Steroid-resistant idiopathic nephrotic syndrome in childrenAuthorPatrick Niaudet, MDSection EditorTej K Mattoo, MD, DCH, FRCPDeputy EditorMelanie S Kim, MDDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Feb 2013. | This topic last updated: Dez 19, 2012.

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, about 10 to 20 percent of patients will fail to respond to initial steroid treatment. In many cases, steroid-resistant cases are due to single-gene mutations that affect glomerular podocyte differentiation and function. Patients with genetic forms of steroid-resistant nephrotic syndrome (SRNS) are usually unresponsive to immunosuppressive therapy. Thus, therapeutic decisions in children with SRNS are based on the underlying etiology.

The causes and management of steroid-resistant idiopathic nephrotic syndrome in children will be reviewed here. The etiology, clinical manifestations, diagnosis, and initial management of NS in children are discussed separately. In addition, the management of children with steroid-sensitive NS is presented elsewhere. (See "Etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children" and "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial pharmacologic therapy' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Steroid-sensitive nephrotic syndrome'.)

ETIOLOGY — In most children with steroid-resistant nephrotic syndrome (SRNS), the underlying cause is not known [1,2]. However, advances in molecular genetics of glomerular diseases have shown single gene defects that affect glomerular podocyte differentiation and function are responsible for a quarter to a third of all pediatric cases of SRNS in many parts of the world [3-5].

Genetic mutations — Mutations of the following genes are the most common cause of hereditary SRNS.

NPHS1 encodes nephrin, slit diaphragm component of the podocyte NPHS2 encodes podocin, slit diaphragm component of the podocyte WT1 encodes the transcription tumor suppressor protein, which is involved in

kidney and gonad development

Other less common genetic forms of SRNS are due to mutations of the LAMB2 gene (encodes lamin beta 2), PLCE1 gene (encodes phospholipase C epsilon), and TRP6 [6] (encodes transient receptor potential 6 ion channel). These gene defects are discussed in

greater detail separately. (See "Congenital and infantile nephrotic syndrome", section on 'Pierson syndrome' and "Congenital and infantile nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Drash syndrome' and "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'TRPC6 gene'.)

The frequency of genetic mutations associated with childhood SRNS was illustrated in the following two studies:

In a single center study of 91 consecutive German patients from 82 families with SRNS including 26 infants below three months of age. Gene mutation were found in 52 percent of the families and included mutations in the following genes, NPHS1 (n = 11), NPHS2 (n = 17), WT1 (n = 11), LAMB2 (n = 1), and TRPC6 (n = 3) [3].

In a second study of 110 Spanish patients with SRNS, genetic mutations were found in two thirds of 24 familial cases and 25 percent of 86 sporadic cases [5].

The likelihood of a monogenetic cause of SRNS is greatest in the first year of life as illustrated in the above Spanish study with the following rates of genetic defects based on age [5]:

0 to 3 months – 100 percent 4 to 12 months – 57 percent 13 months to 5 years – 24 percent 6 to 12 years – 36 percent 13 to 17 years – 25 >18 years – 14 percent

In these older age groups, NPHS2 mutations were most frequently seen.

NPHS1 mutations — NPHS1 encodes nephrin, an integral membrane protein of the slit diaphragm of the podocyte. Mutations of the NPHS1 gene are most often associated with the Finnish-type congenital nephrotic syndrome. (See "Congenital and infantile nephrotic syndrome", section on 'CNS of Finnish type'.)

However, mutations of this gene have also been reported in older patients with SRNS, as illustrated in a study of 160 children with SRNS from 142 families. Once mutations in NPHS2 had been excluded, the authors identified NPHS1 mutations in two related and nine unrelated patients (age range between six months to 11 years) [7]. Initial renal biopsy demonstrated minimal changes in 7 cases and focal segmental glomerulosclerosis in 3. Five patients progressed to ESRD at a mean age of 13 years (range 6 to 25 years). From this study, the authors concluded that about 10 percent of children with SRNS who present before five years of age will carry a NPHS1 gene mutation.

NPHS2 mutations — Mutations in the NPHS2 gene that encodes for podocin, an integral membrane protein found exclusively in glomerular podocytes, are frequently observed in children with familial SRNS, less commonly in those with sporadic SRNS, and not in patients with steroid-sensitive NS [8-10].

This was illustrated in the following studies:

In the first study, NPHS2 mutation analysis was performed in 338 children from 272 families with SRNS [9].

