INTRODUCTION — The majority of children who present with idiopathic nephrotic syndrome (NS) have minimal change disease (MCD), which is generally responsive to steroid therapy. As a result, empirical steroid therapy is given to most children who present with idiopathic NS.
However, approximately 10 to 20 percent of patients fail to respond to initial steroid treatment. Approximately one-third of steroid-resistant cases are due to single gene mutations that affect glomerular podocyte structure and/or function. Patients with genetic forms of steroid-resistant nephrotic syndrome (SRNS) are usually unresponsive to immunosuppressive therapy, disease progression is rapid, and the risk of disease recurrence is low. Thus, therapeutic decisions in children with SRNS are based on the underlying etiology.
The evaluation and management of children with idiopathic SRNS will be reviewed here. The etiology of SRNS is discussed separately, as is the initial management of NS. Congenital and infantile NS are also discussed elsewhere. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology" and "Treatment of idiopathic nephrotic syndrome in children" and "Congenital and infantile nephrotic syndrome".)
DEFINITION
●Steroid-resistant nephrotic syndrome (SRNS) is defined as NS resistant to steroid therapy, defined by the absence of complete remission after four weeks of daily prednisone therapy at a dose of 60 mg/m2 per day [1,2].
●Complete remission is resolution of proteinuria defined as a urine protein to creatinine ratio (UPCR) based on a first morning void or 24-hour collection of ≤20 mg/mmol (0.2 mg/mg) or urine dipstick readings of negative or trace protein on three consecutive days.
●Partial remission is a decrease in proteinuria with an UPCR based on first morning void or 24-hour urine sample of >20 but <200 mg/mmol and, if available, serum albumin ≥30 g/L.
●Relapse is the recurrence of nephrotic-range proteinuria following either complete or partial remission.
MANAGEMENT APPROACH AND GOALS — Our management approach that is outlined in the next sections concurs with the 2020 International Pediatric Nephrology Association practice guidelines (algorithm 1) [2]. Approximately 50 percent of patients with SRNS will progress to kidney failure (previously referred to as end-stage kidney disease [ESKD]) [3,4]. The initial management goal is to determine if complete remission is achievable by administering additional immunosuppressive therapy. Remission reduces the complications associated with NS and preserves kidney function, as patients with complete remission are unlikely to progress to kidney failure (see 'Long-term outcome' below). However, additional immunosuppressive therapy given to patients unlikely to respond will unnecessarily expose them to the serious adverse effects of these agents. As a result, our management begins with identifying patients who are unlikely to respond to additional immunosuppressive therapy, including those with genetic causes of SRNS, who comprise approximately one-third of children with SRNS [2,5-8].
●For patients who are unlikely to respond to additional immunosuppressive therapy, these agents are not administered, as they are unlikely to be beneficial, and they have known serious adverse effects. Therapy is directed at decreasing proteinuria using pharmacologic agents and management of related symptoms and complications of NS, which are discussed separately. (See 'Patients with genetic SRNS' below and "Symptomatic management of nephrotic syndrome in children" and "Complications of nephrotic syndrome in children" and 'Diagnostic evaluation' below and "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Epidemiology'.)
●For patients who do not have genetic SRNS, additional immunosuppressive therapy is provided as these patients are more likely to respond with complete or partial remission. (See 'Patients with nongenetic disease' below.)
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 patients who are unlikely to respond to immunosuppressive therapy. Therapeutic decisions are based on whether the cause of NS is due to a genetic etiology because children with genetic forms of SRNS generally respond poorly to immunosuppressive therapy and are likely to progress to kidney failure.
History and physical examination — A complete history and physical examination is performed to identify factors suggestive of an underlying genetic etiology. This would include a history of family members with SRNS, history of consanguinity, and evidence on physical exam of any extrarenal or syndromic findings [2].
