon, pediatric SRNS may be secondary to infectious diseases such as cytomegalovirus, human immunodeficiency virus (HIV), hepatitis B, malaria, parvovirus B19, syphilis, and subclinical tuberculosis. If not already done, we recommend testing for hepatitis B, hepatitis C, syphilis, HIV, and tuberculosis in endemic areas for patients with SRNS, as many will be candidates for intensive immunosuppression with calcineurin inhibitors (CNIs) and will benefit from treatment of the underlying infection [4].

Genetic testing — Identification of a genetic etiology for SRNS may be beneficial for determining the optimal approach to treatment (algorithm 1).

Patient selection — We suggest performing genetic testing for all children with SRNS (if such testing is available) based on the 2020 guidelines from the International Pediatric Nephrology Association (IPNA) [4,7]. If genetic testing is not readily available or where cost is an issue, we suggest that genetic screening be prioritized for patients who have a high likelihood of monogenic SRNS based on clinical evaluation (table 1 and table 2) [4,8-10] (see 'History and physical examination' above). Genetic testing is not recommended in patients who initially respond to glucocorticoids and subsequently develop steroid resistance [4].

When indicated, genetic testing should preferably be performed before a kidney biopsy, and biopsy may be delayed if genetic test results will be readily available (ie, within two weeks). The benefits of identifying a monogenic cause of SRNS include gaining information about co-occurring phenotypic manifestations and prognosis. In addition, in some cases, genetic diagnosis will allow patients to avoid a diagnostic kidney biopsy and/or excessive exposure to immunosuppressive agents and may identify nonimmunosuppressive treatment options. Additionally, a genetic diagnosis may offer insight on the risk of SRNS for biological relatives [9-15]. (See 'Long-term outcomes' below.)

Choice of genetic test — The preferred approach to genetic testing is discussed below.

●Targeted gene panel, for most patients – Targeted gene panels using next generation sequencing are the preferred method for genetic testing [4,15,16]. This technology is a rapid and efficient way to identify a disease-causing variant because it tests multiple genes simultaneously. A laboratory directory lists commercial and academic laboratories throughout the world that offer molecular genetic testing at the Genetic Testing Registry website, which offers multiple gene panels related to NS.

We typically do not pursue whole exome sequencing as the initial genetic test. While whole exome sequencing may identify variants in genes not covered by gene panel testing [17], it is more likely to identify variants of uncertain clinical significance or incidental findings, which present ethical concerns [18].

●Candidate gene testing, for those with suspected genetic syndrome – We suggest targeted single gene analysis if the clinical presentation is suggestive of a specific monogenic form of SRNS, if there is a family member with a known pathogenic variant of SRNS with the same phenotype, or if a gene panel is not available [4,10,14,19]. The clinical features below can guide this testing (table 1 and table 2).

•Age of presentation – For younger patients (age <3 months), we begin screening for biallelic pathogenic variants in NPHS1 followed by testing for NPHS2 [20]. (See "Congenital nephrotic syndrome".)

•Extrarenal manifestations – In patients with phenotypic features characteristic of known genetic syndromes, prioritize testing for the compatible gene variant(s) (eg, LAMB2 screening for patients with SRNS and ocular abnormalities and WT1 screening for those with SRNS and atypical genital development). (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Denys-Drash syndrome'.)

•Histology – Biopsy findings may suggest a monogenic etiology. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis' and 'Kidney biopsy, when etiology remains unclear' below.)

Kidney biopsy, when etiology remains unclear — Kidney biopsy is helpful in situations where the etiology is unclear.

●Approach – We obtain a kidney biopsy if results from the clinical evaluation and genetic testing do not reveal an etiology for SRNS or if results from genetic testing are delayed beyond a few weeks after the diagnosis, per IPNA clinical practice guidelines [4]. Tissue histology from kidney biopsy may have diagnostic and prognostic utility for some patients with SRNS. However, given that biopsy does not provide diagnostic or prognostic information in the majority of cases, treatment should not be delayed in settings where biopsy is not readily available (algorithm 1).

●Is there diagnostic utility in performing a biopsy? – Most genetic causes of SRNS have histologic features that are not distinguishable from nongenetic disease (primarily focal segmental glomerulosclerosis [FSGS]) [10,17]. As a result, a kidney biopsy often does not identify the underlying cause of SRNS and cannot distinguish between genetic and nongenetic forms of SRNS.