In the 81 families with autosomal recessive SRNS, 43 percent had NPHS2 mutations (homozygous or compound heterozygous). The average age of onset of NS was 58 months.

In 172 patients with sporadic SRNS, 11 percent had homozygous or compound heterozygous NPHS2 mutations. The average age of onset was 103 months.

In a second study, direct sequencing of the NPHS2 gene was performed in 190 patients from 165 families with SRNS and in 124 patients from 120 families with steroid-sensitive NS [10]. The following findings were noted:

In 165 families with SRNS, 43 had homozygous or compound heterozygous NPHS2 mutations (26 percent).

No homozygous or compound heterozygous NPHS2 mutations were noted among the steroid-sensitive patients.

Mutations in NPHS2 have been described in approximately 10 to 30 percent of cases of sporadic SRNS in children from Europe and the Middle East [9,11-15]. These affected children appear to have an early onset of disease, and most progress to end-stage renal disease (ESRD) [11,13,16]. Cardiac defects have also been described in these patients [17]. In contrast, the frequency of NPHS2 mutations is low in African-Americans with SRNS [18].

Although one might expect that patients with NPHS2 mutations would not develop recurrent disease in the transplant, recurrence has been reported, although rarely. (See "Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Risk factors for recurrence'.)

NPHS3 mutations — Mutations in the phospholipase C epsilon gene (PLCE1 or NPHS3) are usually associated with congenital nephrotic syndrome and diffuse mesangial sclerosis, but may also occur in older patients. In a cohort of 139 patients (mean age 23 months, range 0 to 31 years) with early onset SRNS and diffuse mesangial sclerosis, PLCE1 mutations were found in 8 percent (6/78) of FSGS cases without NPHS2 mutations [19]. (See "Congenital and infantile nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)

WT1 mutations — Mutations in WT1, the Wilms' tumor suppressor gene, have been reported in patients who present clinically with sporadic SRNS. In a European study, for example, mutational analysis of the WT1 gene was performed in 115 cases of sporadic SRNS as well as in 100 cases of steroid-sensitive disease [20]. Mutations in WT1 were found in 3 of 60 males (5 percent) and 5 of 55 females (9 percent) with steroid-resistant disease, although no such mutations were found in cases of steroid-sensitive NS. As a result, WT1 mutations should be looked for in all cases of idiopathic steroid resistant nephrotic syndrome regardless of gender, as all affected patients are at risk for Wilms tumor [21].

Other genes — Mutations of several genes, including ACTN4 encoding alpha-actinine4, TRPC6 encoding the transient receptor potential cation channel 6 [22], and INF2

encoding a member of the formin family of actin-regulating proteins, are responsible for autosomal dominant nephrotic syndrome with focal segmental glomerulosclerosis that generally present in adolescence and young adulthood. In African American patients, variants in the apolipoprotein L1 (APOL1) gene, which resides in close proximity to MYH9 on chromosome 22, are associated with FSGS. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'Genetic disease'.)

Syndromic SRNS — Syndromic forms of genetic SRNS are due to the following gene mutations. Nonrenal manifestations are helpful in determining the appropriate gene to test [23]. (See 'Genetic testing' below.)

Mutations in WT1 are associated with several forms of hereditary NS including Frasier syndrome and Denys-Drash syndrome. (See "Congenital and infantile nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Drash syndrome' and "Evaluation of the infant with ambiguous genitalia", section on 'Genes involved in gonadal development'.)

The Denys-Drash syndrome consists of the triad of progressive renal disease with diffuse mesangial sclerosis, male pseudohermaphroditism, and Wilms' tumor.

Frasier syndrome is characterized by the association of male pseudohermaphroditism with female external genitalia and nephrotic syndrome with FSGS [20].

LAMB2 is associated with the Pierson syndrome (diffuse mesangial sclerosis and ocular malformations). (See "Congenital and infantile nephrotic syndrome", section on 'Pierson syndrome'.)

Mutations in SMARCAL1 gene are associated with Schimke syndrome, which is characterized by growth retardation, T-cell deficiency, bone dysplasia, and cerebrovascular disease. Patients may develop SRNS with FSGS progressing to end stage renal disease [24,25].

Mutations in LMX1B gene are associated with nail-patella syndrome. About one half of patients develop proteinuria, sometimes with nephrotic syndrome. (See "Nail-patella syndrome".)