Genetic testing
Who should be tested — We concur with the 2020 International Pediatric Nephrology Association (IPNA) guidelines that suggest genetic testing should be performed in all patients with SRNS, if available, as patients with genetic disease generally do not respond to immunosuppressive therapy [2,8]. Identifying those patients with underlying monogenic SRNS is important, in order to avoid unnecessary exposure to immunosuppressive agents and their side effects, and in some cases a potentially unnecessary diagnostic kidney biopsy [9-14] (see 'Patients with genetic SRNS' below). Moreover, it may uncover genetic forms of SRNS that are amenable to nonimmunosuppressive treatment, such as mutations in the coenzyme Q10 (CoQ10) biosynthetic pathway [15], as well as confirm the diagnosis for syndromic SRNS. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)
However, we recognize that genetic testing may not be available for all patients in every clinical setting.
●We suggest performing genetic testing for all patients with SRNS whenever genetic testing is readily available. Genetic testing should be performed before a kidney biopsy is considered provided the results will be readily available (within a few weeks).
●For settings in which genetic testing is not readily available for all patients or where cost is an issue, we suggest that genetic screening is prioritized for patients who have an increased likelihood of an underlying genetic mutation such as those with a family history of SRNS, whose parents are consanguineous, and all patients with syndromic SRNS (table 1) [2,7,9,10].
●We suggest not to perform genetic testing for all children with the first episode of idiopathic NS, prior to initiation of steroid therapy. Although genetic testing has been proposed for all children with NS to avoid unnecessary exposure to steroid therapy [5], less than 5 percent of cases with NS will have a genetic basis for idiopathic pediatric NS [11] and more than 85 percent of children with idiopathic NS respond to steroid therapy. As a result, genetic testing is not cost effective in this population and is not recommended.
Choice of test — Next-generation sequencing (exome sequencing) using targeted gene panels is the preferred method for genetic testing [2,16,17]. This approach is more likely to identify a disease-causing mutation. However, although more rapid and efficient, these techniques have pitfalls and limitations, mostly related to variant interpretation difficulties and ethical considerations related to incidental findings [18]. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology".)
If next-generation sequencing is not available, a stepwise screening approach should be used to select a single gene test [10,14]. In addition, if the presentation is suggestive of a specific monogenic form of SRNS, a targeted single gene analysis may be performed [2]. The order of testing should be determined by the likelihood of involvement of a specific gene. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Genetic mutations'.)
●Age of presentation – For younger patients, screening for mutations for NPHS1 should first be performed (see "Congenital and infantile nephrotic syndrome"), followed by testing for NPHS2 mutations. For older children, screening should begin with testing for NPHS2 mutations.
●Presence of extrarenal abnormalities suggestive of a syndrome due to a specific gene mutation (eg, LAMB2 screening for patients with ocular abnormalities and WT1 screening for those with ambiguous genitalia) (table 1).
●Type of histologic lesions – Testing for WT1 or PLCE1 in patients with a histologic diagnosis of diffuse mesangial sclerosis (DMS).
A laboratory directory is available that lists commercial and academic laboratories throughout the world that offer molecular genetic testing (www.ncbi.nlm.nih.gov/gtr).
Kidney biopsy — We concur with the 2020 practice guidelines from the IPNA that a kidney biopsy should be performed in all children diagnosed with SRNS, except when there is a secondary etiology due to a known infection or malignancy or underlying genetic, familial, or syndromic cause [2]. 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. (See 'Management with delay in genetic testing results' below.)
The kidney biopsy provides information on the underlying histology:
●For children with idiopathic NS, kidney biopsy generally demonstrates three different histologic patterns: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation (DMP). There is a higher risk of kidney failure for patients with FSGS and DMP compared with those with MCD [19,20]. In the data from the PodoNet Registry, the five-year kidney failure-free survival rates were 92 and 69 percent for patients with MCD and FSGS, respectively [19].
Histologic findings may also be characteristic of specific genetic mutations and help guide genetic testing for specific gene mutation. For example, patients with DMS should be tested for WT1 or PLCE1 gene mutations. (See "Congenital and infantile 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 "Etiology, clinical manifestations, and diagnosis 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 (CMV), human immunodeficiency virus (HIV), hepatitis B, malaria, parvovirus B19, syphilis, and subclinical tuberculosis. Prior to additional immunosuppressive therapy, testing for hepatitis B, hepatitis C, syphilis, and HIV, and in endemic areas, evaluation for tuberculosis, should be performed [2].