In a small number of cases, however, biopsy can identify histologic findings that are commonly associated with monogenic forms of SRNS. If genetic testing results are not available, biopsy results may therefore allow for more targeted testing of single genes. The following histologic features can be suggestive of a specific underlying gene defect:

•Diffuse mesangial sclerosis (DMS) (picture 1A-B) may be caused by variants in the WT1, LAMB2, or PLCE1 genes. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

•Tubulointerstitial changes (picture 2A-B) include irregular microcystic dilatation of proximal tubules and are typically seen in patients with NPHS1 variants. However, dilation of the proximal tubules may be observed in other cases of congenital NS secondary to heavy proteinuria. (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)

•Secondary causes of NS may be identified on biopsy. As an example, membranous nephropathy due to infection (eg, hepatitis B or C) may be first identified on biopsy if testing for these pathogens was not completed earlier in the patient's evaluation. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Secondary nephrotic syndrome' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Overview of therapy' and "Lupus nephritis: Diagnosis and classification", section on 'Characteristic histopathologic findings'.)

●Prognostic information from biopsy, based on histology – Kidney biopsy can identify histological diagnoses associated with greater likelihood of progression to chronic kidney disease (CKD)/kidney failure in patients with SRNS. In a case series of 91 children with SRNS from Germany, 41 patients did not have a pathogenic variant of any of the analyzed genes (NPHS1, NPHS2, WT1, LAMB2, TRPC6, and PLCE1) [9]. Kidney biopsies were performed in 40 of these 41 patients and showed the following histologic diagnoses:

•FSGS (n = 28)

•Minimal change disease (n = 10)

•DMS (n = 1)

•Mesangial proliferation (n = 1)

Children with FSGS have a higher risk of kidney failure compared with those with minimal change disease [21,22]. In the data from the PodoNet Registry, the five-year kidney failure-free survival rate was 92 percent for patients with minimal change disease and 69 percent for those with FSGS [21].

Further details about the management of several specific histologic diagnoses are discussed separately:

•(See "Minimal change disease: Treatment in adults", section on 'Glucocorticoid-resistant MCD'.)

•(See "Membranoproliferative glomerulonephritis: Treatment and prognosis".)

•(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

•(See "Membranous nephropathy: Treatment and prognosis".)

•(See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

COMPONENTS OF INITIAL TREATMENT

Calcineurin inhibitors for most patients

Rationale — For most pediatric patients, we suggest adding a calcineurin inhibitor (CNI) such as tacrolimus or cyclosporine to prednisone, an approach called "intensified immunosuppression" [4]. Tapering prednisone is discussed below. (See 'Tapering glucocorticoids' below.)

When possible, the decision to start CNI treatment should be based on results of genetic testing and the patient's clinical characteristics. When genetic testing is delayed or not available and clinical assessment does not suggest a monogenic cause, we typically initiate CNI therapy and modify treatment based on genetic testing when it returns or based on response (algorithm 1).

There are several important patient groups in whom we do not use CNIs for the treatment of SRNS. These include:

●Children with congenital NS, diffuse mesangial sclerosis (DMS) on biopsy

●Those with severely impaired kidney function (glomerular filtration rate [GFR] <30 mL/min per 1.73 m2), and

●Those with suspected or confirmed monogenic SRNS caused by variants in NPHS1/NPHS2, SMARCAL1, or WT1, or in genes involved in the coenzyme Q10 (CoQ10) biosynthetic pathway (see 'Exceptions to use of calcineurin inhibitors' below)

CNIs reduce protein excretion and the risk of complications associated with nephrosis while preserving kidney function. CNIs are most likely to be effective in those without an identified monogenic cause of SRNS, with a response rate approaching 80 percent [8].

For patients without nongenetic causes of SRNS, immunosuppressive therapy with CNIs often induces remission based on limited evidence from observational studies [2,8,23-27] and small randomized trials (most of which involved cyclosporine and did not report genetic testing) [28-31]. A 2019 meta-analysis found that cyclosporine increased the number of children who achieved complete or partial remission (four studies, 74 participants; relative risk [RR] 3.15, 95% CI 1.04-9.57) by six months compared with placebo or no treatment, though it did not affect progression to kidney failure [28,32].

In general, individuals with genetic SRNS are less likely to respond to CNIs, but responses vary based on the causative gene. [8,9,21,33-35]. Up to 20 percent of patients with monogenic SRNS have a partial or complete response based on limited evidence from two overlapping case series [7,35]. As a result, we believe a trial of CNIs is reasonable for many monogenic forms of SRNS.