Genotype and histology — In some cases, the histologic findings are suggestive of a specific underlying gene defect.

Diffuse mesangial sclerosis – WT1 or LAMB2 mutations (picture 1 and picture 2) (see "Congenital and infantile nephrotic syndrome", section on 'Diffuse mesangial sclerosis').

Tubulointerstitial changes including irregular microcystic dilatation of proximal tubules are typically seen in patients with NPSH1 mutations (picture 3 and picture 4). However, dilation of the proximal tubules may be observed in other cases of congenital nephrotic syndrome secondary to heavy proteinuria. (see "Congenital and infantile nephrotic syndrome", section on 'CNS of Finnish type').

Histologic findings that are consistent with specific gene mutations can help guide genetic testing. However, most genetic causes of SRNS have histological features that are not distinguishable from nongenetic disease, primarily focal segmental glomerulosclerosis [5]. As a result, a renal biopsy will generally not distinguish between genetic and nongenetic forms of SRNS.

Genetic testing is recommended in children likely to have a genetic etiology because of the histologic overlap and difference in therapeutic decisions between genetic and nongenetic disease causes of SRNS. (See 'Genetic testing' below and 'Treatment' below.)

Nongenetic forms — As of 2011, no underlying genetic defects were identified in about 50 to 60 percent of pediatric patients with SRNS in Europe and the Middle East [3]. The prevalence of nongenetic forms of SRNS in patients from North America, which is a more heterogenetic population, is unknown. In patients in whom an underlying cause is unknown, it is possible that mutations in yet-to-be identified genes are responsible [26].

In the previously mentioned case series of 91 children with SRNS from Germany, 41 patients did not have a mutation of any of the analyzed genes (NPHS1, NPHS2, WTI, LAMB2, TRPC6, and PLCE1) [3]. Kidney biopsies were performed in 40 of the 41 patients and showed the following histological diagnoses:

Focal segmental glomerulosclerosis (FSGS, n = 28) Minimal change disease (MCD, n = 10) Diffuse mesangial sclerosis (n = 1) Mesangial proliferation (n = 1)

THERAPEUTIC INTERVENTIONS — About 20 percent of patients with steroid-resistant nephrotic syndromes (SRNS) will progress to end-stage renal disease (ESRD) [27]. The goals of therapy for SRNS are to achieve complete resolution of proteinuria, thereby reducing the complications associated with NS, and preservation of kidney function. However, there is no currently optimal therapy for SRNS that consistently meets these two goals.

The therapeutic options for SRNS include the following:

Immunosuppressive therapy, which is focused on inducing a complete remission. In some cases, there is only a partial remission with a reduction in proteinuria. Genetic forms of SRNS are particularly refractory to immunosuppressive therapy.

Nonimmunologic therapy directed towards reducing protein excretion. Adult data have shown improved kidney survival in patients with NS who achieve a 50 percent or greater reduction in baseline proteinuria by either administration of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). (See 'Nonimmunologic antiproteinuric therapy' below and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Immunosuppressive therapy — Remission of the nephrotic syndrome is the goal of immunosuppressive therapy, thereby reducing protein excretion and the risk of complications associated with nephrosis, and to preserve renal function.

The following immunosuppressive agents have been used to treat SRNS with varying clinical benefit:

Alkylating agents Calcineurin inhibitors (CNIs)– Cyclosporin and tacrolimus Mycophenolate mofetil Rituximab

Immunosuppressive therapy generally has not been shown to be effective in treating children with SRNS due to genetic causes. This was illustrated in two of the previously discussed case series:

In the study that identified steroid-resistant patients with NPHS2 gene defects, neither cyclosporine nor cyclophosphamide induced a complete remission in 29 treated patients [10].

In the previously mentioned study of 91 patients, none of the 43 patients with an identified genetic cause responded with a complete remission to cyclosporin therapy, and only two achieved a partial response. In contrast, two-thirds of the 31 patients with nongenetic SRNS responded to cyclosporin therapy including 17 patients who achieved complete remission [3].

Patients with SRNS who are heterozygotic carriers for either NPHS1 or NPHS2 gene mutation may be more likely to respond to immunosuppressive therapy than homozygous patients including steroids [28]. However, further investigation is needed to confirm this observation.

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 those who continue to receive steroid therapy alone [27,29-32].

This was illustrated in a randomized trial from the International Study of Kidney Disease in Children (ISKDC) comparing cyclophosphamide plus prednisone with prednisone alone in 60 patients with SRNS and focal segmental glomerulosclerosis (FSGS) [30]. The same proportion of children in both groups went into remission by six months.