THERAPY BASED ON RESULTS/AVAILABILITY OF GENETIC TESTING
Therapeutic options — The pharmacologic options for SRNS include (algorithm 1) [2]:
●Nonimmunologic pharmacotherapy directed towards reducing protein excretion – Blockade of the renin-angiotensin-aldosterone (RAAS) system 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 'Nonimmunologic antiproteinuric therapy' below and "Chronic kidney disease in children: Overview of management", section on 'Reduction of proteinuria'.)
●Immunosuppressive therapy directed towards inducing a complete remission – In some cases, there is only a partial remission with a reduction in proteinuria. Immunosuppressive therapy typically has significant adverse effects. Genetic forms of SRNS are particularly refractory to immunosuppressive therapy [6,7,9,19,21], whereas the reported response rate to immunosuppressive therapy for SRNS without a proven genetic mutation is high (approaching 80 percent) [7]. Therefore, the decision to provide further immunosuppressive therapy beyond the initial course of corticosteroids is dependent on the underlying etiology. Specific immunosuppressive agents are discussed below.
●Directed therapy – For patients with mutations in the coenzyme Q10 (CoQ10) biosynthetic pathway, direct therapy with CoQ10 supplementation. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)
Patients with genetic SRNS — In patients with SRNS caused by genetic disorders, we recommend not to administer additional immunosuppressive therapy because it is not effective and has significant adverse effects (algorithm 1) [7,19]. The use of immunosuppressive therapy does not delay the progression to kidney failure for most patients with SRNS due to genetic mutations. Although data are lacking in children, we suggest treating patients with persistent proteinuria with ACE inhibitors or ARBs based on data from clinical trials in adults. (See 'Immunosuppressive therapy' below and 'Nonimmunologic antiproteinuric therapy' below and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
There are reports that some patients with NS mutations may respond, at least partially, to cyclosporine [7,19,22-24]. This may be due to the stabilization of the actin cytoskeleton in the podocytes, such as in cases of SRNS due to WT1 mutations [24,25]. In a systematic review of the literature that identified 178 patients with genetically proven SRNS treated with a calcineurin inhibitor (CNI), three-quarters of the 27 patients with WT1 mutations had either a full response (n = 4) or partial response (n = 14) to CNI therapy and appeared to have reduced risk of kidney failure [24]. As a result, some experts suggest a short trial (two to three months) be given to children with SRNS [24]. (See 'Nonimmunologic effect of calcineurin inhibitors' below.)
As noted above, direct therapy with CoQ10 supplementation for patients with mutations in the CoQ10 biosynthetic pathway can result in reduced proteinuria and, in some individuals, complete remission [26-29]. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Specific gene variants'.)
Patients with nongenetic disease — The optimal approach to idiopathic SRNS not due to a genetic defect is uncertain (algorithm 1). The therapeutic approach for several specific histologic diagnoses is discussed separately. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Minimal change variants' and "Focal segmental glomerulosclerosis: Treatment and prognosis" and "Membranoproliferative glomerulonephritis: Treatment and prognosis" and "Membranous nephropathy: Treatment and prognosis".)
In our practice, we use calcineurin inhibitor (CNI) therapy as the initial immunosuppressive agent while we taper prednisone therapy, which is discontinued after six months in cases of sustained complete remission or later in cases of partial remission [1,2]. However, if the patient has severe impaired kidney function (defined as a glomerular filtration rate [GFR] <30 mL/min per 1.73 m2), CNI therapy is contraindicated. In this setting, if immunosuppression is used, mycophenolate mofetil can be used as an alternative immunosuppressive agent, although we generally do not administer immunosuppressive therapy to a child with severe impaired kidney function, as they are unlikely to have significant clinical benefit, and complications of nephrosis are less likely due to the reduced proteinuria from the low GFR. However, children with this level of impaired kidney function usually no longer exhibit complications (eg, edema, hypogammaglobulinemia) associated with NS as the loss of protein is significantly reduced with such a low GFR. As a result, in our practices, we do not typically offer immunosuppressive therapy to children with SRNS and GFR <30 mL/min per 1.73 m2. (See 'Calcineurin inhibitors' below and 'Mycophenolate mofetil' below.)