Choice of agent and dosing — Counseling prior to initiating CNI treatment should address the potential benefits of CNIs while balancing potential adverse effects, including risk of nephrotoxicity and infection. Whenever possible, CNIs should be administered by a clinician with expertise in caring for children with SRNS, with close monitoring of kidney function. (See 'Recommended monitoring' below.)

Initial treatment regimens with CNIs include either of the following:

●Cyclosporine – Cyclosporine is initiated at a daily dose of 3 to 5 mg/kg/day (maximum 250 mg) divided every 12 hours. The dose is adjusted to achieve a target trough concentration of 80 to 120 ng/mL. It should not be given to patients with impaired kidney function, defined as an estimated GFR <30 mL/min/1.73 m2.

●Tacrolimus – Tacrolimus is initiated at a daily dose of 0.10 to 0.20 mg/kg/day (maximum 5 mg/day) divided every 12 hours. The dose is adjusted to achieve a target trough concentration between 4 and 8 ng/mL.

We initially give CNIs in combination with prednisone; if patients experience a full remission, gradually taper the prednisone [4]. (See 'Tapering glucocorticoids' below.)

We adjust CNI dose based on response and additional clinical information, such as a monogenic cause of SRNS that is unlikely to respond to CNIs. (See 'Exceptions to use of calcineurin inhibitors' below.)

Limited data suggest that the beneficial effect of tacrolimus is similar to that of cyclosporine [28,36-39]. In small clinical trials that compared tacrolimus with cyclosporine therapy for patients with SRNS, rates of remission between the two agents were similar up to two years [37,40,41]. Some data suggest that tacrolimus has fewer adverse effects compared with cyclosporine, including fewer cosmetic side effects and a lower blood cholesterol level [41]. However, tacrolimus is associated with greater risk of nephrotoxicity. Both agents require similar monitoring with serial measurements of serum creatinine (SCr) and periodic kidney biopsy to detect evidence of kidney interstitial fibrosis. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Exceptions to use of calcineurin inhibitors — We do not initiate CNIs as a first-line treatment for SRNS in the following patient groups due to poor response rates or high likelihood of toxicity (algorithm 1).

Congenital NS or variants in NPHS1/NPHS2, SMARCAL1, or WT1 — We do not trial CNIs in individuals with SRNS due to NPHS1 or NPHS2 variants due to the very low response rate in these patients (2 of 58 children with these genotypes achieved complete remission in one series) [42,43]. We are also less likely to do a trial of CNIs in individuals with suspected SMARCAL1 or WT1 mutation due to increased risks for adverse effects of immunosuppression (marked risk of infection and risk of tumors, respectively). We avoid CNIs in those with congenital NS (ie, NS onset at age <3 months) because they are very unlikely to respond (0 of 15 children in the case series [42]).

For such patients, we continue prednisone and manage proteinuria and hypertension. Treatment is discussed elsewhere (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome and NPHS2 variants' and "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Denys-Drash syndrome'.)

Severely impaired kidney function — For children with severely impaired kidney function (defined as a GFR <30 mL/min per 1.73 m2), our practice is to avoid CNI therapy because of the potential for nephrotoxicity. Some experts consider use of mycophenolate mofetil (MMF) as an alternative immunosuppressive agent, but we generally do not take this step because these children are unlikely to have significant clinical benefit. Moreover, children with severely impaired kidney function are unlikely to experience the common complications of NS associated with significant proteinuria (eg, edema, hypogammaglobulinemia) because the loss of protein is significantly reduced with such a low GFR. As a result, the potential benefits of MMF treatment for kidney function and symptoms generally do not outweigh the risks. (See 'Alternatives and later line options' below.)

For such patients, we continue prednisone and manage proteinuria and hypertension as below. (See 'Management of proteinuria' below and 'Management of hypertension' below.)

Variants in the CoQ10 biosynthetic pathway — For children with known or suspected variants in genes associated with CoQ10 biosynthesis (COQ8B, COQ6, COQ2, PDSS2) we do not trial CNIs and instead treat with the combination of a renin-angiotensin-aldosterone system (RAAS) inhibitor and CoQ10 supplements. The CoQ10 dose is 5 to 30 mg/kg daily (in three divided doses) for infants and children, 300 to 1500 mg daily for adolescents, and up to 2400 mg daily for adults [44] (see "Mitochondrial myopathies: Treatment", section on 'CoQ10 deficiency'). Limited data from small case series suggest that this treatment is associated with reduced proteinuria and, occasionally, with complete remission [45-49].