Calcineurin inhibitors

Cyclosporin — The efficacy of cyclosporine children with SRNS has been confirmed in several reports [32-41].

In a randomized trial of 138 children and young adults with FSGS that compared cyclosporin to a combination of oral pulse dexamethasone and mycophenolate mofetil (MMF), partial or complete remission was achieved in 33 of 72 (46

percent) patients who were randomly assigned to receive cyclosporine [42]. Although the remission rate was higher in the cyclosporin group, it was not significantly different from those who were assigned the combination therapy of steroids and MMF (33 percent).

In a meta-analysis of interventions for SRNS, an analysis of three trials (n = 49 patients) demonstrated that the administration of cyclosporin compared with placebo or no treatment increased the number of children who achieved complete remission (RR 7.66, 95% CI 1.06-55.34) [32]. In addition, one trial of 32 patients showed cyclosporine was more effective than cyclophosphamide in inducing a partial remission in children with SRNS.

Observational studies also report a benefit of cyclosporin in combination with steroid therapy as illustrated by the following:

In the first study conducted by the French Society of Pediatric Nephrology, 65 children with SRNS were treated with cyclosporine (150 to 200 mg/m2 per day) in combination with prednisone (30 mg/m2 per day for one month followed by alternate day prednisone for five months) [34]. Complete remission was observed in 27 patients and partial remission in 4 children. Complete remission was achieved in 48 percent (21 of 45 patients) of patients with minimal change disease (MCD) and 30 percent (6 of 20 patients) with focal segmental glomerulosclerosis (FSGS). One-half of responding patients remitted within the first month of therapy, and in 17 patients, complete remission lasted from 14 to 60 months. Eight responders became steroid-sensitive when they subsequently relapsed. None of the responders progressed to end-stage renal disease (ESRD), 15 had persistent NS, 5 were in complete remission, and 2 in partial remission. Most patients with a poor outcome had FSGS.

In a retrospective German study of 86 children with SRNS, remission rates using cyclosporin in combination with steroids were dependent upon the underlying histologic findings obtained by kidney biopsy [41]. In the group of 52 patients with FSGS, the 25 children treated with cyclosporine (150 mg/m2 per day) in combination with the initial use of high dose intravenous pulse methylprednisolone (300 to 1000 mg/m2 per day for 3 to 8 days) and oral prednisone (40 mg/m2 per day following pulse therapy) were more likely to undergo remission compared with the 27 children with FSGS treated with cyclosporine and only oral prednisone (40 mg/m2 every other day) (84 versus 64 percent). All 14 patients with MCD included in this study underwent remission regardless of which combination regimen was used. In contrast, none of the 20 patients with genetic or syndromic form of FSGS responded to any of the combination therapy.

However, cyclosporin does not appear to have a beneficial effect in patients with genetic forms of SRNS.

In the above retrospective study, none of the 20 patients with genetic or syndromic form of FSGS responded to combination therapy of cyclosporin and steroid [41].

In the previously discussed case series of 91 patients with SRNS, none of the 12 patients with genetic mutations who were treated with cyclosporin achieved complete remission with cyclosporin therapy, and only two had a partial response [3]. In contrast, 17 of the 31 patients without an identifiable genetic

defect who received cyclosporine therapy achieved complete remission, and 4 had a partial response.

In patients who are responsive to cyclosporin therapy, there is a high relapse rate following the cyclosporin withdrawal. This results in prolonged administration of cyclosporin, which increases the risk of nephrotoxicity. In patients who require ongoing cyclosporin therapy to maintain remission, the plasma creatinine concentration should be monitored regularly, and serial renal biopsies should be performed to detect nephrotoxicity. Because histologic signs of cyclosporin nephrotoxicity are observed without clinical evidence of renal function impairment, we routinely perform a renal biopsy in asymptomatic patients after 18 months of therapy [43,44]. (See "Cyclosporine and tacrolimus nephrotoxicity".)

The recommended cyclosporin dose is 150 mg/m2 per day divided into two oral doses. The dose should be adjusted to maintain trough whole blood levels between 100 and 200 ng/mL, and the level should not exceed 200 ng/mL.