Initial CNI therapy options include:
●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.
or
●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.
When CNI therapy is started, it remains controversial whether agents that block RAAS, which decrease proteinuria, should also be initiated as concomitant therapy.
●Some experts in the field, including one of the authors (WS), will use either ACE inhibitors or ARBs to decrease proteinuria when CNI therapy is started. 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 [2].
●Others (including the other authors PN and OGB) prefer to wait to see the response to CNI therapy within three months, as there is a possibility that CNI therapy alone may result in complete remission. Moreover, there is an increased risk of nephrotoxicity when CNI are used in combination with ACE inhibitors/ARBs [30]. After four months, if there is not complete remission, ACE inhibitor or ARB therapy is provided.
For patients who respond, most will do so within three months. Therapy is adjusted based on the response as follows:
●Complete remission – For patients with complete and sustained remission, CNI is tapered to a minimal effective dose for 12 to 15 months, and then gradually tapered off over approximately 3 months, as tolerated [31].
●Partial remission – For patients with a partial response, CNI dosages are reduced to the lowest level that is needed to maintain partial remission. A repeat kidney biopsy should be performed to detect potential development of renal interstitial fibrosis (which is irreversible) 18 to 24 months after the initiation of CNI therapy or earlier if these is a persistent deterioration of kidney function. CNI is 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, mycophenolate can be used if the CNI is being discontinued.
●No response – If there is no response after six months, CNI therapy is discontinued and patients should be encouraged to participate in a clinical trial evaluating novel potential therapies [2]. If this not possible, rituximab may be considered. (See 'Rituximab' below.)
We do not suggest using the following immunosuppressive agents as initial therapy:
●Alkylating agents – Consistent with Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, we do not administer alkylating agents based on evidence that shows no additional benefit over placebo therapy and a poorer response rate compared with CNIs [19,32-35]. 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 to steroids alone [2].
●Mycophenolate mofetil – We suggest not to use mycophenolate mofetil (MMF) as initial routine therapy, because there remains a paucity of data showing that MMF is effective or safe in the treatment of children with SRNS. We use MMF for patients in partial remission in whom CNI therapy is discontinued. Others in the field have reported that the combination of MMF with steroid therapy may be beneficial in achieving remission [36].
Some experts suggest that MMF can be used as initial therapy for patients with severe kidney impairment (defined as a GFR <30 mL/min per 1.73 m2) because of the concern of additional nephrotoxicity with CNI therapy [2]. However, in our practices, we do not administer immunosuppressive therapy to a child with severe impaired kidney function as they are unlikely to have significant complications of nephrosis due to the reduced proteinuria from the low GFR.
●Combination therapy – We do not recommend combination therapy of multiple immunosuppressive agents outside the research setting because the potential limited benefit is outweighed by the significant adverse events associated with these therapeutic agents. Patients who fail to respond to CNI therapy are encouraged to participate in clinical trials as further research is needed to determine the optimal approach for managing children with nongenetic SRNS. In the rare circumstance of a patient with SRNA refractory to CNI and steroids who is unable to enroll in a clinical trial, the use of rituximab may be considered [2].
Patients for whom genetic testing is not performed — We strongly urge that genetic testing be performed for all patients with SRNS; however, in the unfortunate setting where genetic testing is not available, several therapeutic options may be considered, as there are no data on optimal treatment (algorithm 1):
●Immunosuppressive therapy using a combination of CNIs (cyclosporine or tacrolimus) and prednisone for six months to induce remission. If there is no response, an attempt should be made to obtain genetic testing for confirmation of the underlying disorder (eg, genetic cause) and change therapy to ACE inhibitors or ARBs. (See 'Calcineurin inhibitors' below.)
●Administration of ACE inhibitors or ARBs to reduce proteinuria. (See 'Renin-angiotensin-aldosterone system inhibition' below.)