Biopsy with diffuse mesangial sclerosis — We do not initiate CNI therapy in patients with DMS on biopsy. These patients are likely to have monogenic forms of SRNS, which are poorly responsive to CNIs [50,51].

For such patients, we continue prednisone and manage proteinuria and hypertension. Further details about treatment in patients with DMS are discussed elsewhere. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

Management of proteinuria — Inhibitors of the RAAS, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are the mainstays of proteinuria management in SRNS, and their use may result in partial remission.

Choice of ACEIs or ARBs, as well as management of related symptoms and complications of NS, are discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)

Patients being treated with calcineurin inhibitors — The optimal timing for initiating ACEIs or ARBs in relation to intensive immunosuppression using CNIs remains controversial. In patients with hypertension, we start ACEIs or ARBs as soon as hypertension is diagnosed.

However, in the absence of hypertension, we initiate the CNI first and then add an RAAS inhibitor after approximately three or four months if the patient has not achieved complete remission on the CNI. We use this sequential strategy because of the increased risk of nephrotoxicity when CNIs and RAAS inhibitors are used concurrently [52]; we can then identify which drug is responsible for any responses or complications (particularly hyperkalemia or significant increase in SCr). For patients who do not respond to the trial of CNIs, RAAS therapy is continued, directed at decreasing proteinuria.

Other experts in the field initiate the RAAS inhibitor and CNI treatment at the same time. The goal of this approach is to reduce proteinuria as quickly as possible and is consistent with the 2020 International Pediatric Nephrology Association (IPNA) practice guidelines [4]. (See "Symptomatic management of nephrotic syndrome in children" and "Complications of nephrotic syndrome in children" and 'Evaluation for etiology' above and 'Possible etiologies' above.)

Patients not being treated with calcineurin inhibitors — In patients for whom CNIs are not initiated, we initiate RAAS inhibitor therapy as soon as SRNS is diagnosed, even if the patient is normotensive. RAAS inhibition slows the progression of chronic kidney disease (CKD).

Antiproteinuric therapy is particularly important for patients with an identified monogenic cause of SRNS. In an international registry study, treatment of children with monogenic SRNS with RAAS inhibitors for six months was associated with complete remission in 2 of 27 (7.4 percent) and partial remission in another 9 of 27 (33 percent), but 6 of 27 (22 percent) progressed to kidney failure by three years [5].

Management of hypertension — For children with CKD including NS, aggressive blood pressure (BP) control slows the progression of CKD. Hypertension is more commonly seen in patients with SRNS than in those with steroid-sensitive disease [3]. BP goals for pediatric patients with NS are systolic and diastolic BPs of <90th percentile for age, sex, and height based on office BP measurements and, in adolescents (≥13 years of age), a target BP of ≤120/80 mmHg (calculator 1) (table 3). Hypertension is defined as systolic and diastolic BP greater than the targeted goal on three occasions. If ambulatory BP monitoring is available, the targeted BP goal is a mean arterial BP <50th percentile based on 24-hour monitoring.

BP management consists of:

●Nonpharmacologic measures – This includes measures to maintain a healthy weight; a regular aerobic exercise regimen (ie, >30 minutes of at least moderate exercise at least five days per week); dietary measures (eg, diet rich in fruit/vegetables, reduced fat and salt intake); avoidance of excessive consumption of alcohol, caffeine, and energy drinks; and avoidance of smoke exposure.

●Pharmacologic therapy – For children with hypertension despite nonpharmacologic measures, we suggest initiating pharmacologic therapy using ACEIs or ARBs rather than other antihypertensive agents as they provide the additional benefit of reducing proteinuria.

Hypertension and its management in children with CKD are discussed in greater detail separately. (See "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

MONITORING AND ADJUSTMENT OF TREATMENT

Recommended monitoring — For all patients with SRNS, we monitor the following:

●Kidney function – For patients with SRNS (regardless of calcineurin inhibitor [CNI] treatment), we initially measure serum creatinine (SCr) every three months; if stable, testing is performed every six months. We monitor kidney function because of high risk of progression to chronic kidney disease (CKD) among children with SRNS [53]. Nephrotoxicity is a significant adverse effect of prolonged CNI therapy and may be exacerbated with the concomitant use of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) [52]. We stop CNI therapy in patients who develop CKD stages 4 to 5. However, CNI therapy may be stopped earlier if a genetic variant that is poorly responsive to CNIs is identified, if nephrotoxicity develops, or in the absence of at least partial remission.