Tacrolimus — Limited data suggest that the beneficial effect of tacrolimus is similar to that of cyclosporine [45-50]. In small clinical trials that compared tacrolimus to cyclosporine therapy in patients with SRNS, rates of remission between the two agents were similar up to two years [48,51]. Tacrolimus was associated with a lower rate of relapse, fewer cosmetic side effects, and a lower blood cholesterol level.

The combination of tacrolimus and corticosteroid therapy has a higher rate of remission compared to intravenous cyclophosphamide. This was illustrated in a multicenter trial of 131 children with SRNS that compared relapse rates in children who received the combination therapy of tacrolimus and prednisolone for 12 months compared with those who received six monthly intravenous infusion of cyclophosphamide. Children treated with a combination therapy of tacrolimus and corticosteroid had a higher complete or partial remission rate (52 versus 15 percent) [52].

Further studies are needed to confirm whether tacrolimus offers any advantage over cyclosporin in the management of patients with SRNS.

Mycophenolate — Limited data demonstrate inconsistent results regarding the efficacy of mycophenolate mofetil (MMF) in patients with SRNS as demonstrated by the following small studies.

In the above mentioned clinical trial of 138 patients with FSGS, partial or complete remission was achieved in 22 of 66 patients (33 percent) who were randomly assigned to the combination therapy of oral pulse dexamethasone and MMF [42].

Observational studies of children with SRNS also report potential benefit of MMF.

In a study of 52 Brazilian children with steroid and cyclophosphamide resistant NS, 12 patients (22 percent) achieved complete remission, 19 (35 percent) partial remission, and in 21 (39 percent) patients there was no response [53].

In a study from China of 24 children less than two years of age with SRNS, MMF in combination with prednisone at an initial dose of 2 mg/kg was

associated with complete remission in 15 patients, partial remission in six patients, and no response in the remaining three patients [54]. Steroid therapy was tapered in a step-wise manner.

In contrast, two small trials report limited benefit of MMF in patients with SRNS [55,56].

More consistent data indicating a beneficial effect without significant adverse effects are needed before MMF can be routinely recommended to treat children with SRNS.

Rituximab — It remains uncertain whether rituximab, an anti-CD20 B cell monoclonal antibody, is beneficial in the treatment of SRNS.

Several case series have reported that the addition of rituximab to glucocorticosteroid and/or CNI therapy improves remission rates in patients with SRNS [57-59]. In one case series that included patients with SRNS and steroid dependent patients, treatment with rituximab and alternate day steroid therapy resulted in complete remission in 9 of 33 patients with SRNS (including two adult patients), and partial remission in seven other patients [59]. Four patients also received concomitant therapy with a CNI, and the two adult patients received mycophenolate mofetil. Side effects included mild infusion related reactions of chills and myalgias, and no serious adverse event was observed.

In contrast, an open-label clinical trial of 31 children with SRNS demonstrated that the addition of rituximab to the standard therapy of prednisone and CNI therapy did not reduce proteinuria compared with control patients treated with standard therapy alone at three months follow-up [60]. Three patients in both groups entered remission during the study period. These six patients who entered remission were initial steroid responders but late nonresponders. No patient with early steroid resistance entered remission in either treatment arm.

Serious adverse effects of rituximab include infusion-related reactions (hypotension, fever, and rigors), serious infections, and progressive multifocal leukoencephalopathy [61]. In addition, there is one published case report of death associated with rituximab therapy in a child with nephrotic syndrome due to lung fibrosis [62]. (See "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

As a result, we do not recommend the routine use of rituximab in treating children with SRNS until there are data demonstrating that it is both effective and safe.

Combination therapy — More aggressive combination regimens have been tried in relatively small numbers of patients. Data are too limited to determine whether these therapies were efficacious and safe.

One regimen included vincristine, cyclophosphamide, and prednisolone [63]. Lasting remission was observed in only 7 of 21 patients, starting six months to three years after initiation of treatment.

Combination therapy of tacrolimus, mycophenolate, and prednisolone in 14 patients who were resistant or intolerant of cyclosporin therapy resulted in complete remission in all nine patients with steroid-dependent NS and two of the

four patients with SRNS [64]. One of the patients with SRNS due to focal segmental glomerulosclerosis developed end-stage renal disease.

Another regimen combines intravenous methylprednisolone pulses (30 mg/kg per dose, initially given every other day and then tapered to weekly and monthly dosing), oral prednisone (2 mg/kg every other day), and, if proteinuria does not improve by the week two of pulse therapy, an alkylating agent is added [65-67].