Management with delay in genetic testing results — In many centers, there often is a delay in obtaining results of genetic testing, which may be up to two months or more. In cases of significant delay, we suggest similar therapeutic options used for individuals in whom genetic testing is not performed of CNI therapy with or without ACE inhibitors or ARBs, unless there is clinical information making a potential clinical response highly unlikely (ie, familial disease, consanguinity, syndromic SRNS). In those cases in which response to additional immunosuppressive therapy is unlikely, initial therapy consists only of either ACE inhibitors or ARBs administration.
BLOOD PRESSURE MANAGEMENT — Hypertension is more commonly seen in patients with idiopathic SRNS than those with steroid-sensitive disease [1]. For children with chronic kidney disease (CKD) including idiopathic NS, aggressive blood pressure (BP) control slows the progression of CKD. In these patients, targeted BP goals 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. If ambulatory blood pressure monitoring (ABPM) is available, the targeted BP goal is a mean arterial BP <50th percentile based on 24-hour monitoring.
BP management consists of:
●Nonpharmacologic measures that includes weight reduction for children who are 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.
●If pharmacologic therapy is necessary, we suggest use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), 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'.)
SPECIFIC PHARMACOLOGIC INTERVENTIONS
Immunosuppressive therapy — The goal of 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 has not been shown to be effective in children with SRNS due to genetic causes [4,5,7,9,19].
The following immunosuppressive agents have been used to treat SRNS with varying clinical benefit. However, the evidence is generally of poor quality as it is based primarily on observational studies with few randomized controlled trials with the exception of cyclosporine [37].
●Alkylating agents
●Calcineurin inhibitors (CNIs) – Cyclosporine and tacrolimus
●Mycophenolate mofetil (MMF)
●Continuation of steroid therapy for an additional one to two weeks, or three doses of methylprednisolone pulse therapy (1000 mg/1.73 m2 per day)
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 percent of cases following a course of cyclophosphamide, but this is similar to the remission rate of nontreated patients or that of those who continue to receive steroid therapy alone [3,6,33,37,38]. Because of its low efficacy in SRNS and substantial toxicity, we do not recommend use of alkylating agents in patients with SRNS.
Calcineurin inhibitors
Cyclosporine — The efficacy of cyclosporine in children with SRNS has been confirmed in several reports, including a 2016 systematic review that demonstrated that cyclosporine compared with placebo or no treatment increased the number of children who achieved complete remission (relative risk [RR] 7.66, 95% CI 1.06-55.34) [4,35,37,39-45]. In addition, cyclosporine was more effective than cyclophosphamide in inducing a partial remission in children with SRNS.
The beneficial effect of cyclosporine is dependent on whether the patient has a nongenetic or genetic form of SRNS:
●Nongenetic SRNS – The majority of patients who do not have a genetic form of SRNS appear to respond to cyclosporine. In an observational multicenter study of patients with SRNS, complete remission was observed in 49 (78 percent) and partial remission in 15 (18 percent) of the 82 patients with nongenetic SRNS treated with cyclosporine therapy [7]. Although data were not available for all patients, the median time for complete remission was 2.5 months and for partial remission 10.5 months. At a median follow-up of 94 months, kidney function was normal for 72 percent of patients, 25 percent progressed to kidney failure, and 3 percent developed chronic kidney disease (CKD). In this study, kidney biopsy demonstrated histologic findings consistent with focal segmental glomerular sclerosis (FSGS) in 69 percent of patients with SRNS, minimal change disease (MCD) in 24 percent, and diffuse mesangial proliferation (DMP) in 1 percent.
●Genetic SRNS – There is a poorer response rate to immunosuppression therapy, including cyclosporine for patients with genetic forms of SRNS [4,7,46]. In the above multicenter observational study, only 56 of 131 patients with genetic SRNS were treated with cyclosporine, resulting in a complete remission in 3 percent and partial remission in 16 percent of treated patients [7]. In addition, 66 percent of patients with genetic SRNS progressed to kidney failure. However, a review of the literature of 178 cases suggest a better response of 35 percent (full or partial) for individuals with genetic SRNS and a biopsy that demonstrates minimal change [24]. In this study, patients with variants of WT1 were most likely to respond to CNI compared to those with variants of other genes.