●Proteinuria – For patients with SRNS, regardless of CNI treatment, we monitor urine protein-to-creatinine ratio (UPCR) from a morning urine sample monthly. For patients with SRNS who continue to have persistent proteinuria (≥20mg/mmol of creatinine), we recommend reducing protein excretion with initiation or up-titration of a renin-angiotensin-aldosterone system (RAAS) inhibitor (see 'Patients being treated with calcineurin inhibitors' above). This recommendation is based on data from clinical trials that showed RAAS inhibition improved kidney survival in adults with proteinuria, who achieved a 50 percent or greater reduction in baseline proteinuria, as well as pediatric data that showed RAAS inhibition reduced protein excretion [54-57]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management", section on 'Reduction of proteinuria'.)

Special considerations for those on calcineurin inhibitors — The goal of intensified immunosuppressive therapy with CNIs is to induce remission; patients who achieve complete remission are unlikely to progress to kidney failure. For patients who respond to CNI therapy, most will do so within three months. Many patients who respond to CNIs require prolonged treatment to avoid relapse [58], which can cause irreversible kidney interstitial fibrosis.

A kidney biopsy is recommended to assess for kidney interstitial fibrosis if there is an unexpected rise in SCr in the setting of prolonged partial remission. The results may inform a decision regarding changing from CNIs to less nephrotoxic alternatives [52,59]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Therapy is adjusted based on the response as follows:

●Complete remission – For patients who enter remission with CNI therapy, prednisone is tapered and discontinued after six months of sustained complete remission. (See 'Tapering glucocorticoids' below.)

If the remission continues, CNIs are tapered to a minimum effective dose for 12 to 15 months and then gradually tapered off over approximately three months, as tolerated [60].

●Partial remission – For patients with a partial response, CNIs and prednisone doses are reduced to the lowest level needed to maintain partial remission. We generally taper glucocorticoids first to ensure ongoing improvement in proteinuria when steroids are discontinued. (See 'Definitions' above.)

In patients in partial remission, the benefits of CNI continuation may not be justified because of nephrotoxicity. For these patients, it may be useful to perform a follow-up kidney biopsy to detect the development of interstitial fibrosis [61]. The timing of a biopsy should be individualized based on response to CNIs. As an example, in a patient with partial response to CNIs after three months, a biopsy showing evidence of nephrotoxicity may warrant discontinuation of CNIs as the benefit is not outweighed by the risk of CNI-related kidney injury (see "Cyclosporine and tacrolimus nephrotoxicity", section on 'Pathogenesis and pathology'). If nephrotoxicity warrants discontinuation of CNIs, mycophenolate mofetil (MMF) can be used as an alternate therapy. However, MMF is likely to be of limited benefit in patients with little response to CNIs.

●No response – If there is no response after three months, CNI therapy is discontinued, usually while initiating or continuing antiproteinuric treatment. We usually discontinue CNI therapy prior to discontinuing prednisone. Additional options for patients with nongenetic disease include participating in a clinical trial evaluating novel potential therapies or a trial of rituximab [4]. (See 'Alternatives and later line options' below.)

●Relapse – Relapse of SRNS is defined by the recurrence of nephrotic-range proteinuria following either complete or partial remission. In patients who relapse, we restart prednisone at 60mg/m2. If patients achieve remission on prednisone treatment, they are considered to have steroid-sensitive NS and are treated accordingly. (See "Treatment of idiopathic nephrotic syndrome in children".)

If patients do not respond to prednisone, we restart CNIs at the lowest previously effective dose.

Tapering glucocorticoids — We generally continue glucocorticoids while CNIs are initiated and then taper if full remission occurs, typically over the course of approximately six months after remission is achieved.

A sample approach to tapering prednisone after remission (or in patients who are not candidates for CNIs) is based on International Pediatric Nephrology Association (IPNA) guidelines: 40 mg/m2 every other day for four weeks, 30 mg/m2 every other day for four weeks, 20 mg/m2 every other day for four weeks, 10 mg/m2 every other day for eight weeks, and discontinuing thereafter.

In patients who achieve partial remission or are slow responders to CNI therapy, we may continue prednisone for longer than six months and/or taper prednisone more slowly.

In patients who have demonstrated no response to CNIs after three months of treatment, we stop treatment with CNIs and then taper prednisone. In such patients, we may reduce prednisone dose over three months, though we individualize the taper based on patient characteristics. (See "Glucocorticoid withdrawal", section on 'Tapering regimens'.)