In one study utilizing this protocol, 21 of 32 children went into remission [67]. The five-year incidence of end-stage renal disease was approximately 5 percent versus 40 percent in historical controls [67]. A poor outcome was associated with segmental sclerosis on renal biopsy prior to pulse therapy [68]. Side effects included nausea during the infusion of pulse methylprednisolone in almost all, impaired growth in four (one of whom caught up with cessation of therapy), small cataracts that did not interfere with vision in five, and infections in two (cellulitis and Herpes zoster). There were no cases of abdominal striae, diabetes mellitus, or aseptic necrosis of bone.

An abstract report of 15 children with FSGS was unable to confirm the efficacy of this regimen [69]. A mean of 15 pulses were given, and eight patients also received an alkylating agent. At the end of the study, only four patients maintained remission, and five had a poor outcome with progression to end-stage renal disease or death.

These regimens are not recommended because the potential limited benefit is outweighed by the significant adverse events associated with these therapeutic agents.

Nonimmunologic antiproteinuric therapy — Adult data have shown improved kidney survival in patients with NS who achieve a 50 percent or greater reduction in baseline proteinuria. Interventions to reduce protein excretion have mainly focused on angiotensin antagonism by either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Similar observational data in children also show angiotensin antagonism reduces protein excretion.

In one small study of nine children with steroid-resistant FSGS, ACE inhibitor or ARB therapy plus mycophenolate resulted in a 72 percent decrease in proteinuria from baseline values at six months that was maintained for a minimum period of 24 months [70].

In a study of 52 children with persistent proteinuria (mean protein excretion 3.3 g per day), administration of losartan, an ARB, reduced proteinuria by 34, 64, and 67 percent at mean follow-up of 0.4, 0.7, and 2.5 years [71]. Only 9 of 22 patients with baseline nephrotic range proteinuria had persistent nephrotic range proteinuria at last follow-up.

In a study of 25 children with SRNS, the administration of enalapril reduced protein excretion in a dose-related manner [72]. After eight weeks of high doses of enalapril (0.6 mg/kg per day divided into two doses), the median protein excretion was reduced by 63 percent. In comparison, a lower dose (0.2 mg/kg) for eight weeks reduced median protein excretion by 35 percent.

There are no data in children regarding the long-term prognosis of progression to chronic kidney disease with the use of ACE inhibitors or ARBs. Nevertheless, based on evidence from the adult literature, these agents are widely used as antiproteinuric therapy in children with SRNS [73].

ACE inhibitor 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. (See "Angiotensin converting enzyme inhibitors and receptor blockers in pregnancy", section on 'Approach to treatment in women of childbearing potential'.)

The partial response to CNI therapy in patients with genetic forms of SRNS has been attributed in part to its nonimmunologic effects [74-76]. 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 has resulted in partial remission in patients with SRNS and is commonly used in patients who have been refractory to other immunosuppressive therapy or 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. If used, monitoring of renal function is needed including measurements of serum creatinine and serial renal biopsies. (See 'Calcineurin inhibitors' above.)

MANAGEMENT APPROACH — Treatment decisions are based on the underlying etiology determined by renal histology and genetic screening.

Evaluation — Evaluation for steroid-resistant nephrotic syndrome (SRNS) includes a renal biopsy to determine the underlying histology and possibly genetic screening. Therapeutic decisions are based on the histologic diagnosis and whether the cause of the nephrotic syndrome (NS) is due to a genetic etiology. (See 'Treatment' below.)

A renal biopsy should be performed in a child with SRNS to confirm the diagnosis of idiopathic nephrotic syndrome. Renal biopsy may show three patterns: minimal changes, diffuse mesangial proliferation, and focal and segmental glomerulosclerosis (FSGS). These histological variants of nephrosis may be found alone or in any combination on sequential biopsies in the same patient. Histologic findings may be characteristic of specific genetic mutations and help guide genetic testing.

A report of the International Study of Kidney Disease in Children showed that among 354 patients with idiopathic nephrotic syndrome, 55 patients did not respond to prednisone, 45.5 percent had minimal change disease, 47.5 percent had FSGS, and 7.0 percent had diffuse mesangial proliferation. This study also found among the 37 patients with FSGS, 70.3 percent did not respond to steroids.

Genetic testing — Because immunosuppressive therapy generally has been shown to be not as effective in treating children with SRNS due to genetic causes, it is important to

identify patients with genetic disease so that unnecessary exposure to immunosuppressive agents and their side effects can be avoided [3,5,20,23,26,77].

