Steroid-resistant nephrotic syndrome in children: Management

INTRODUCTION — Most children with idiopathic nephrotic syndrome (NS) have minimal change disease, which is generally responsive to steroid therapy. As a result, the initial treatment for idiopathic NS is empirical steroid therapy and 80 to 90 percent of patients respond to this treatment.

Steroid-resistant NS (SRNS) describes the cases that do not respond to initial steroid therapy. Approximately one-third of these cases are due to single gene variants that affect glomerular podocyte structure and/or function. These monogenic forms of SRNS are poorly responsive to immunosuppressive therapy, and disease progression is rapid. Approximately 50 percent of patients with SRNS will progress to kidney failure [1,2]. Thus, therapeutic decisions in children with SRNS depend in part on 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 "Steroid-resistant nephrotic syndrome in children: Etiology".)

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

●(See "Congenital nephrotic syndrome".)

DEFINITIONS

●Steroid-resistant nephrotic syndrome (SRNS) – SRNS is traditionally defined as the absence of complete remission after four weeks of daily prednisone therapy at a dose of 60 mg/m²/day, though some patients may require additional two weeks of therapy (confirmation period) before being designated as steroid resistant [3,4].

●Confirmation period – For patients who achieve only partial remission after four weeks of prednisone, the subsequent two weeks is known as the confirmation period. This period is used to determine their response to further interventions, such as continuation of oral prednisone and/or pulses of intravenous methylprednisolone and renin-angiotensin-aldosterone system (RAAS) inhibitors [5]. Those who achieve complete remission by six weeks are considered late responders, whereas those who are not in remission by six weeks have SRNS.

●Complete remission – Resolution of proteinuria, defined as a urine protein-to-creatinine ratio of ≤20 mg/mmol (0.2 mg/mg), based on a first morning void or 24-hour collection, or urine dipstick readings of negative or trace protein on three consecutive days.

●Partial remission – A decrease in proteinuria, with a urine protein-to-creatinine ratio of >20 but <200 mg/mmol, based on first morning void or 24-hour urine sample, and serum albumin ≥30 g/L (if measured).

●Relapse – The recurrence of nephrotic-range proteinuria following either complete or partial remission.

OVERVIEW OF MANAGEMENT — Management of SRNS involves:

●Genetic testing – To identify those patients with a monogenic cause of SRNS (table 1). The results inform decisions about immunosuppressive therapy and predict prognosis for disease progression. (See 'Genetic testing' below.)

●Immunosuppressive therapy – Most patients warrant a trial of intensified immunosuppressive therapy using a calcineurin inhibitor (CNI) [4]. The decision depends, in part, on the results of genetic testing because the likelihood of response is greater for children without an identifiable monogenic cause of SRNS (up to 80 percent respond) compared with those with an identified monogenic cause (approximately 20 percent respond) [6].

If immunosuppressive therapy induces complete remission, it reduces the complications associated with NS and preserves kidney function; patients who achieve complete remission are unlikely to progress to kidney failure. These potential benefits should be weighed against the potential adverse effects of CNI, which include nephrotoxicity and infection risk. We generally avoid CNI therapy in those with congenital NS (ie, NS onset at birth or age <3 months) since they are ineffective [6] and in those with certain genotypes due to low likelihood of response and/or increased risks for adverse effects of immunosuppression. (See 'Indications and considerations' below and 'Immunosuppressive therapy' below.)

●Antiproteinuric therapy – For patients who do not respond to the trial of CNI, therapy is directed at decreasing proteinuria using an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), as well as management of related symptoms and complications of NS, which are discussed separately. (See "Symptomatic management of nephrotic syndrome in children" and "Complications of nephrotic syndrome in children" and 'Diagnostic evaluation' below and "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Epidemiology'.)

Because of the complexity of decision-making and the potential for serious adverse effects of immunosuppressive agents, the care of children with SRNS should be supervised by a clinician with expertise in the management of these patients.

