Version May 2024
INTRODUCTION — The majority of children who present with idiopathic nephrotic syndrome (NS) have minimal change disease, which is generally responsive to steroid therapy. As a result, empirical steroid therapy is given to most children who present with idiopathic NS.
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. Thus, therapeutic decisions in children with SRNS depend in part on the underlying etiology.
The causes of SRNS in children will be reviewed here. The clinical manifestations, diagnosis, and initial management of NS, as well as the etiology of NS in children, are also discussed separately. In addition, the management of children with steroid-sensitive NS (SSNS) and those with SRNS are presented elsewhere. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children" and "Treatment of idiopathic nephrotic syndrome in children", section on 'Initial therapy' and "Treatment of idiopathic nephrotic syndrome in children", section on 'Steroid-sensitive nephrotic syndrome' and "Steroid-resistant nephrotic syndrome in children: Management".)
OVERVIEW — In most children with 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, structure, and function are responsible for one-third or more of all pediatric cases of SRNS (table 1) [3-10]. Confirmation of a genetic cause of SRNS is clinically important because patients with a genetic etiology respond poorly to immunosuppressive therapy and there is a lower risk of recurrence of primary disease after renal transplantation compared with those without a genetic etiology. (See "Steroid-resistant nephrotic syndrome in children: Management".)
GENETIC VARIANTS
Epidemiology — Monogenic variants in over 60 genes have been identified as the etiology of SRNS in approximately 30 percent of children who present with SRNS (table 1). This rate is likely to increase as more genes are identified in which variants result in SRNS. The likelihood of identifying a monogenic cause of SRNS increases with decreasing age and increases to 50 percent in children who are from a consanguineous family [9].
Variants of the following genes are the most common causes of hereditary isolated SRNS (table 2) [6,9]:
●NPHS1 encodes nephrin, a slit diaphragm component of the podocyte
●NPHS2 encodes podocin, a slit diaphragm component of the podocyte
●PLCE1 encodes phospholipase C epsilon
●WT1 encodes a transcription tumor suppressor protein, which is involved in kidney and gonad development
SRNS is less commonly due to variants in the following genes [9]:
●INF2 (encodes an actin-regulating protein). (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'INF2 gene'.)
●LAMB2 (encodes lamin beta 2, a basement membrane protein); a variant of this gene results in Pierson syndrome (MIM #609049; also referred to as microcoria-congenital nephrosis syndrome), a rare autosomal recessive syndrome with characteristic findings of congenital NS, ocular malformations (microcoria, abnormal lens with cataracts, and retinal abnormalities), and neurologic symptoms (hypotonia, psychomotor retardation). (See "Congenital nephrotic syndrome", section on 'Pierson syndrome'.)
●SMARCAL1 (encodes a chromatin remodeling protein); a variant results in Schimke immunoosseous dysplasia (MIM #242900), an autosomal recessive condition with skeletal, kidney, and immune abnormalities. (See "Syndromic immunodeficiencies", section on 'Schimke immunoosseous dysplasia'.)
●TRPC6 (encodes the transient receptor potential 6 ion channel). (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'TRPC6 gene'.)
The frequency of specific genetic variants based on age was illustrated in a multicenter study of individuals from 1783 unrelated families with SRNS who presented before 25 years of age [9]. In this cohort, a monogenic cause was identified in 30 percent of families, including 50 percent of consanguineous families and 25 percent of nonconsanguineous families.
●The likelihood of a monogenetic cause of SRNS decreased with increasing age, as noted by the following relative frequencies of a monogenic diagnosis in families based on age:
•0 to 3 months – 69 percent
•4 to 12 months – 50 percent
•13 months to 6 years – 25 percent
•7 to 12 years – 18 percent
•13 to 17 years – 11 percent
•>18 years – 21 percent
●The prevalence of specific underlying genetic variants also varied with age:
•For patients who presented in the first three months of age, the most common causative variants occurred in NPHS1, NPHS2, WT1, and LAMB2.
•NPHS2 variants were most frequently identified in patients who presented after one year of age.
•WT1 variants showed a biphasic distribution, with a first peak at 4 to 12 months and a second peak beyond 18 years of age.
•In 1 percent of cases, variants were identified in genes involved in the coenzyme Q10 biosynthesis pathway (COQ2, COQ6, PDSS2, and ADCK4). This is an important etiology as it is the only one with an existing potential specific treatment (ie, COQ10 supplementation) [11].
•Other monoallelic pathogenic gene variants (INF2 and TRPC6) were most frequently detected in early adulthood.