Factors that increase the likelihood of an underlying genetic cause of SRNS include the following (see 'Genetic mutations' above):

Family history of SRNS [3,5] Presentation in the first year of life [5] Parental consanguinity Syndromic SRNS (see 'Syndromic SRNS' above)

In our center, we perform genetic testing for all patients with SRNS because screening is readily available in our research laboratory. For other settings in which genetic testing is not readily available, we suggest screening should be performed for all patients with a familial history of steroid-resistant NS (SRNS), patients whose parents are consanguineous, children less than one year who present with SRNS, and in all patients with syndromic SRNS. For the remaining patients with SRNS, we consider the utility of performing genetic screening based on the histology, and age of the patient.

In patients in whom there is a strong suspicion for a genetic etiology, a step-wise screening approach is warranted given the number of different gene defects [5,23]. The order of testing is determined by the likelihood of involvement of a specific gene as follows:

Age of presentation – For patients with congenital nephrotic syndrome, screening for mutations for NPHS1 should first be performed, followed by testing for NPHS2 mutations. For older children, screening should begin with identifying NPHS2 mutations.

Presence of extrarenal abnormalities – LAMB2 screening for patients with ocular abnormalities, and WT1 screening for those with ambiguous genitalia.

Type of histologic lesions – WT1 or LAMB2 screening for patients with a histologic diagnosis of diffuse mesangial sclerosis.

Gene testing for NPHS1, NPHS2, and WT1 mutations is commercially available. The laboratory directory for Gene tests supported by the National Institutes of Health provides a voluntary listing of commercial and academic laboratories throughout the world that offer molecular genetic testing (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests).

Some have suggested that, to avoid unnecessary exposure to steroid therapy, all children with a first episode of the NS should be screened for NPHS2 mutations [10]. However, given that over 85 percent of children with idiopathic NS are steroid-sensitive and only approximately one third of steroid-resistant patients have a genetic mutation, less than five percent of all cases would have a genetic basis for idiopathic pediatric NS [77]. As a result, we do not currently recommend genetic testing for all children with idiopathic nephrotic syndrome.

Treatment

Genetic causes — In patients with SRNS caused by genetic disorders, we do not administer additional immunosuppressive therapy because it is not effective and has significant adverse effects. Although data are lacking in children, we treat these patients with persistent proteinuria with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) based on data from studies in adults. (See 'Immunosuppressive therapy' above and 'Nonimmunologic antiproteinuric therapy' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Nongenetic disease — The optimal approach to steroid-resistant idiopathic NS not due to a genetic defect is uncertain. The therapeutic approach for several specific histologic diagnoses is discussed separately. (See "Minimal change variants: Mesangial proliferation; IgM nephropathy; C1q nephropathy" and "Treatment of primary focal segmental glomerulosclerosis" and "Evaluation and treatment of membranoproliferative glomerulonephritis" and "Treatment of idiopathic membranous nephropathy".)

Our approach — In our practice, an initial combination of cyclosporine and prednisone is given to children with steroid-resistant minimal change disease or focal glomerulosclerosis, provided they have normal glomerular filtration rate. If there is a response to therapy, we begin to taper steroid therapy to minimize or reduce steroid toxicity. In nonresponsive patients, we administer angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) to reduce protein excretion.

Other experts in the field will begin either an ACE inhibitor or ARB when the diagnosis of SRNS is initially made. However, because ACE inhibitors or ARBs may increase the nephrotoxicity of cyclosporine, we prefer to wait to see if the patient responds to the combination therapy of cyclosporine and prednisone prior to adding an angiotensin antagonistic agent.

We do not recommend the administration of alkylating agents based on evidence that shows no additional benefit over placebo therapy and a poorer response rate compared with CNIs [30,52]. We also do not suggest the routine use of mycophenolate mofetil (MMF) or rituximab because there remains a paucity of data showing these are effective and safe agents in the treatment of children with SRNS. However, as noted above, others in the field have shown that MMF in combination with oral pulse dexamethasone may be beneficial in achieving remission. These drugs (alkylating agents, MMF, and rituximab) should only be used under the supervision of a clinician with expertise in treating children with SRNS. (See 'Alkylating agents' above and 'Mycophenolate' above and 'Rituximab' above.)

KDIGO guidelines — In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO), an international organization focused on improving the outcome of patients with kidney disease, globally developed guidelines to manage children with steroid-resistant NS, which is similar to our approach discussed above [78].

Calcineurin inhibitor (CNI) therapy is administered for at least six months in combination with low-dose corticosteroid therapy. If there is no response, CNI is discontinued. If there is either a partial or complete remission, it is continued for at least 12 months. (See 'Calcineurin inhibitors' above.)

ACE inhibitor or ARB therapy. (See 'Nonimmunologic antiproteinuric therapy' above.)

For patients who do not respond to CNI therapy, consider the use of mycophenolate mofetil, high-dose corticosteroids, or a combination of the two. Alkylating agents (eg, cyclophosphamide) are NOT recommended to treat children with steroid-resistant nephrotic syndrome. Data are insufficient to determine whether rituximab should be used to treat these patients. (See 'Mycophenolate' above and 'Alkylating agents' above and 'Rituximab' above.)

SUMMARY AND RECOMMENDATIONS

Ten to 20 percent of children with idiopathic nephrotic syndrome will fail to respond to initial empirical steroid therapy. These children with steroid-resistant nephrotic syndrome (SRNS) are at increased risk for developing end-stage renal disease. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Steroid response' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Outcome based upon response'.)

Increasingly, genetic mutations have been shown to cause SRNS in a substantial number of patients. Mutations of the NPHS1, NPHS2, and WT1 genes are the most commonly identified genetic defects observed in pediatric SRNS. (See 'Genetic mutations' above.) However, in most pediatric patients with SRNS, no underlying cause is currently identified. In these patients, the most common histological diagnosis based on kidney biopsies was focal segmental glomerulosclerosis followed by minimal change disease. (See 'Nongenetic forms' above.)

The goals for SRNS therapy are to attain complete resolution of proteinuria, thereby reducing the complications associated with nephrotic syndrome, and preserve kidney function. Therapeutic options include immunosuppressive and nonimmunologic antiproteinuric therapies. (See 'Therapeutic interventions' above.)

Immunosuppressive therapy that has been used in children with SRNS includes alkylating agents, calcineurin inhibitors (CNIs), mycophenolate, and rituximab. Immunosuppressive therapy has not generally been 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) reduces protein excretion in patients with SRNS. However, there are no data in children regarding the long-term prognosis of progression to chronic kidney disease with the use of these agents. (See 'Nonimmunologic antiproteinuric therapy' above.)

Management — We suggest the following management approach in children with SRNS.

We suggest performing a kidney biopsy in all children with SRNS to determine the underlying histology (Grade 2C). (See 'Evaluation' above.)

We suggest performing genetic screening in patients with SRNS in whom there is a strong suspicion for a genetic etiology (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. (See 'Genetic testing' above.)

In patients with SRNS caused by genetic disorders, we recommend no additional immunosuppressive therapy because it is not effective and has significant adverse effects (Grade 1B). In these patients, we suggest the administration of either an ACE inhibitor or ARB to reduce protein excretion (Grade 2C). (See 'Genetic causes' above and 'Therapeutic interventions' above and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Optimal treatment of steroid-resistant NS not due to a genetic disorder is unknown. (See 'Immunosuppressive therapy' above and 'Nongenetic disease' above.)

In children with nongenetic SRNS, we suggest a combination of cyclosporine or tacrolimus and prednisone, provided they have normal glomerular filtration rate (Grade 2C).

In unresponsive patients to the combination of a CNI and prednisone, we suggest the administration of either an ACE inhibitor or ARB to reduce protein excretion (Grade 2C). Other experts in the field advocate administering ACE inhibitor or ARB when the diagnosis of SRNS is initially made. We prefer to see whether the patient responds initially to the combination therapy of CNI and prednisone because concomitant use of an angiotensin antagonist will increase the nephrotoxicity of the CNI. (See 'Cyclosporin' above and 'Nonimmunologic antiproteinuric therapy' above.)

We do not recommend the use of alkylating agents in the treatment of pediatric SRNS (Grade 1B). (See 'Alkylating agents' above.)

We do not suggest the routine use of mycophenolate mofetil to treat patients with SRNS because it has not been shown to be more effective in this group of patients (Grade 2B). We also do not suggest the routine use of rituximab because of the lack of consistent data demonstrating efficacy and safety in children with SRNS (Grade 2B). These agents should only be used under the direction of a clinician with expertise in treating children with SRNS. (See 'Mycophenolate' above and 'Rituximab' above.)

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