ALTERNATIVES AND LATER LINE OPTIONS — 

The following are available options for patients who do not tolerate or experience improvement on treatments discussed above.

●Mycophenolate mofetil – Mycophenolate mofetil (MMF) is a second-line agent for treating children with SRNS because the available evidence regarding its efficacy is limited and inconsistent [60,62-67]. MMF can be used for patients who respond partially to calcineurin inhibitors (CNIs) but require an alternative therapy because of concerns about nephrotoxicity [4,60,64,66]. Some centers use MMF as initial therapy for children with SRNS and severe kidney function impairment (glomerular filtration rate [GFR] <30 mL/min per 1.73 m2) [4]. If MMF is used, the suggested dose is 1200 mg/m2 daily (maximum daily dose 2000 mg/day), with subsequent dose adjustments based on therapeutic drug monitoring, aiming for an area under the curve >50 micrograms*hour/mL [4].

We generally avoid all immunosuppressive therapy including MMF in children with severely impaired kidney function as the benefits of this medication do not outweigh the risks.

●Rituximab – We do not routinely use rituximab for treatment of SRNS due to limited evidence demonstrating its efficacy and safety in this population. Reported adverse effects include infusion-related reactions (hypotension, fever, and rigors), serious infections, and progressive multifocal leukoencephalopathy. One published report described the death of a child with NS due to lung fibrosis [68,69]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Immunomodulatory therapy'.)

Published data consists primarily of case series, which have mixed patient populations, including patients who were initially responsive to glucocorticoids and subsequently developed steroid resistance (late) as well as those with initial steroid resistance. These data were summarized by a systematic review performed before April 2017, which included seven case series and one open-label clinical trial with a total of 226 patients [70]. For the group of patients who were initially resistant to glucocorticoids (n = 165 patients), the rate of complete or partial remission was 42 percent. Of note, in the only clinical trial included, the remission rate was only 19 percent. Serious adverse events occurred in five patients and included agranulocytosis, severe pneumonia due to influenza H1N1 virus, cardiomyopathy, rapid progression to kidney failure, and pancolitis. Other adverse effects included infusion-related fever, abdominal pain, diarrhea, vomiting, skin rash, bronchospasm, tachycardia, and hypertension.

We do not to routinely use rituximab in the treatment of SRNS as evidence does not demonstrate a degree of efficacy that outweighs the potential adverse effects of this drug.

●Combination immunosuppressive therapy – Combination immunosuppressive regimens have been tried in relatively small numbers of patients [60,71-77]. Data are too limited to determine whether these therapies were efficacious and safe. Patients with multidrug resistance are encouraged to participate in clinical trials of various drugs and extracorporeal interventions (eg, plasmapheresis, immunoadsorption) for SRNS. An updated list of active glomerular disease trials is available through NephCure Kidney International.

We do not utilize combination immunosuppressive regimens because the potential limited benefit is outweighed by the significant adverse events associated with these therapeutic agents.

●Alkylating agents – There are limited data showing a beneficial effect of alkylating agents (eg, cyclophosphamide) in children with SRNS. Partial or complete remissions have been reported in 20 to 50 percent of cases following a course of cyclophosphamide, but this is based on small studies; the lower end of the range is similar to the remission rate of nontreated patients or that of those who continue to receive glucocorticoid therapy alone [28,31,78-81].

Because of its low efficacy in SRNS and substantial toxicity, we do not recommend use of alkylating agents in patients with SRNS [82]. Although the 2020 International Pediatric Nephrology Association (IPNA) guidelines suggest that cyclophosphamide (an oral alkylating agent) may be offered to patients when CNIs are not available (ie, in low-resource settings), they also note that cyclophosphamide offered no additional benefit compared with glucocorticoids alone [4].

LONG-TERM OUTCOMES — 

Data are limited regarding long-term outcomes for children with SRNS [8,23,35].

A review of 1354 children with SRNS in the PodoNet Registry described an overall kidney failure-free survival rate of 74 percent (95% CI 71-77 percent) at five years, 58 percent (95% CI 53-61 percent) at 10 years, and 48 percent (95% CI 43-53 percent) at 15 years [21].

Risk factors for kidney failure included:

●Known monogenic variant

●Failure to respond to intensified immunosuppressive therapy

●Histologic diagnosis of diffuse mesangial sclerosis (DMS) or focal segmental glomerulosclerosis (FSGS)

25 percent of patients experienced complete remission of proteinuria, with the highest rates of complete or partial remission associated with treatment with calcineurin inhibitors (CNIs) [21].