DIAGNOSTIC EVALUATION — Diagnostic evaluation, which includes genetic testing and kidney biopsy, is focused on identifying a specific cause of the SRNS when possible. The results inform selection of treatment, further evaluation, prognosis, and genetic counseling.

History and physical examination — A complete history and physical examination is performed to identify factors suggestive of an underlying monogenic etiology, including a history of family members with SRNS, history of consanguinity, and evidence on physical examination of any extrarenal or syndromic findings [4].

Genetic testing — Monogenic causes of SRNS are listed in the table (table 1). (See "Steroid-resistant nephrotic syndrome in children: Etiology".)

Who should be tested — We suggest performing genetic testing for all children with SRNS if such testing is readily available, consistent with a 2020 guideline from the International Pediatric Nephrology Association (IPNA) [4,7]. Genetic testing should preferably be performed before a kidney biopsy, provided that the genetic test results will be readily available (within a few weeks). Genetic testing is not recommended in patients who initially respond to steroids and subsequently develop steroid resistance [4].

Identification of a monogenic cause of SRNS has several potential benefits [8-13]:

●It helps to avoid excessive exposure to immunosuppressive agents and their side effects because children with monogenic disease are less likely to respond.

●It avoids a diagnostic kidney biopsy in some cases.

●If a syndromic form of SRNS is diagnosed, the information helps to guide further evaluation and management of extrarenal manifestations.

●It may identify a form that is amenable to an alternate (nonimmunosuppressive) treatment, ie, variants in the coenzyme Q10 (CoQ10) biosynthetic pathway [14].

●It informs genetic counseling, including prognosis and risk of recurrence post-transplantation. The vast majority of patients with monogenic SRNS eventually progress to kidney failure. However, if they undergo kidney transplant, their risk of disease recurrence after transplant is low. (See 'Long-term outcome' below.)

If genetic testing is not readily available for all patients or where cost is an issue, we suggest that genetic screening be prioritized for patients who have an increased likelihood of an underlying genetic variant such as those with a family history of SRNS or unexplained proteinuria or hematuria, those with a history of familial consanguinity, and all patients with syndromic SRNS (table 2) [4,8,9,15].

By contrast, genetic testing is not indicated for patients with a first episode of idiopathic NS, prior to initiation of steroid therapy. This is because more than 85 percent of children with idiopathic NS respond to steroid therapy and less than 5 percent will have a monogenic form of the disease [10]. Earlier genetic testing is suggested only for selected patients with NS and features that suggest a hereditary cause, such as those with congenital NS (presenting before age three months) or who have syndromic features or a strong family history of NS. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Genetic testing in selected children'.)

Choice of test

●Targeted gene panel – Next-generation sequencing using targeted gene panels is the preferred method for genetic testing [4,16,17]. This technology is a rapid and efficient way to identify a disease-causing variant because it tests multiple genes simultaneously. However, it also has pitfalls and limitations because it is more likely to identify variants of uncertain clinical significance or incidental findings, which present ethical considerations [18]. 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. (See "Steroid-resistant nephrotic syndrome in children: Etiology".)

●Candidate gene testing – If next-generation sequencing is not available, a stepwise screening approach should be used to select a single gene test [9,13]. In addition, if the presentation is suggestive of a specific monogenic form of SRNS, a targeted single gene analysis may be performed [4]. The order of testing should be determined by the likelihood of involvement of a specific gene, as determined by the patient's characteristics (see "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Specific gene variants'):

•Age of presentation – For younger patients, begin screening for biallelic pathogenic variants in NPHS1 (see "Congenital nephrotic syndrome"), followed by testing for NPHS2 [19]. For older children, screening should begin with testing for NPHS2 variants.

•Syndromic features – If syndromic features are present, prioritize testing for the compatible gene variant(s) (eg, LAMB2 screening for patients with ocular abnormalities and WT1 screening for those with atypical genital appearance) (table 2). (See "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Syndromic steroid-resistant nephrotic syndrome'.)

•Histology – Test for WT1, LAMB2, and PLCE1 in patients with a histologic diagnosis of diffuse mesangial sclerosis (DMS). In few cases, the findings of DMS may be associated with mutations in other genes, eg, nuclear pore (NUP) genes. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

Kidney biopsy

●Indications – We concur with the 2020 practice guidelines from the IPNA, which recommend a kidney biopsy in all children diagnosed with SRNS, except for children with [4]:

•An underlying monogenic, familial, or syndromic cause

•A secondary etiology due to an underlying infection or malignancy

Accordingly, genetic testing should generally be performed prior to kidney biopsy when possible. However, if results from genetic testing are delayed beyond a few weeks after the diagnosis of SRNS, a kidney biopsy should be performed to provide guidance during the interim time before genetic test results are available.

●Histology – If performed, the kidney biopsy provides information on the underlying histology. For children with idiopathic NS, kidney biopsy generally demonstrates four different histologic patterns:

•Minimal change disease

•Diffuse mesangial proliferation

•Focal segmental glomerulosclerosis (FSGS)

•DMS

●Implications – Children with FSGS have a higher risk of kidney failure compared with those with minimal change disease [20,21]. 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 [20].

Histologic findings may also be characteristic of specific monogenic variants and help guide genetic testing for a specific gene variant. For example, patients with DMS should be tested for WT1, LAMB2, and PLCE1 gene variants. (See 'Choice of test' above and "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

Kidney biopsy results may also identify a secondary cause of NS such as lupus nephritis or membranous nephropathy that may be amenable to specific therapeutic interventions. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Secondary nephrotic syndrome'.)

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. Candidates for intensified immunosuppressive therapy should have pretreatment testing for hepatitis B, hepatitis C, syphilis, and HIV and, in endemic areas, evaluation for tuberculosis [4].

TREATMENT

Therapeutic options — The pharmacologic options for SRNS include [4]:

●Immunosuppressive therapy – For most patients with SRNS, we proceed to a trial of intensified immunosuppressive therapy, using a calcineurin inhibitor (CNI) [4]. This therapy is most likely to be effective in those without an identified monogenic mutation, with a response rate approaching 80 percent [15]. It is substantially less likely to be effective for children with monogenic forms of SRNS [6,8,15,20,22,23], but a trial is still worthwhile for selected patients because up to 20 percent may respond and a favorable response delays the progression to kidney failure. (See 'Immunosuppressive therapy' below.)

●Nonimmunologic antiproteinuric therapy – Blockade of the renin-angiotensin-aldosterone system (RAAS) with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) decreases proteinuria and may result in partial remission. In addition, RAAS inhibition slows the progression of chronic kidney disease (CKD). (See 'Antiproteinuric therapy' below and "Chronic kidney disease in children: Overview of management", section on 'Reduction of proteinuria'.)

●Coenzyme Q10 (CoQ10) supplements – These are useful only for individuals with pathogenic variants in the CoQ10 biosynthetic pathway (COQ2, COQ6, PDSS2, and COQ8B).

Immunosuppressive therapy

Indications and considerations — The goal of intensified immunosuppressive therapy is to induce remission, thereby reducing protein excretion and the risk of complications associated with nephrosis, and to preserve kidney function. In general, immunosuppressive therapy is most likely to be effective in children with SRNS without an identified monogenic cause [2,8,15,20,24]. The limited available evidence informs our approach, as follows (algorithm 1):

●Nongenetic SRNS or genotype not available – If testing does not identify a monogenic cause of SRNS, the clinical approach depends on the patient's histologic diagnosis. It typically includes intensified immunosuppressive therapy, and subsequent steps depend on the patient's response to therapy (algorithm 1). Although we prefer to have genetic testing results before planning therapy, the discussion below also applies if the genetic testing results are not available or are delayed. For example, in our practice, genetic testing typically takes one or two months, so we initiate immunosuppressive therapy while awaiting those results, provided that the histology results suggest that the patient may be responsive (minimal change disease or focal segmental glomerular sclerosis [FSGS] but not diffuse mesangial sclerosis [DMS]) and that kidney function is not severely impaired.