In another study from the SRNS Study Group, whole-exome sequencing identified genetic variants in 74 of 300 families (25 percent) [12]. A variant was found in 38 percent of consanguineous families and in 13 percent of non-consanguineous families. Variants were detected in 20 of 33 SRNS genes. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which a variant was detected.
It also appears that variants in a second gene may also occur in patients with SRNS [13]. Although they might have modifier effects, the pathogenic potential of these additional sequence variants remains unclear.
Genotype and histology — Histologic findings that are consistent with specific gene variants can help guide genetic testing. However, most genetic causes of SRNS have histologic features that are not distinguishable from nongenetic disease, primarily focal segmental glomerulosclerosis (FSGS) [5]. As a result, a kidney biopsy will generally not distinguish between genetic and nongenetic forms of SRNS.
The following histologic features can be suggestive of a specific underlying gene defect:
●Diffuse mesangial sclerosis – WT1, LAMB2, or PLCE1 variants (picture 1 and picture 2). (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)
●Tubulointerstitial changes – These include irregular microcystic dilatation of proximal tubules and are typically seen in patients with NPHS1 variants (picture 3 and picture 4). However, dilation of the proximal tubules may be observed in other cases of congenital NS secondary to heavy proteinuria. (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)
Syndromic steroid-resistant nephrotic syndrome — Syndromic forms of genetic SRNS are due to the following gene variants. Nonrenal manifestations are helpful in determining the appropriate gene to test (table 3) [14]. (See "Steroid-resistant nephrotic syndrome in children: Management", section on 'Genetic testing'.)
●Monoallelic pathogenic variants in WT1 are associated with several forms of hereditary NS, including Denys-Drash syndrome and Frasier syndrome. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis with Denys-Drash syndrome' and "Causes of differences of sex development", section on 'Global defects in testicular function'.)
•Denys-Drash syndrome (MIM #194080) consists of the triad of progressive kidney disease with diffuse mesangial sclerosis, male pseudohermaphroditism, and Wilms tumor.
•Frasier syndrome (MIM #136680), characterized by male pseudohermaphroditism with female external genitalia and NS with FSGS, is considered a disease spectrum/continuum [15-17].
●Biallelic pathogenic variants in LAMB2 cause Pierson syndrome (MIM #609049; diffuse mesangial sclerosis and ocular malformations). (See "Congenital nephrotic syndrome", section on 'Pierson syndrome'.)
●Variants in SMARCAL1 are associated with Schimke syndrome (MIM #242900), characterized by growth retardation, T cell deficiency, bone dysplasia, and cerebrovascular disease. Patients may develop SRNS with FSGS progressing to kidney failure [18,19]. (See "Syndromic immunodeficiencies", section on 'Schimke immunoosseous dysplasia'.)
●Monoallelic pathogenic variants in LMX1B are associated with nail-patella syndrome (MIM#161200). Approximately one-half of patients develop proteinuria, sometimes with NS. (See "Nail-patella syndrome".)
●Monoallelic pathogenic variants in INF2 have been identified in patients with Charcot-Marie-Tooth neuropathy, including deafness associated with FSGS [20]. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)
●Galloway-Mowat syndrome (MIM #251300 and others) is characterized by NS, microcephaly, and neurologic impairment [21-24]. Disease-causing variants have been identified in 10 genes: OSGEP, TP53RK, TPRKB, LAGE3, and GON7 encoding the five subunits of the KEOPS complex; YRDC involved in the same pathway along with WDR4, WDR73, and NUP107; and NUP133 [21,24-27].
●Biallelic pathogenic variants in SCARB2 (LIMP2), which encodes a lysosomal-membrane protein, are responsible for the action myoclonus-renal failure syndrome (MIM #254900), an autosomal recessive disorder with FSGS, and progressive myoclonus epilepsy associated with storage material in the brain [28].
●Biallelic pathogenic variants in SGPL1, encoding the ubiquitous sphingosine-1-phosphate enzyme, are responsible for SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurologic defects [29].
Specific gene variants
●NPHS1 – NPHS1 encodes nephrin, an integral membrane protein of the slit diaphragm of the podocyte. Biallelic pathogenic variants in NPHS1 are most often associated with Finnish-type congenital NS (MIM #256300), which is generally diagnosed before three months of age. (See "Congenital nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type'.)
However, variants 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 that identified NPHS1 variants in two related and nine unrelated patients (age range between 6 months and 11 years) [30]. Another study reported compound heterozygous or homozygous NPHS1 variants in five familial and seven sporadic cases of SRNS, including three with childhood-onset and one with adult-onset FSGS (patient 27 years old at onset) [31].
●NPHS2 – NPHS2 encodes podocin, an integral membrane protein found exclusively in glomerular podocytes. Biallelic pathogenic variants in NPHS2 are frequently observed in children with familial SRNS, less commonly in those with sporadic SRNS, and are not found in patients with steroid-sensitive NS (SSNS) [32-34]. The incidence of NPHS2 variants varies among populations. NPHS2 variants occur in approximately 10 to 30 percent of cases of sporadic SRNS in children from Europe and the Middle East [33,35-39] and approximately 30 to 40 percent of familial cases [33,39,40]. In contrast, the frequency of NPHS2 pathogenic variants is low in Black Americans with SRNS [41].
More than 110 variants in the NPHS2 have been reported [40]. Most affected children appear to have an early onset of disease and progress to kidney failure [35,37,42]. Cardiac defects have also been described in these patients [43].
However, some affected patients have milder disease and present in adolescence or young adulthood. These patients have common p.R229Q variants inherited in combination with trans-associated variant in the N-terminal region of the gene [44]. This does not follow Mendelian laws. In addition, some affected patients may respond to intensified immunosuppression and others may have recurrent nephrosis following kidney transplantation. This association of the p.R229Q variant and an N-terminal variant may account for the rare cases of recurrent primary disease in the transplant for patients with NPHS2 gene variants. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS2 gene' and "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney", section on 'Epidemiology and risk factors'.)
●PLCE1 – Biallelic pathogenic variants of PLCE1 cause NS type 3 (MIM #610725) and are usually associated with congenital NS and diffuse mesangial sclerosis but may also occur in older patients. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)
In a cohort of 139 patients (mean age 23 months, range 0 to 31 years) with early-onset SRNS and diffuse mesangial sclerosis, PLCE1 variants were found in 8 percent (6 of 78) of FSGS cases without NPHS2 variants [45]. Incomplete penetrance was demonstrated with three unaffected and unrelated individuals found to carry the homozygous pathogenic variants identified in their respective families, a very rare finding in autosomal recessive disorders [45]. It is speculated that modifier genes or environmental factors, yet to be identified, may play a role in the kidney phenotype variability observed. This observation needs to be considered when genetic counselling is offered to families. (See "Congenital nephrotic syndrome", section on 'Diffuse mesangial sclerosis'.)
●WT1 – Monoallelic pathogenic variants of WT1, the Wilms tumor suppressor gene, have been reported in patients who present clinically with sporadic SRNS. In a European study of 115 cases of sporadic SRNS and 110 cases of SSNS, WT1 variants were found in 3 of 60 males (5 percent) and 5 of 55 females (9 percent) with steroid-resistant disease and no variant was found in cases of SSNS [15]. In addition, WT1 variants have been identified in families with autosomal dominant FSGS [46].
Patients with WT1 variants and SRNS are at risk for other extrarenal manifestations, including genitourinary abnormalities, Wilms tumor, and, less frequently, gonadoblastoma [47]. (See "Presentation, diagnosis, and staging of Wilms tumor", section on 'WAGR syndrome'.)
●Mitochondrial cytopathies – Variants in the nuclear or mitochondrial genome that cause mitochondrial cytopathies include:
•The mitochondrial 3243A>G variant in the MTTL1 gene is responsible for the MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, MIM #540000), which may also cause nephrotic-range proteinuria with FSGS that progresses to chronic kidney disease in 50 percent of cases [48].
•Variants in the mitochondrial gene complex MTATP6 were associated with nephrotic-range proteinuria with FSGS in an individual with NARP syndrome (neuropathy, ataxia, retinitis pigmentosa, MIM #551500) [49].
•Biallelic pathogenic variants of several genes encoding proteins involved in the biosynthesis of CoQ10 (ubiquinone) may be responsible for steroid-resistant FSGS, including COQ2 [50], COQ6 [51-53], PDSS2 [54], and COQ8B (ADCK4) [55-57]. Case reports suggest that CoQ10 administration may reduce proteinuria and potentially be renoprotective [9,58,59]. Of note, variants of these genes have presented with both steroid-resistant FSGS and sensorineural hearing loss [52].
●Other genes:
•Autosomal dominant (see "Focal segmental glomerulosclerosis: Genetic causes"):
-Variants of ACTN4, TRPC6 [60], and INF2 have been associated with SRNS with FSGS that typically presents in adolescence and young adulthood [61]. INF2 variants are a major cause of autosomal dominant SRNS/FSGS and are detected in 12 to 17 percent of affected families [62].
-Variants in PAX2 have been reported in patients with FSGS, aged 7 to 68 years at onset of disease, and in the absence of extrarenal symptoms [63,64].
-Variants of ARHGAP24, which encodes an actin regulatory protein expressed in podocytes, were identified in a family with FSGS progressing to kidney failure [65].
-Variants of ANLN, which encodes anillin, were identified in two families with autosomal dominant FSGS, with an age at onset of proteinuria ranging from 9 to 69 years [66].
•Autosomal recessive:
-Variants of CRB2 were reported in four different families affected by SRNS [67]. The protein product is implicated in podocyte apico-basal polarity.
-Variants in TTC21B cause nephronophthisis. In addition, the most common variant (p.P209L) was identified in seven families with FSGS, with onset ranging from 9 to 23 years [68].
-Variants in nuclear pore genes NUP93, NUP205, NUP107, and XPO5, which encode components of the nuclear pore complex [69,70].
-Variants in EMP2 have been found in four individuals from three unrelated families. Three of these patients had SSNS, while one had SRNS with minimal changes on kidney biopsy [71].
-Variants in PTPRO (GLEPP1) were identified in five children from two unrelated Turkish families. Four of the five patients were partially responsive to intensified immunosuppressive treatment. One patient progressed to kidney failure [72].
-Variants in KANK1, KANK2, and KANK4 have been detected in three children with SSNS and three children with SRNS and hematuria [73].
-Variants in MYO1E have been identified in children with SRNS and FSGS in two families [74].
-Genetic variants in APOL1, which encodes apolipoprotein L1, have been found to be associated with FSGS in individuals of sub-Saharan African descent [75].
•X-linked – Two different X-linked TBC1D8B hemizygous missense variants in two unrelated pedigrees were identified in boys affected with early-onset SRNS and FSGS, whereas the mothers and a sister bearing the same variant had no or milder symptoms [76].
NONGENETIC IDENTIFIABLE CAUSES — As of 2015, no underlying genetic defects were identified in approximately 50 to 70 percent of pediatric patients with SRNS in Europe and the Middle East [3,9]. 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 pathogenic variants in yet-to-be-identified genes are responsible [77]. For example, one report found that children with initial steroid resistance show decreased glucocorticoid receptor expression in peripheral blood mononuclear cells before starting therapy compared with steroid-sensitive children [78]. This low expression, which may be genetically based, may be one of the pathophysiologic mechanisms of steroid resistance in children.
In a case series of 91 children with SRNS from Germany, 41 patients did not have a pathogenic variant of any of the analyzed genes (NPHS1, NPHS2, WTI, LAMB2, TRPC6, and PLCE1) [3]. Kidney biopsies were performed in 40 of these 41 patients without an identifiable genetic cause and showed the following histologic diagnoses:
●Focal segmental glomerulosclerosis (FSGS; n = 28)
●Minimal change disease (n = 10)
●Diffuse mesangial sclerosis (n = 1)
●Mesangial proliferation (n = 1)
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
●Ten to 20 percent of children with idiopathic nephrotic syndrome (NS) will fail to respond to initial empirical steroid therapy. These children with steroid-resistant NS (SRNS) are at increased risk for developing kidney failure. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Outcome based on response' and "Treatment of idiopathic nephrotic syndrome in children".)
●Monogenic pathogenic variants in over 60 genes have been identified as the etiology of SRNS in approximately 30 percent of children who present with SRNS (table 1). This rate is likely to increase as more genes are identified, in which variants result in SRNS. The likelihood of identifying a monogenic cause of SRNS decreases with increasing age and increases to 50 percent in children who are from a consanguineous family. (See 'Epidemiology' above.)
●Variants of the NPHS1, NPHS2, PLCE1, and WT1 genes are the most commonly identified genetic defects observed in pediatric SRNS. (See 'Genetic variants' above.)
●Several monogenic variants result in syndromic forms of SRNS (table 3). Nonrenal manifestations are helpful in determining the appropriate gene to test. (See 'Syndromic steroid-resistant nephrotic syndrome' above.)
●Despite the growing number of identified causative variants, no underlying cause can be identified in most pediatric patients with SRNS. In these patients, the most common histologic diagnosis based on kidney biopsies is focal segmental glomerulosclerosis (FSGS), followed by minimal change disease. (See 'Nongenetic identifiable causes' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William Smoyer, MD, FASN, who contributed to earlier versions of this topic review.
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