Similar results were also seen in an analysis of the United Kingdom National Registry of Rare Kidney Diseases [7]. In this smaller cohort of 271 children with SRNS, patients who had complete remission rarely progressed to kidney failure. Those with monogenic SRNS typically were unresponsive and likely to progress to kidney failure but did not have recurrence following kidney transplantation, whereas nonresponders without an underlying monogenic etiology had poor kidney survival after transplantation and a high post-transplant rate of disease recurrence.

Chronic kidney disease and transplantation are discussed elsewhere. (See "Kidney transplantation in children: General principles" and "Chronic kidney disease in children: Epidemiology, etiology, and course".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nephrotic syndrome in children".)

SUMMARY AND RECOMMENDATIONS

●Definitions – We define steroid-resistant nephrotic syndrome (SRNS) as the persistence of proteinuria after four weeks of daily prednisone therapy at a dose of 60 mg/m2/day (maximum daily dose 60mg/day), followed by two weeks of either continuation of oral prednisone and/or adding three pulses of intravenous methylprednisolone and renin-angiotensin-aldosterone system (RAAS) inhibitors. (See 'Definitions' above.)

●Diagnostic evaluation – Diagnostic evaluation for SRNS includes screening for secondary causes of SRNS (infection, malignancy, or autoimmune disease), genetic testing, and, in some cases, kidney biopsy. (See 'Evaluation for etiology' above.)

•Genetic testing – If possible, all patients with SRNS should have genetic testing for a panel of genetic variants known to cause SRNS as the results can determine the likelihood of responding to intensified immunosuppressive therapy as well as overall prognosis. (See 'Genetic testing' above.)

•Kidney biopsy – If genetic screening is not performed or does not identify a monogenic etiology, or if the results are significantly delayed, patients should have a kidney biopsy where possible. The results may demonstrate secondary causes that are amenable to therapy, inform prognosis, or, rarely, suggest a monogenic etiology. (See 'Kidney biopsy, when etiology remains unclear' above.)

●Treatment

•No monogenic cause of SRNS – For most patients without a monogenic cause of SRNS, we suggest the addition of a calcineurin inhibitor ([CNI] cyclosporine or tacrolimus) and a RAAS inhibitor to prednisone rather than other regimens (Grade 2C) given potential to achieve remission. Patients with severe kidney failure are an exception. The RAAS inhibitor is typically started three to four months after the CNI unless hypertension is present, in which case it is initiated concurrently. (See 'Calcineurin inhibitors for most patients' above and 'Management of proteinuria' above.)

•Monogenic causes of SRNS – For patients with confirmed or suspected congenital NS (age of onset <3 months) or variants in NPHS1/NPHS2, SMARCAL1, or WT1, we suggest RAAS inhibitor therapy alone rather than RAAS inhibitors plus CNIs (Grade 2C). (See 'Congenital NS or variants in NPHS1/NPHS2, SMARCAL1, or WT1' above.)

For patients with variants in the coenzyme Q10 (CoQ10) biosynthetic pathway, we suggest the combination of a RAAS inhibitor and CoQ10 supplements rather than CNIs (Grade 2C). (See 'Variants in the CoQ10 biosynthetic pathway' above.)

For most other forms of monogenic SRNS with adequate kidney function, we suggest use of both a CNI and RAAS inhibitor therapy rather than either component on its own (Grade 2C); the RAAS inhibitor is typically started three to four months after the CNI unless hypertension is present, in which case it is initiated concurrently. (See 'Patients being treated with calcineurin inhibitors' above.)

Decision to initiate CNIs should involve a discussion of the potential to preserve kidney function balanced with adverse effects including nephrotoxicity and infection risk. Kidney function should be closely monitored in patients on CNIs, and the medication should be discontinued in patients who do not respond with remission. (See 'Calcineurin inhibitors for most patients' above.)

•Blood pressure management – In all children with SRNS regardless of etiology, elevated blood pressure (BP) should be aggressively treated to slow the progression of chronic kidney disease (CKD). BP management includes nonpharmacologic measures and possible pharmacologic treatment, preferably with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) (table 3). (See "Chronic kidney disease in children: Complications", section on 'Hypertension' and 'Management of hypertension' above.)

•Prognosis – Approximately one-half of children with SRNS progress to kidney failure within 15 years. Risk factors include a monogenic diagnosis, failure to respond to intensified immunosuppressive therapy, and a histologic diagnosis of diffuse mesangial sclerosis (DMS). (See 'Long-term outcomes' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges William Smoyer, MD, FASN, who contributed to earlier versions of this topic review.