Further details about management of several specific histologic diagnoses are discussed in separate topic reviews:

•(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".) – Includes DMS.

•(See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Secondary nephrotic syndrome'.) – For NS due to systemic lupus erythematosus, immunoglobulin A (IgA) nephropathy, or other causes.

We use CNI therapy for immunosuppression while we taper prednisone therapy [3,4]. (See 'Implementation' below.)

For children with severely impaired kidney function (defined as a glomerular filtration rate [GFR] <30 mL/min per 1.73 m²), our practice is to avoid immunosuppressive therapy. For these children, CNI therapy is contraindicated. Mycophenolate mofetil (MMF) could be used 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. (See 'Efficacy and safety' below and 'Other immunosuppressive agents' below.)

●Monogenic SRNS – Clinical decisions about treatment of monogenic SRNS are more complicated because of a substantially lower likelihood of response to intensified immunosuppressive therapy.

For a few children with an identified monogenic cause of SRNS, we suggest a trial of a CNI (ie, cyclosporine or tacrolimus) because up to 20 percent have a partial or complete response, based on limited evidence from two overlapping case series [6,7]. We make this decision depending on the child's characteristics, using shared decision-making with the child's family. The possibility of a beneficial effect of CNI must be balanced against potential adverse effects, including nephrotoxicity (especially if given in combination with an ACE inhibitor or ARB [25]) and infection risk. (See 'Efficacy and safety' below.)

As examples:

•We are most likely to do a trial of CNI for children with rare variants such as CRB2, especially if the patient achieved partial remission during the initial course of steroids for NS.

•By contrast, we are less likely to do a trial of CNI in individuals with 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 [6]). We are also less likely to do a trial of CNI in individuals with a SMARCAL1 or WT1 mutation due to increased risks for adverse effects of immunosuppression (marked risk of infection and risk of tumors, respectively).

•We avoid CNI in those with congenital NS (ie, NS onset at birth or age <3 months) because they are very unlikely to respond (0 of 15 children in the case series [6]).

•We do not do a trial of CNI for individuals with pathogenic variants in the CoQ10 biosynthetic pathway (COQ2, COQ6, PDSS2, and COQ8B). Instead, we treat with the combination of a 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 [26-28] (see "Mitochondrial disorders: 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 [29-32]. (See "Steroid-resistant nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)

Our suggestion to consider a trial of CNI in selected patients with monogenic SRNS is a deviation from the 2020 guidance from the International Pediatric Nephrology Association (IPNA) [4]. This is because of new evidence from a case series in which some individuals with monogenic SRNS responded to CNI therapy (21.3 percent partial response, 6.3 percent complete response), although some of this effect may have been due to concurrent treatment with an RAAS inhibitor. (See 'Efficacy and safety' below.)

Implementation

●Initial treatment – If the decision is made to initiate CNI therapy, options are:

•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 give CNI in combination with prednisone initially, then gradually taper the prednisone for responders, as described below [4].

●Subsequent adjustments of immunosuppression – For patients who respond to CNI therapy, most will do so within three months. Therapy is adjusted based on the response, as follows:

•Complete remission – For patients who enter remission with CNI therapy, the prednisone is tapered and discontinued after six months of sustained complete remission. If the remission continues, CNI is tapered to a minimal effective dose for 12 to 15 months and then gradually tapered off over approximately three months, as tolerated [33].

•Partial remission – For patients with a partial response, CNI and prednisone doses are reduced to the lowest level needed to maintain partial remission. A repeat kidney biopsy may be indicated to detect potential development of renal interstitial fibrosis (which is irreversible) 18 to 24 months after the initiation of CNI therapy or earlier if there is a persistent deterioration of kidney function [4]. CNI and prednisone are discontinued if there is evidence of nephrotoxicity or may be discontinued after 12 to 24 months to reduce the risk of nephrotoxicity. In these patients with partial response, MMF can be used if the CNI is being discontinued.

•No response – If there is no response after six months, CNI therapy is discontinued, usually while initiating or continuing antiproteinuric treatment. Additional options for patients with nongenetic disease include participating in a clinical trial evaluating novel potential therapies or a trial of rituximab [4]. (See 'Other immunosuppressive agents' below.)

●Follow-up – Many patients who respond to CNI require prolonged treatment to avoid relapse [34], which can cause irreversible renal interstitial fibrosis. In patients who require ongoing cyclosporine therapy to maintain remission, we perform the following tests to monitor for nephrotoxicity:

•Monitor kidney function – Serum creatinine (SCr) concentration is measured initially every three months, and, if stable, the testing is performed every six months.

•Kidney biopsy – A kidney biopsy is recommended if there is an unexpected rise in SCr and prolonged partial remission. The results may inform a decision regarding changing from CNI to less nephrotoxic alternatives [25,35]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Efficacy and safety — The above approach is based on the following evidence:

●Nongenetic SRNS – For patients with nongenetic SRNS, escalating immunosuppressive therapy often induces remission, based on limited evidence from observational studies [2,15,36-40] and small randomized trials (most of which involved cyclosporine and did not report genetic testing) [41-44]. A 2019 meta-analysis found that cyclosporine compared with placebo or no treatment increased the number of children who achieved complete or partial remission (four studies, 74 participants; relative risk 3.15, 95% CI 1.04-9.57) by six months [41]. This meta-analysis did not detect an effect of cyclosporine on progression to kidney failure. Longer-term outcomes are illustrated in an observational multicenter study of 82 such patients, in which cyclosporine induced complete remission in 49 (60 percent) and partial remission in 15 (19 percent) [15]. Although data were not available for all patients, the median time for complete remission was 2.5 months and, for those who did not achieve complete remission, 10.5 months. At a median follow-up of 94 months, kidney function was normal for 72 percent of patients, 25 percent had progressed to kidney failure, and 3 percent developed CKD. In this study, kidney biopsy demonstrated histologic findings consistent with FSGS in 69 percent of patients with SRNS, minimal change disease in 24 percent, and diffuse mesangial proliferation in 1 percent.

Limited data suggest that the beneficial effect of tacrolimus is similar to that of cyclosporine [41,45-48]. In small clinical trials that compared tacrolimus with cyclosporine therapy in patients with SRNS, rates of remission between the two agents were similar up to two years [46,49,50]. Some data suggest that tacrolimus has fewer adverse effects compared with cyclosporine, including less cosmetic side effects and a lower blood cholesterol level [50]. However, tacrolimus is associated with nephrotoxicity and similar monitoring with serial measurements of SCr and periodic kidney biopsy to detect evidence of renal interstitial fibrosis. Further studies are needed to confirm whether tacrolimus offers any other advantages over cyclosporine in the management of patients with SRNS.

●Monogenic SRNS – Children with an identifiable monogenic cause of SRNS are less likely to respond to CNI or other escalating immunosuppressive therapy. As a result, CNI was not recommended for these children in the past [4]. Somewhat more favorable outcomes were reported in a 2023 case series of 141 children with monogenic SRNS, in which treatment with CNI for six months was associated with complete remission in 6.3 percent and partial remission in 21.3 percent [6]. Children with higher baseline albumin level were more likely to respond to therapy, and a favorable response to treatment was associated with a 65 percent lower risk of progressing to kidney failure at two years. In this study, no children with congenital NS achieved even partial remission [6]. These data are consistent with other reports, some of them including the same patients [15,20,51-53]. However, some of the partial remissions reported in these studies may have been related to concurrent treatment with RAAS inhibitors or decreased proteinuria due to progression of CKD. This might explain the appearance of more favorable outcomes compared with the PodoNet registry study, which adjusted for the latter factor [20]. (See 'Long-term outcome' below.)

The partial response to CNI therapy in patients with monogenic forms of SRNS has been attributed, in part, to its nonimmunologic effects [54]. These include antiproteinuric afferent arteriole vasoconstriction and, possibly, stabilization of the actin cytoskeleton in the podocytes and downregulation of TRPC6, a transient receptor potential channel that increases calcium influx in the podocytes.

Nephrotoxicity is a significant adverse effect of prolonged CNI therapy and may be exacerbated with the concomitant use of an ACE inhibitor or ARB [25]. This is a key consideration when making decisions about whether to initiate CNI therapy in children with monogenic SRNS, who are less likely to respond to CNI than those with nongenetic SRNS. If CNI therapy is used, it should be administered by a clinician with expertise in caring for children with SRNS, with close monitoring of kidney function, including measurements of SCr and serial kidney biopsies. (See 'Indications and considerations' above and 'Implementation' above.)

Antiproteinuric therapy — For patients who continue to have persistent proteinuria, we recommend reducing protein excretion with the use of an RAAS inhibitor (ACE inhibitors or ARBs).

Efficacy — This recommendation is based on data from clinical trials that showed RAAS inhibition improved kidney survival in adults with proteinuria who achieve a 50 percent or greater reduction in baseline proteinuria as well as pediatric data that showed RAAS inhibition reduced protein excretion [55-58]. (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'.)

This therapy is particularly important for patients with an identified monogenic cause of SRNS because intensified immunosuppression (eg, CNI) is often ineffective in this population. 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].

Implementation and timing

●Timing

•Patients treated with CNI – For patients who embark on CNI therapy, it remains controversial whether antiproteinuric treatment with RAAS inhibitors (ARBs or ACE inhibitors) should be initiated sequentially or concurrently:

-Sequential therapy – In our practice, we initiate CNI first (if the decision is made to try CNI therapy), 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 CNI and RAAS inhibitors are used concurrently [25] and also so we can identify which drug is responsible for any response or for complications, particularly hyperkalemia or significant increase in SCr.

-Concurrent therapy – 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 IPNA practice guidelines [4].

•No CNI treatment – If CNI is not started (eg, for most patients with monogenic SRNS), we initiate the RAAS inhibitor as soon as SRNS is diagnosed.

●Dose and dose adjustment – Starting doses of ACE inhibitors or ARBs for treatment of proteinuria are similar to those used for treatment of hypertension (table 3). The dose can be advanced to the lowest effective dose to achieve complete remission of proteinuria, using caution because these patients are at risk for hyperkalemia and prerenal acute kidney injury caused by concomitant administration of a CNI or dehydration. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Management approach'.)

●Safety considerations – Female patients of childbearing age must be counseled regarding the teratogenic effects of ACE inhibitors and ARBs prior to initiation of therapy. ACE inhibitors and ARBs should be terminated if hyperkalemia cannot be controlled or the plasma creatinine concentration increases more than 30 percent above the baseline value. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy", section on 'Clinical approach to use of RAAS inhibitors in females of childbearing potential'.)

Blood pressure management — Hypertension is more commonly seen in patients with SRNS than those with steroid-sensitive disease [3]. For children with CKD including NS, aggressive blood pressure (BP) control slows the progression of CKD. In these patients, targeted BP goals are systolic and diastolic BPs of <90^th 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 (table 4). Hypertension is defined as BP greater than the targeted goal on three occasions. If ambulatory BP monitoring is available, the targeted BP goal is a mean arterial BP <50^th percentile based on 24-hour monitoring.

BP management consists of:

●Nonpharmacologic measures – This includes weight reduction for children with overweight, 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 and reduced fat and salt intake); and avoidance of excessive alcohol consumption, caffeine, energy drinks, and smoke exposure.

●Pharmacologic therapy – For children with hypertension despite nonpharmacologic measures, we suggest initiating pharmacologic therapy, using ACE inhibitors 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'.)

Other immunosuppressive agents

●MMF – Mycophenolate mofetil (MMF) is a second-line agent for treating children with SRNS because the available evidence regarding its efficacy is limited and inconsistent [33,59-64]. MMF be used for patients who respond partially to CNI but require an alternative therapy because of concerns about nephrotoxicity [4,33,61,63]. Some centers use MMF as initial therapy for children with SRNS and severe kidney function impairment (GFR <30 mL/min per 1.73 m²) [4]. However, we generally avoid all immunosuppressive therapy in children with severely impaired kidney function because their low GFR protects them from complications of nephrosis. 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].

●Rituximab – Rituximab is a second-line agent for treating children with 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 [65,66]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Immunomodulatory therapy'.)

Published data continue to accumulate but are primarily based on case series, which have mixed patient populations, including patients who were initially responsive to steroids 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 [67]. For the group of patients who were initially resistant to steroids (n = 165 patients), the rate of complete or partial remission was 42 percent. Of note, in the only included clinical trial, 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.

These data confirm our recommendation not to routinely use rituximab in the treatment of SRNS until further evidence demonstrates 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 [33,68-74]. Data are too limited to determine whether these therapies were efficacious and safe. As a result, we do not recommend these regimens, because the potential limited benefit is outweighed by the significant adverse events associated with these therapeutic agents. However, 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.

●Alkylating agents – There are no data showing a beneficial effect of alkylating agents 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 steroid therapy alone [41,44,75-78]. Because of its low efficacy in SRNS and substantial toxicity, we do not recommend use of alkylating agents in patients with SRNS [79]. Although the 2020 IPNA guidelines suggest that cyclophosphamide (an oral alkylating agent) may be offered to patients when CNI is not available (ie, in low-resource settings), they also note that cyclophosphamide offered no additional benefit compared with steroids alone [4].

LONG-TERM OUTCOME — Data are limited regarding long-term outcome for children with SRNS. The best available long-term data are from a review of 1354 children with SRNS in the PodoNet Registry [20]. The overall kidney failure-free survival rates were 74 percent (95% CI 71-77 percent) at 5 years, 58 percent (95% CI 53-61 percent) at 10 years, and 48 percent (95% CI 43-53 percent) at 15 years. 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)

Complete remission of proteinuria was observed in 25 percent of patients, with the highest rates of complete or partial remission associated with calcineurin inhibitors (CNIs) [20]. Of the 74 patients diagnosed with a genetic variant who received intensified immunosuppressive therapy, only two responded transiently to immunosuppressive therapy (cyclosporine), one of whom progressed to kidney failure within five years. A somewhat higher remission rate was reported in a separate study (21.3 percent partial response, 6.3 percent complete response), but this may have been related to concurrent treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors or shorter follow-up or because it did not distinguish between true partial remission and decreased proteinuria due to progression of chronic kidney disease (CKD) [6].

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 a 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.

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 – Steroid-resistant nephrotic syndrome (SRNS) is defined as the absence of remission after four weeks of initial daily prednisone therapy at a dose of 60 mg/m²/day. (See 'Definitions' above.)

●Diagnostic evaluation – Diagnostic evaluation for SRNS generally includes genetic testing, kidney biopsy, and screening for secondary causes of SRNS (infection, malignancy, or autoimmune disease). The results inform selection of treatment, further evaluation, prognosis, and genetic counseling. (See 'Diagnostic evaluation' above.)

•Genetic testing – All patients with SRNS should have genetic testing for a panel of genetic variants known to cause SRNS (table 1). The results help to determine the likelihood of responding to intensified immunosuppressive therapy, as well as overall prognosis. A less preferred approach is to prioritize genetic testing for patients with features suggesting monogenic SRNS, including those with congenital or syndromic SRNS (table 2), a family history of SRNS or unexplained proteinuria, or consanguinity. (See 'Genetic testing' above.)

•Kidney biopsy – If genetic screening is not performed or does not identify a monogenic etiology, or the results are delayed beyond two weeks, most patients should have a kidney biopsy to determine the underlying histology. A biopsy may not be needed in patients with an identified monogenic or secondary cause. The results of a kidney biopsy may demonstrate secondary causes that are amenable to therapy, or idiopathic NS (ie, minimal change disease, diffuse mesangial proliferation, or focal segmental sclerosis [FSGS]). If one of these histologic patterns is identified, we suggest genetic testing, if not already done. (See 'Kidney biopsy' above.)

●Treatment

•Immunosuppressive therapy – Decisions about intensified immunosuppressive therapy depend, in part, on results of genetic testing:

-Nongenetic SRNS – For patients with SRNS and no identifiable monogenic cause, we suggest a trial of intensified immunosuppressive therapy with a calcineurin inhibitor (CNI; ie, cyclosporine or tacrolimus) rather than no immunosuppressive therapy (Grade 2B) and rather than other immunosuppressive agents (Grade 2C). If immunosuppressive therapy is successful, it reduces the complications associated with NS and preserves kidney function. These potential benefits should be weighed against the potential adverse effects of CNI, which include nephrotoxicity and infection risk. Most children without an identifiable monogenic cause of SRNS respond to CNI (up to 80 percent). (See 'Immunosuppressive therapy' above and 'Efficacy and safety' above.)

-Genetic SRNS – For most patients with SRNS with a monogenic cause, we suggest against intensified immunosuppressive therapy (Grade 2C). For most monogenic causes, response rates to CNI are low and intensified immunosuppression is associated with increased risk for adverse effects. However, decisions for this group are complex and depend on the genotype. A rare exception is the patient with a CRB2 variant, for whom we may trial CNI therapy, especially if the patient achieved partial remission during the initial course of steroids for NS. We do not use CNI therapy for children with congenital NS (age of onset <3 months), severely impaired kidney function, or biallelic pathogenic variants in the coenzyme Q10 (CoQ10) biosynthetic pathway. (See 'Immunosuppressive therapy' above.)

•Nonimmunologic antiproteinuric therapy – For patients who are not candidates for CNI therapy (ie, most patients with a monogenic cause of SRNS), and for those treated with CNI therapy who do not achieve complete remission after approximately three or four months, we suggest adding a renin-angiotensin-aldosterone system (RAAS) inhibitor (either an angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor blocker [ARB]) (Grade 2C). Blockade of the RAAS system decreases proteinuria and may result in partial remission. Practice varies regarding the sequencing of these therapies. Our practice is to add the RAAS inhibitor after the CNI in an effort to reduce the risk of additive nephrotoxic effects. Other experts initiate both therapies simultaneously in an attempt to increase the likelihood of remission. (See 'Antiproteinuric therapy' above.)

•CoQ10 therapy – For individuals with biallelic pathogenic variants in the CoQ10 biosynthetic pathway, we suggest treatment with CoQ10 supplements and an RAAS inhibitor, rather than immunosuppressive therapy (Grade 2C). (See 'Indications and considerations' above.)

•Blood pressure (BP) management – In all children with SRNS, elevated BP should be aggressively treated as aggressive BP control slows the progression of chronic kidney disease (CKD). BP management includes nonpharmacologic measures and pharmacologic treatment. If antihypertensive therapy is necessary, ACE inhibitors or ARBs are generally the preferred agents since they reduce proteinuria. BP targets are summarized in the table (table 4). BP management in children with CKD is discussed in detail separately. (See "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

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

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