The recommended cyclosporine starting dose is 3 to 5 mg/kg/day (maximum 250 mg) divided every 12 hours aiming to achieve a target trough concentration of 80 to 120 ng/mL [2]. It should not be given to patients with impaired kidney function defined as an estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2.
In patients who are responsive to cyclosporine therapy, there is a high relapse rate following cyclosporine withdrawal. This results in prolonged administration of cyclosporine [46], which increases the risk of irreversible renal interstitial fibrosis. In patients who require ongoing cyclosporine therapy to maintain remission, we perform the following tests to detect 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 – Serial kidney biopsies should be performed to screen for potential nephrotoxicity. Because histologic signs of cyclosporine nephrotoxicity are observed without clinical evidence of kidney function impairment, we routinely perform a kidney biopsy in asymptomatic patients initially prior to the CNI administration and then every 18 to 24 months of therapy or if there is an unexpected rise in SCr [30,47]. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Tacrolimus — Limited data suggest that the beneficial effect of tacrolimus is similar to that of cyclosporine [48-53]. 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 [51,54,55]. There are data that suggest fewer adverse effects with tacrolimus compared with cyclosporine, including less cosmetic side effects and a lower blood cholesterol level [55]. 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.
Mycophenolate mofetil — We do not recommend the routine initial use of MMF in treating children with SRNS, as limited data demonstrate inconsistent results regarding its efficacy [31,56-61]. However, we suggest MMF be used as an alternative to CNI when CNI therapy is discontinued due to concerns of its nephrotoxicity in responsive patients [2,31,58,60]. As noted above, some centers will use MMF as initial therapy for children with SRNS and severe kidney function impairment (GFR <30 mL/min per 1.73 m2) [2].
Rituximab — We do not recommend the routine initial use of rituximab in 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, progressive multifocal leukoencephalopathy, and one published report of death in a child with NS due to lung fibrosis [62,63]. (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 [64]. For the group of patients who were initially resistant to steroids (n = 165 patients), the overall remission rate including both complete and partial remission was 42 percent. Of note, in the only clinical trial, the remission rate was considerably lower at 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 therapy — More aggressive combination regimens have been tried in relatively small numbers of patients [31,36,65-70]. 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 multi-drug 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.
Nonimmunologic antiproteinuric therapy
Renin-angiotensin-aldosterone system inhibition — For patients who continue to have persistent proteinuria, we recommend reducing protein excretion with the use of a renin-angiotensin-aldosterone system (RAAS) inhibitor (angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs]). 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 and pediatric data that showed RAAS inhibition reduced protein excretion [71-74]. (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'.)
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. Female patients of childbearing age must be counseled regarding the teratogenic effects of these agents prior to initiation of therapy. (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'.)
Nonimmunologic effect of calcineurin inhibitors — The partial response to calcineurin therapy in patients with genetic forms of SRNS has been attributed in part to its nonimmunologic effects [21,25,75]. These include antiproteinuric afferent arteriole vasoconstriction and possibly prevention of the degradation of the actin-organizing protein synaptopodin and downregulation of TRPC6, a transient receptor potential channel that increases calcium influx in the podocytes. The combination of angiotensin antagonism therapy (ie, ACE inhibitors or ARBs) and CNI therapy has resulted in partial remission in patients with SRNS and is commonly used in patients who have been refractory to other immunosuppressive therapy or in those with SRNS due to genetic disorders.
However, nephrotoxicity is a significant adverse effect of prolonged CNI therapy, which may be exacerbated with the concomitant use of an ACE inhibitor or ARB [30]. As a result, we do not recommend the routine use of CNI therapy in patients with SRNS due to genetic mutations. If used, it should be administered by a clinician with expertise in caring for children with SRNS, and monitoring of kidney function is needed, including measurements of serum creatinine and serial kidney biopsies. (See 'Calcineurin inhibitors' above.)
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 [19]. The overall kidney failure-free survival rates were 74 percent (95% CI 71 to 77 percent) at 5 years, 58 percent (95% CI 53 to 61 percent) at 10 years, and 48 percent (95% CI 43 to 53 percent) at 15 years. Risk factors for kidney failure included a known genetic mutation, failure to respond to intensified immunosuppressive therapy (ITT), and a histologic diagnosis of diffuse mesangial proliferation (DMP) followed by 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). Of the 74 patients diagnosed with a genetic mutation who received ITT, only two responded transiently to immunosuppressive therapy (cyclosporine), one of whom progressed to kidney failure within five years.
Similar results were also seen in an analysis of the United Kingdom National Registry of Rare Kidney Diseases [8]. 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
●Steroid-resistant nephrotic syndrome (SRNS) is defined as the absence of remission after one month of initial daily prednisone therapy at a dose of 60 mg/m2/day. (See 'Definition' above.)
●The goal of management for children with SRNS is to determine if complete remission with resolution of proteinuria is achievable by administering additional immunosuppressive therapy (algorithm 1). Remission reduces the complications associated with NS, and preserves kidney function as patients with complete remission are unlikely to progress to kidney failure (previously referred to as end-stage kidney disease). However, additional immunosuppressive therapy given to patients unlikely to respond will unnecessarily expose them to the serious adverse effects of these agents. (See 'Management approach and goals' above.)
●Patients with SRNS due to genetic mutations, who account for one-third of children with SRNS, do not typically respond to therapeutic interventions and therefore are unlikely to achieve complete remission. For those patients, further immunosuppressive therapy with significant adverse effects should generally be avoided. (See 'Management approach and goals' above and 'Patients with genetic SRNS' above and "Steroid-resistant idiopathic nephrotic syndrome in children: Etiology", section on 'Epidemiology'.)
●The diagnostic evaluation for children with SRNS is focused on determining the underlying etiology and particularly identifying patients who are unlikely to respond to additional immunosuppressive therapy (algorithm 1). The evaluation includes history and examination, genetic screening, and kidney biopsy. (See 'Diagnostic evaluation' above.)
•We suggest performing genetic screening in all patients with SRNS (Grade 2B). It is important to identify children with genetic forms of SRNS as they respond poorly to additional immunosuppressive therapy and are likely to progress to kidney failure. (See 'Genetic testing' above.)
•If genetic screening is not readily available or cost is a concern, we suggest that gene testing be performed in patients with an increased likelihood of a genetic form of SRNS (Grade 2C). This would include all patients with a family history of SRNS, all congenital cases, patients whose parents are consanguineous, and all patients with syndromic SRNS (table 1).
Genetic testing should be performed before performing a kidney biopsy, as a kidney biopsy may not be necessary in a child who has been diagnosed with SRNS due to a genetic cause.
•If genetic screening is not performed, does not identify a monogenic etiology, or the results are delayed beyond two weeks, we suggest a kidney biopsy to determine the underlying histology (Grade 2C). Exceptions for the performance of a biopsy include those patients in whom there is known secondary cause due to infection or malignancy or those with familial and/or syndromic cases suggesting an underlying genetic defect. The results of a kidney biopsy may demonstrate secondary causes that are amenable to therapy, or idiopathic NS (ie, minimal change disease [MCD], diffuse mesangial proliferation [DMP], or focal segmental sclerosis [FSGS]). (See 'Kidney biopsy' above.)
•If genetic screening is not readily available or cost is a concern and the patient is not likely to have a genetic form of SRNS (eg, no history of familial or syndromic SRNS), we suggest genetic testing if a kidney biopsy demonstrates findings consistent with a diagnosis of idiopathic NS (FSGS. MCD, or DMP) (Grade 2C).
●Therapeutic options include immunosuppressive and nonimmunologic antiproteinuric therapies. (See 'Specific pharmacologic interventions' above.)
•Immunosuppressive therapies that have been used in children with SRNS include alkylating agents, calcineurin inhibitors (CNIs), mycophenolate, and rituximab. Immunosuppressive therapy is not generally effective in children with SRNS due to genetic causes. (See 'Immunosuppressive therapy' above.)
•Angiotensin antagonism by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) effectively reduces protein excretion in patients with SRNS. However, there are no clear data in children demonstrating reduced risk for progression to chronic kidney disease with the use of these agents. (See 'Nonimmunologic antiproteinuric therapy' above.)
●Our management approach is as follows for children with SRNS due to genetic disorders (algorithm 1):
•For patients with SRNS caused by genetic disorders, we recommend no additional immunosuppressive therapy because it is not effective and has significant potential adverse effects (Grade 1B). (See 'Patients with genetic SRNS' above.)
•For patients with mutations in the Coenzyme Q10 (CoQ10) biosynthetic pathway, we suggest direct therapy with CoQ10 supplementation, which may reduce proteinuria and in some cases result in complete remission (Grade 2C).
•In patients with SRNS due to other genetic disorders, we suggest the administration of either an ACE inhibitor or ARB to reduce protein excretion (Grade 2C). (See 'Patients with genetic SRNS' above and 'Nonimmunologic antiproteinuric therapy' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●Optimal treatment of SRNS not due to a genetic disorder remains unclear. (See 'Patients with nongenetic disease' above.)
•For children with nongenetic SRNS who do not have severely impaired kidney function (eg, glomerular filtration rate <30 mL/min per 1.73 m2), we suggest administration of CNI therapy (cyclosporine or tacrolimus) while tapering prednisone therapy (Grade 2C). (See 'Calcineurin inhibitors' above.)
•For children with nongenetic SRNS and severe kidney function impairment, administration of mycophenolate mofetil (MMF) can be used as an alternative due to concerns about nephrotoxicity from CNIs (Grade 2C). However, we do not suggest the initial routine use of MMF for patients, as there is little benefit for those with severe kidney function impairment (Grade 2B). MMF can also be used as an alternative agent for patients who responded to CNI but now have evidence of CNI-associated nephrotoxicity. (See 'Mycophenolate mofetil' above.)
•We suggest the administration of either an ACE inhibitor or ARB to reduce protein excretion (Grade 2C). The timing of administration of ACE inhibitor or ARB varies. Some experts in the field advocate administering an ACE inhibitor or ARB when the diagnosis of SRNS is initially made in conjunction with a CNI to try to optimize proteinuria reduction. Others prefer to see whether the patient responds initially to CNI therapy due to concerns that concomitant use of an angiotensin antagonist may increase CNI nephrotoxicity. (See 'Patients with nongenetic disease' above and 'Calcineurin inhibitors' above.)
•We do not recommend the use of alkylating agents in the treatment of pediatric SRNS as there are no data demonstrating any beneficial effect and there are known serious adverse effects (Grade 1B). (See 'Alkylating agents' above.)
•We do not recommend the initial routine use of rituximab because of the lack of data demonstrating its efficacy and because of its known potential serious side effects (Grade 2B). (See 'Rituximab' above.)
●Management options for patients in whom genetic testing has not been performed or while pending the results of genetic testing include:
•Addition of CNI
•Administration of ACE inhibitors or ARBs to reduce proteinuria
•Concomitant administration of immunosuppressive therapy (CNI and prednisone) and administration of ACE inhibitor or ARB
●In all children with SRNS, elevated blood pressure (BP) should be aggressively treated, as aggressive BP control slows the progression of chronic kidney disease (CKD). BP management includes nonpharmacologic measures (eg, weight reduction for children who are overweight, a regular aerobic exercise regimen, diet rich in fruit/vegetables, and reduced fat and salt intake, and avoidance of excessive alcohol consumption, caffeine, energy drinks, and smoke exposure) and pharmacologic treatment. If pharmacologic therapy is necessary, we recommend that an ACE inhibitor or an ARB be used rather than other classes of antihypertensive agents due to their added ability to reduce proteinuria (Grade 1B). Targeted BP goals are systolic and diastolic BPs of less than 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. (See 'Blood pressure management' above.)
●Long-term data are limited. Risk factors for kidney failure include a genetic diagnosis, failure to respond to intensified immunosuppressive therapy, and a histologic diagnosis of DMP. (See 'Long-term outcome' above.)