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Topic 117983 Version 30.0

References

1 : Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children.

2 : Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated.

3 : The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children.

4 : IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.

5 : Outcomes of steroid-resistant nephrotic syndrome in children not treated with intensified immunosuppression.

6 : A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.

7 : Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome.

8 : Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome.

9 : Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome.

10 : Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome.

11 : Podocin and nephrotic syndrome: implications for the clinician.

12 : Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome.

13 : Genetic forms of nephrotic syndrome.

14 : Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations.

15 : Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome.

16 : Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations.

17 : Comparison of different genetic testing modalities applied in paediatric patients with steroid-resistant nephrotic syndrome.

18 : Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing.

19 : Genetic testing in steroid-resistant nephrotic syndrome: when and how?

20 : Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

21 : Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

22 : The significance of pure diffuse mesangial proliferation in idiopathic nephrotic syndrome.

23 : Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis.

24 : Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology.

25 : Long-term cyclosporine therapy for pediatric nephrotic syndrome: a clinical and histologic analysis.

26 : Aggressive, long-term cyclosporine therapy for steroid-resistant focal segmental glomerulosclerosis.

27 : Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine given as a single daily dose.

28 : Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

29 : Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial.

30 : A randomized double-blind placebo-controlled trial of cyclosporine in steroid-resistant idiopathic focal segmental glomerulosclerosis in children.

31 : Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie.

32 : Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

33 : Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: superiority of response to corticosteroid therapy over histopathologic patterns.

34 : Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation.

35 : A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

36 : Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children.

37 : Efficacy and safety of tacrolimus versus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial.

38 : Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus.

39 : Experience with tacrolimus in children with steroid-resistant nephrotic syndrome.

40 : Treatment of tacrolimus or cyclosporine A in children with idiopathic nephrotic syndrome.

41 : Efficacy and Safety of Cyclosporine versus Tacrolimus in Steroid and Cyclophosphamide Resistant Nephrotic Syndrome: A Prospective Study.

42 : Calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene mutations: a systematic review.

43 : Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

44 : The efficacy of coenzyme Q10 treatment in alleviating the symptoms of primary coenzyme Q10 deficiency: A systematic review.

45 : Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency.

46 : CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy-a case report.

47 : Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment.

48 : Primary coenzyme Q10 nephropathy, a potentially treatable form of steroid-resistant nephrotic syndrome.

49 : Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency.

50 : Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations.

51 : Systematic Review of Clinical Characteristics and Genotype-Phenotype Correlation in LAMB2-Associated Disease.

52 : Risk factors for cyclosporin A nephrotoxicity in children with steroid-dependant nephrotic syndrome.

53 : Long-Term Outcomes in Children with Steroid-Resistant Nephrotic Syndrome Treated with Calcineurin Inhibitors.

54 : Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade.

55 : Long-term antiproteinuric and renoprotective efficacy and safety of losartan in children with proteinuria.

56 : Enalapril dosage in steroid-resistant nephrotic syndrome.

57 : Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome.

58 : Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis.

59 : Comparison between pre- and posttreatment renal biopsies in children receiving ciclosporine for idiopathic nephrosis.

60 : Clinical trial of focal segmental glomerulosclerosis in children and young adults.

61 : Calcineurin inhibitors and renal biopsy in children with idiopathic nephrotic syndrome.

62 : Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis.

63 : Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome.

64 : Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome.

65 : Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome.

66 : Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome.

67 : Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome.

68 : Rituximab in steroid-resistant nephrotic syndrome in children: a (false) glimmer of hope?

69 : Fatal pulmonary fibrosis after rituximab administration.

70 : Rituximab in The Management of Pediatric Steroid-Resistant Nephrotic Syndrome: A Systematic Review.

71 : Mycophenolate Mofetil Following Rituximab in Children With Steroid-Resistant Nephrotic Syndrome.

72 : Remission of proteinuria in multidrug-resistant idiopathic nephrotic syndrome following immunoglobulin immunoadsorption.

73 : Novel multidrug therapy for children with cyclosporine-resistant or -intolerant nephrotic syndrome.

74 : Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults.

75 : Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents.

76 : Intravenous methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: a long-term follow-up.

77 : Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome.

78 : Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children.

79 : Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome.

80 : Response to cyclophosphamide in steroid-resistant focal segmental glomerulosclerosis: a reappraisal.

81 : Kidney biopsy prior to cyclophosphamide therapy in primary nephrotic syndrome.

82 : Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO.