Genetic Steroid-Resistant Nephrotic Syndrome

Hereditary podocytopathies and glomerulopathies presenting with nephrotic proteinuria unresponsive to glucocorticoids, from congenital nephrotic syndrome to adult focal segmental glomerulosclerosis, including WT1 disorder (Denys-Drash and Frasier), syndromic forms and APOL1-mediated kidney disease.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definitions and the place of genetic SRNS in childhood and adult nephrotic syndrome

Nephrotic syndrome is defined by the combination of nephrotic proteinuria, hypoalbuminaemia and oedema. The 2020 recommendations of the International Pediatric Nephrology Association (IPNA) defined nephrotic proteinuria as a UPCR of 200 mg/mmol (2 mg/mg) or higher in the first morning urine, or excretion of at least 1000 mg/m²/day in a 24-hour urine collection, corresponding to 3+ or 4+ on a dipstick; nephrotic syndrome additionally requires serum albumin below 30 g/l or, if this value is unavailable, oedema [3]. The 2025 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for childhood nephrotic syndrome adopted the same definitions [4]. Approximately 85% of children with idiopathic nephrotic syndrome achieve complete remission with standard-dose PDN and are termed steroid-sensitive; the remainder, approximately 15%, have persistent proteinuria after 4 to 6 weeks and constitute SRNS [1, 3]. The 2023 French PNDS (French National Diagnosis and Care Protocol) gives similar but not identical figures: between 2 and 12 years of age, childhood nephrotic syndrome is idiopathic in approximately 90% of cases, proteinuria resolves within one month in 90% of treated children (median 10 days), approximately 10% do not respond to corticosteroids and, without response to subsequent treatments, half of these progress to ESKD [30]. The difference between 10% and 15% arises mainly from the definition of steroid resistance: the PNDS declares it only after 4 weeks of PDN and three pulses of methylprednisolone, whereas IPNA defines it at 4 weeks and confirms it by 6 weeks (Table 5.1a) [30].

SRNS is not a single disease. In one group, described in the literature as non-genetic and presumed to be immune-mediated by as yet unidentified circulating factors, approximately half of patients achieve sustained remission with intensified immunosuppression, and approximately 70% of those who undergo transplantation have rapid recurrence of disease in the graft [1]. In the other group, genetic SRNS, one or two pathogenic variants impair the formation or maintenance of the glomerular filtration barrier, which comprises the fenestrated endothelium, the glomerular basement membrane (GBM) and the podocytes with their slit diaphragm [1]. This group responds little or not at all to immunosuppression, progresses to ESKD in most cases and, because it is an intrinsic kidney disease, is corrected by kidney transplantation, with very low graft recurrence rates [1, 3]. A monogenic cause is found in approximately 30% of childhood-onset SRNS and in 10–15% of adult-onset cases, distributed across approximately 60 known genes [1].

CNS is nephrotic syndrome presenting in utero or within the first 3 months of life; in most patients it results from genetic podocyte defects and only rarely from congenital infections or maternal alloimmune disease [2]. The genes NPHS1, NPHS2, WT1 and LAMB2 account for more than 80% of all CNS [1, 7].

1.2. Historical overview and milestones in molecular discovery

Finnish-type CNS was characterised as a clinical entity before the molecular era. In 1976, Huttunen assembled the 75 patients born in Finland between 1965 and 1973 and estimated an incidence of 12.2 per 100,000 births; he described a large placenta and proteinuria from birth as hallmarks of the disease, oedema or abdominal distension at birth in approximately a quarter of patients and complete nephrotic syndrome before 2 months in all, and showed that, before dialysis and transplantation, more than half died before 6 months and none survived beyond 2 years and 3 months of age [24]. The name ‘Finnish type’ derives from this high incidence, approximately 1:8000 live births, underpinned by two NPHS1 founder variants [7].

WT1 disorder was the first podocytopathy with a molecular basis. In 1991, Pelletier and colleagues identified, in 10 independent cases of Denys-Drash syndrome (kidney failure, genital anomalies and Wilms tumour), heterozygous germline variants in the zinc fingers of the tumour suppressor gene WT1, nine in exon 9 and one in exon 8, which alter DNA recognition [31]. In 1997, Barbaux and colleagues demonstrated that Frasier syndrome, with a female phenotype, 46,XY karyotype, streak gonads, frequent gonadoblastoma and more slowly progressive glomerulopathy without Wilms tumour, is caused by variants at the WT1 intron 9 splice donor site that reduce the ratio of +KTS to −KTS isoforms [32].

Positional cloning of NPHS1 in 1998 identified nephrin, a 1241-amino-acid transmembrane protein of the immunoglobulin superfamily, expressed specifically in glomeruli [33]. In 2000, Boute and colleagues identified NPHS2, encoding podocin, a stomatin-family protein expressed almost exclusively in podocytes, in families with autosomal recessive SRNS of early-childhood onset, focal segmental glomerulosclerosis (FSGS) and rapid progression to ESKD [34]. In the same year, autosomal dominant FSGS caused by ACTN4 variants was described; this gene encodes α-actinin-4, an actin filament cross-linking protein [35]. In 2005, two groups associated variants in the TRPC6 cation channel with adult familial FSGS, shifting attention from podocyte structure to calcium signalling [36, 37].

Forms with diffuse mesangial sclerosis and syndromic forms followed. In 2004, Zenker and colleagues showed that laminin β2 deficiency caused by biallelic LAMB2 variants causes Pierson syndrome, CNS with diffuse mesangial sclerosis (DMS) and microcoria [38]. Hinkes and colleagues identified PLCE1 in 2006 in early-onset nephrotic syndrome with DMS and described two patients who responded to treatment, the first molecular cause of potentially reversible nephrotic syndrome [39]. The discovery of COQ6 in 2011, in 13 individuals from 7 families with SRNS and sensorineural deafness, and of ADCK4 (now COQ8B) in 2013, in 15 individuals from 8 families, opened up the category of coenzyme Q10 deficiency nephropathies, potentially treatable with supplementation [40, 41]. Loss-of-function WDR73 variants were described in Galloway-Mowat syndrome in 2014, and SGPL1 variants in nephrosis with ichthyosis and adrenal insufficiency in 2017 [42, 43].

The association between African ancestry and FSGS was initially attributed to MYH9. In 2010, Genovese and colleagues and Tzur and colleagues showed that the risk resides in two variants of the neighbouring gene APOL1, G1 and G2, which confer resistance to Trypanosoma brucei rhodesiense and underwent positive selection in Africa: in African Americans, the odds ratio (OR) for FSGS associated with two risk alleles was 10.5 (95% confidence interval [CI] 6.0–18.4) [44, 45].

1.3. Nomenclature and reclassifications

The terminology reflects the transition from a histological and pharmacological classification to an aetiological classification. The designation ‘idiopathic’ or ‘primary SRNS’ is controversial when applied to patients with a genetic cause, and ‘hereditary glomerulopathy’ is preferred for non-syndromic forms [1]. KDIGO 2021 began classifying FSGS by cause, calling disease with an identified monogenic cause ‘genetic FSGS’ and disease without one ‘FSGS of undetermined cause’ [46]. In WT1 disorder, GeneReviews no longer considers Denys-Drash, Frasier and Meacham useful clinical diagnoses, because they are points on a phenotypic continuum caused by heterozygous WT1 variants; the terms survive in the literature to denote constellations (Frasier: SRNS, complete 46,XY gonadal dysgenesis and gonadoblastoma; Denys-Drash: SRNS with DMS, Wilms tumour and 46,XY difference of sex development [DSD]), and the expression ‘male pseudohermaphroditism’ is obsolete [8]. The gene ADCK4 was renamed COQ8B [22], and the former ‘MYH9-associated nephropathies’ in populations of African ancestry are now understood as APOL1-mediated kidney disease [45], for which the United States has created specific ICD-10-CM codes [47].

1.4. Scope of the article

This article covers genetic SRNS in its broad sense: non-syndromic forms (NPHS1, NPHS2, PLCE1, TRPC6, INF2, ACTN4 and other podocyte genes), CNS, WT1 disorder with the Denys-Drash and Frasier constellations, syndromic forms (Pierson, primary CoQ10 deficiencies, Schimke, SPLIS, Galloway-Mowat, nail-patella, MYH9-related disease) and APOL1-mediated kidney disease. Predisposition to Wilms tumour and its detailed oncological surveillance, Alport syndrome and collagen IV nephropathies, and WAGR syndrome caused by an 11p13 deletion of WT1 and PAX6 are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The glomerular filtration barrier and disease pathways

The filtration barrier retains albumin through the combined action of the fenestrated endothelium, GBM and podocytes, whose interdigitating foot processes are connected by the slit diaphragm [1]. Genetic SRNS genes fall into functional pathways. The first group encodes slit diaphragm proteins: nephrin (NPHS1), whose molecules on adjacent foot processes bind to each other to form the albumin-retaining pore and anchor the diaphragm to the actin cytoskeleton, and podocin (NPHS2), which regulates permeability and links the membrane to the cytoskeleton [5]. The second group acts in the podocyte actin cytoskeleton (ACTN4, INF2, ARHGDIA, MYO1E, ANLN), the third in calcium and phosphoinositide signalling (TRPC6, PLCE1) and the fourth in the GBM matrix and podocyte adhesion (LAMB2, LAMA5, COL4A3/4/5, ITGA3, ITGB4, CD151) [1, 36–39]. Transcription factors involved in kidney and gonadal development (WT1, LMX1B, PAX2, MAFB) form another group; WT1 regulates, among others, slit diaphragm genes [8]. The spectrum is completed by mitochondrial coenzyme Q10 biosynthesis (COQ2, COQ6, COQ8B, PDSS2 and others), the nuclear pore complex (NUP93, NUP107, NUP133, NUP160, NUP205, NUP85), the tRNA-modifying KEOPS complex (OSGEP, TP53RK, TPRKB, LAGE3, GON7) and WDR73, sphingolipid metabolism (SGPL1) and chromatin remodelling (SMARCAL1) [1, 5, 7, 22].

The common consequence is massive urinary protein loss. In NPHS1-related CNS, initial morbidity results from protein loss rather than kidney failure: hypovolaemia and haemodynamic collapse, severe infections due to loss of immunoglobulin G (IgG) and opsonins, thrombosis due to loss of antithrombin III and plasminogen with compensatory hepatic synthesis of fibrinogen and procoagulant factors, hypothyroidism due to loss of thyroxine-binding globulin, vitamin D deficiency, anaemia due to loss of erythropoietin, iron and transferrin, and severe growth retardation [2, 5].

2.2. Genetic architecture: non-syndromic and syndromic forms

GeneReviews organises the genes into syndromic forms, non-syndromic forms and phenocopies [1]. The proportion attributed to each non-syndromic gene derives from different series and is approximate; the percentages do not add up to 100% [1]. Some genes are both syndromic and non-syndromic, such as COL4A3/4/5, COQ8B, CRB2, INF2, LMX1B and WT1 [1].

Table 2.1 — Non-syndromic genetic SRNS (proportion of all non-syndromic SRNS). Source: GeneReviews [1].

AR, autosomal recessive; AD, autosomal dominant; XL, X-linked.

Table 2.2 — Syndromic genetic SRNS (findings beyond SRNS). Source: GeneReviews, adapted from Preston 2019 and Trautmann 2020 [1].

The panel recommended by IPNA adds genes with more recently identified associations or a mixed phenotype, such as DLC1, EMP2, ITSN1, ITSN2, KANK1, KANK2, KANK4, KIRREL1, CFH, CLCN5, CUBN, FN1, LCAT, LMNA, MMACHC, NEU1 and NPHP4, several of which cause steroid-sensitive nephrotic syndrome or proteinuria through another mechanism [3].

2.3. NPHS1 and Finnish-type congenital nephrotic syndrome

NPHS1 is located at 19q13.12 and encodes nephrin [5, 33]. Loss of nephrin produces massive proteinuria from fetal life, without an enzymatic defect or measurable circulating metabolite [5]. In Finland, two founder variants account for most cases: Fin-major, NM_004646.4(NPHS1):c.121_122del, p.(Leu41fs), designated p.Leu41Aspfs in the literature, which causes an early frameshift and complete absence of nephrin in homozygosity, and Fin-minor, NM_004646.4(NPHS1):c.3325C>T, p.(Arg1109Ter) [5, 48]. Complete absence of nephrin in Fin-major homozygotes underlies alloimmunisation against graft nephrin after transplantation [2]. The ERKNet and European Society for Paediatric Nephrology (ESPN) consensus found no difference between truncating and missense NPHS1 variants in age at diagnosis, the proportion of patients with ESKD or death, or the need for albumin infusions; a milder subgroup is associated with NM_004646.4:c.3478C>T, p.(Arg1160Ter) [7].

2.4. NPHS2, podocin and variant-dependent inheritance

NPHS2 (1q25.2) encodes podocin, and its biallelic variants are the single most frequent cause of non-syndromic genetic SRNS [1, 5]. The European founder variant NM_014625.4(NPHS2):c.413G>A, p.(Arg138Gln), is frequent in CNS without NPHS1 variants; homozygotes develop nephrotic syndrome at a median of 2 months and ESKD usually after 5 years (median 79 months; 24–159) [7, 48]. The variant NM_014625.4(NPHS2):c.779T>A, p.(Val260Glu), is associated with earlier onset and more rapid progression [7]. Patients with two pathogenic variants usually present before 6 years and progress rapidly; truncating variants and p.Arg138Gln manifest earlier [5, 49, 50].

The variant NM_014625.4(NPHS2):c.686G>A, p.(Arg229Gln), is hypomorphic and has conflicting classifications in ClinVar [48]. Tory and colleagues demonstrated that its pathogenicity depends on the variant in trans [51]: it causes disease only when associated with certain pathogenic variants in exons 7 or 8 [7], and subsequent studies attributed this behaviour to interactions between the products of the two alleles mediated by C-terminal podocin oligomerisation [3]. These combinations cause later-onset nephrotic syndrome, with a median of 17 months and cases extending into adulthood, which has implications for prognosis, counselling and selection of related donors [7, 52]. The carrier frequency of p.Arg229Gln is 3% in the multiethnic general population, 7% in Finns and 0.01% in East Asians, so that a patient's parent may themselves have a biallelic genotype and a risk of late-onset SRNS [1].

2.5. WT1: one transcription factor, two variant types and a phenotypic continuum

WT1 (11p13) encodes a transcription factor with a proline- and glutamine-rich domain and four zinc fingers encoded by exons 7 to 10; it is expressed in renal progenitors and podocytes, in the urogenital ridge and in gonadal progenitors, generates more than 30 isoforms through alternative splicing, alternative translation initiation sites and RNA editing, and acts as both a tumour suppressor and an oncogene [8]. An alternative donor site in intron 9 adds the amino acids lysine, threonine and serine (KTS) between the third and fourth zinc fingers; the ratio of +KTS to −KTS isoforms regulates 46,XY testicular development [8, 32].

Two mechanisms explain the spectrum. Missense variants in the DNA-binding residues of zinc fingers 2 and 3 (residues 439–454 in exon 8 and 467–474 in exon 9, according to protein NP_077742.3) act in a dominant-negative manner, altering DNA binding and specificity [8]. Variants at positions +4 and +5 of intron 9 reduce the +KTS:−KTS ratio [8]. As a tumour suppressor, germline loss of WT1 function confers a high risk of Wilms tumour under Knudson's two-hit model [8]. In the older literature, exonic variants were called ‘Denys-Drash-type’ and intronic KTS variants ‘Frasier-type’ [8].

WT1 variant nomenclature is a common source of error, because different transcripts give the same variant different HGVS designations [8]. In the MANE Select transcript NM_024426.6, the most common exonic variant is c.1399C>T, p.(Arg467Trp), originally described as p.Arg394Trp in the shorter isoform and also as c.1384C>T, c.1180C>T or p.Arg462Trp; Frasier syndrome variants are c.1447+4C>T, historically c.1432+4C>T or IVS9+4C>T, and c.1447+5G>A, historically c.1432+5G>A or IVS9+5G>A [8, 48]. In the genome, c.1447+4C>T corresponds to NC_000011.10:g.32391968G>A; correspondence with the historical transcripts follows the equivalences published by GeneReviews [8, 48].

Genotype–phenotype correlations in WT1 disorder. Truncating variants (nonsense, frameshift and splice variants outside the KTS site) are associated with Wilms tumour as a frequent first manifestation, a higher risk of bilateral tumour (OR 18.4), CAKUT in approximately one in five patients, 46,XY DSD in the vast majority of phenotypic males, and proteinuria typically in the second decade, with a slower course [8]. The ERKNet-ESPN consensus gives a Wilms tumour risk of approximately 80% and a CAKUT risk of approximately 25% for these variants [7]. Missense variants in the DNA-binding residues of exons 8 and 9 confer the highest risk of CNS or early, rapidly progressive SRNS, with 50% of patients reaching ESKD by 2.5 years, and, in 46,XY individuals, approximately 80% DSD and 20% complete gonadal dysgenesis [8]. Missense variants in exons 8 and 9 outside the DNA-binding region produce an intermediate glomerulopathy, manifesting before 5 years, with ESKD around 10 years [8]. Intron 9 splice donor variants are associated with later onset, slow progression with ESKD typically in adolescence, complete 46,XY gonadal dysgenesis in most cases, a higher risk of gonadoblastoma and a Wilms tumour risk of 3% or less [8]. Penetrance is high and age-dependent, approximately 90% by the end of puberty; asymptomatic carrier parents have been described, and penetrance appears higher when the variant is of paternal origin, although data are limited [8].

No other phenotypes are known for germline intragenic WT1 variants; contiguous deletions of WT1 and PAX6 cause WAGR syndrome [8]. Somatic WT1 variants occur in approximately 15% of sporadic Wilms tumours and in 6–15% of de novo acute myeloid leukaemias, and the EWS-WT1 fusion is pathognomonic of desmoplastic small round cell tumour; these oncological aspects belong to predisposition to Wilms tumour [8].

2.6. PLCE1 and LAMB2: causes of diffuse mesangial sclerosis

PLCE1 encodes phospholipase C ε, and its biallelic variants cause early-onset nephrotic syndrome type 3 with DMS, interpreted as arrested glomerular development [39]. In a worldwide cohort of isolated DMS, median age at onset was 11 months (1–72), and biallelic PLCE1 variants were found in 10 of 35 families (28.6%) [53]; in another series, PLCE1 accounted for 8 of 24 DMS cases (33%) and 6 of 78 FSGS cases without NPHS2 variants (8%), the latter with later onset [54]. PLCE1 splice variants (source numbering in NM_016341.3; MANE transcript NM_016341.4) are associated with earlier onset than C-terminal truncating variants, after residue 1000, and missense variants [7]. According to data from Sadowski and colleagues, DMS is associated with dominant WT1 in 23.1% of cases, PLCE1 in 17.8%, LAMB2 in 13.6% and NPHS1 in 4.9% [7]. DMS with genital anomalies or Wilms tumour points towards WT1 rather than PLCE1 [5].

LAMB2 (3p21.31) encodes the laminin β2 chain, concentrated in the GBM, neuromuscular junction and intraocular muscles [5]. Most Pierson syndrome alleles are truncating, with loss of laminin β2 expression in the kidney [38]. The spectrum follows residual function: N-terminal truncating variants manifest before 2 months, C-terminal variants later, while missense variants and small in-frame deletions are associated with later onset and absence of neurological abnormalities; DMS is present in 61% of LAMB2-associated nephrotic syndromes [7]. At the mild end lies nephrotic syndrome type 5 (OMIM 614199), with early progressive kidney failure and mild or absent ocular anomalies (myopia, nystagmus, strabismus) [5]. At a distinct allelic extreme, two truncating LAMB2 variants caused a severe synaptic congenital myasthenic syndrome with congenital nephrosis and ocular malformations; muscle biopsy showed profound distortion of the neuromuscular junction, and the patient had a severe adverse reaction to acetylcholinesterase inhibitors [55].

2.7. Autosomal dominant genes in adult FSGS: TRPC6, INF2, ACTN4 and collagen IV

INF2, TRPC6 and the collagen IV genes (COL4A3/4/5) are the main causes of adult-onset SRNS [1]. TRPC6 encodes a slit diaphragm cation channel; the variant NM_004621.6(TRPC6):c.335C>A, p.(Pro112Gln), described in a large family, increases TRPC6-mediated calcium signals in response to agonists such as angiotensin II, and in five families with autosomal dominant FSGS two variants increased current amplitude, suggesting a gain-of-function mechanism [36, 37]. In two multicentre cohorts published in 2025, TRPC6-associated podocytopathy presented with proteinuria or nephrotic syndrome in 83.7% of patients and FSGS in 89.4% of biopsies, with a mean age at onset of 22 years (standard deviation 14); 48.9% of 141 patients had kidney failure at a median age of 33 years (interquartile range [IQR] 17–40), sporadic cases progressed earlier and had nephrotic syndrome more frequently (OR 4.34), and median kidney survival was 21 years with NM_004621.6:c.523C>T, p.(Arg175Trp), and 38 years with NM_004621.6:c.2683C>T, p.(Arg895Cys) [5, 56, 57]. All 31 variants were missense, and sequencing of 37,542 individuals did not support the causality of truncating variants, so a truncating TRPC6 variant or deletion should not be reported as a cause of FSGS [5, 56].

INF2 causes autosomal dominant FSGS with onset mainly in adolescence or adulthood through a gain-of-function mechanism [5, 58]. It was found in 17% of 54 families with dominant FSGS and in 1 of 84 sporadic cases [59]. It is associated with dominant intermediate Charcot-Marie-Tooth disease type E (CMT): in 16 probands with CMT and FSGS without PMP22 or MPZ variants, 12 (75%) had INF2 variants [60]. ACTN4 causes FSGS1, with mild to moderate, often non-nephrotic proteinuria in adolescence or adulthood and slow decline; de novo variants at residues 260–265 are associated with collapsing glomerulopathy and failure in childhood [5]. Electron microscopy shows cytoplasmic electron-dense aggregates in podocytes, and ACTN4 accounts for approximately 4% of familial FSGS [5, 61]. COL4A3/4/5 variants account for 10–30% of non-syndromic SRNS with onset from the second decade, and all males with X-linked Alport syndrome develop proteinuria, approximately 30% with nephrotic syndrome [1, 62].

2.8. Primary coenzyme Q10 deficiencies

Primary CoQ10 deficiency is defined by reduced tissue CoQ10 with biallelic variants in one of its 10 biosynthesis genes (COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9, PDSS1, PDSS2), all nuclear and autosomal recessive [22, 63]. SRNS is unusual in mitochondrial diseases generally but is a hallmark of this group; it has been described with PDSS1, PDSS2, COQ2, COQ6 and COQ8B, but not with COQ4, COQ8A or COQ9 [22]. The former five-phenotype classification has been abandoned [22].

Table 2.3 — CoQ10 biosynthesis genes and organs involved. Source: GeneReviews [22].

COQ6 (primary CoQ10 deficiency type 6) causes SRNS with sensorineural deafness; validated in yeast, its knockdown in podocytes and zebrafish causes apoptosis partially reversed by CoQ10, and expression in the stria vascularis explains the otorenal phenotype [40]. COQ8B (ADCK4) interacts with COQ6 and COQ7; patient cells show reduced CoQ10 and respiratory chain activity, and reduced podocyte migration is reversed by CoQ10 [41]. Robust genotype–phenotype correlations have not been established [7]. The mitochondrial MT-TL1 variant NC_012920.1:m.3243A>G may associate nephropathy with FSGS with diabetes and deafness in the fourth decade [63].

2.9. Other syndromic forms: SGPL1, SMARCAL1, Galloway-Mowat, LMX1B and MYH9

SGPL1 encodes sphingosine-1-phosphate lyase; biallelic variants cause sphingosine phosphate lyase insufficiency syndrome (SPLIS, also designated NPHS14 or RENI syndrome), with increased plasma sphingosine-1-phosphate and sphingosine/sphinganine ratio [9, 43, 64]. Approximately half of variants cause complete loss of function. The variant NM_003901.4(SGPL1):c.665G>A, p.(Arg222Gln), accounts for 29–30% of alleles and occurs almost always in homozygosity, and the variant NM_003901.4:c.1247A>G, p.(Tyr416Cys), is a founder variant in North American Dariusleut Hutterites [9, 48]. SPLIS shows intrafamilial variability, from fetal loss to late onset [9].

SMARCAL1 (2q35) encodes an ATP-dependent annealing helicase involved in chromatin remodelling; the severity of Schimke immuno-osseous dysplasia is inversely proportional to the expression, stability, localisation and chromatin binding of the mutant protein, and some patients with a typical phenotype have no SMARCAL1 variants [6]. Truncating variants are associated with an early, severe phenotype, but not with renal severity; renal variability is low and extrarenal variability high [10, 65].

Galloway-Mowat syndrome (GAMOS) combines neurodevelopmental defects and podocytopathy. It is caused by biallelic variants in at least 10 genes: KEOPS complex subunits (OSGEP, TP53RK, TPRKB, LAGE3, GON7), WDR73, WDR4 (post-transcriptional tRNA modification), NUP107 and NUP133 (nuclear pore complex) and PRDM15 [5, 7, 66]. LAGE3 is X-linked [1].

LMX1B (9q34), a transcription factor with LIM domains and a homeodomain, causes nail-patella syndrome (autosomal dominant), and homeodomain variants are associated with more frequent and more marked proteinuria [11, 67]. An allelic disorder is isolated LMX1B-associated FSGS without other signs of the syndrome, described in one family with NM_001174147.2(LMX1B):c.737G>A, p.(Arg246Gln), and another with three affected individuals with FSGS and GBM thinning and the variant c.349G>A, p.(Gly117Ser) [11, 48]. MYH9 encodes the non-muscle myosin heavy chain IIA; variants at codon Arg702 are associated with severe thrombocytopenia, nephropathy and deafness in all patients before 40 years, and rapid progression to ESKD [23].

2.10. APOL1: risk alleles with toxic gain of function

APOL1 (22q12.3) encodes apolipoprotein L1, present in a subfraction of high-density lipoproteins and an active component of the trypanosome lytic factor in human serum, which forms pores in the parasite's lysosomal membrane [5]. The African-origin G1 and G2 variants lyse T. b. rhodesiense, explaining their positive selection [44]. G1 is a haplotype of two missense variants in cis, NM_003661.4(APOL1):c.1024A>G, p.(Ser342Gly), and c.1152T>G, p.(Ile384Met) (haplotype NM_003661.4:c.[1024A>G;1152T>G]); G2 is the in-frame deletion NM_003661.4(APOL1):c.1164_1169del, p.(Asn388_Tyr389del) [48]. In other isoforms, G1 appears as S358G/I400M [48]. ClinVar classifies these variants as ‘risk factor’ [48].

The model is recessive and non-Mendelian: the high-risk genotype comprises two alleles (G1/G1, G2/G2 or G1/G2), and heterozygotes are essentially unaffected [5]. The mechanism is toxic gain of function, with channel or pore activity damaging to the podocyte [5]. Penetrance is low and requires a genetic or environmental ‘second hit’, such as viral infections, of which untreated human immunodeficiency virus (HIV) infection is the strongest example [5, 68]. An APOL1 result is not diagnostic, does not prove the cause of a patient's kidney disease, does not predict failure in a healthy carrier and carries no Mendelian recurrence risk [5]. Risk is linked to recent African ancestry rather than a racial category; only genotyping determines each person's status [5].

2.11. Normalised reference variants

Table 2.4 — Reference variants cited in the article, with MANE transcript and historical designation. Source: ClinVar and VariantValidator, accessed October 2026 [48].

The COQ2 variants in the case in section 10 were published in the numbering of transcript NM_015697.9 (421-amino-acid isoform); in the MANE transcript NM_001358921.2 the numbering is lower by 150 nucleotides and 50 amino acids, and both notations are given in the text [69].

2.12. Allelic disorders, modifiers and penetrance

Variability within the same gene is the rule. LAMB2 ranges from Pierson syndrome to isolated nephrotic syndrome type 5 and congenital myasthenic syndrome [5, 55]; LMX1B from nail-patella syndrome to isolated FSGS [11]; INF2 from isolated FSGS to its association with CMT [60]; and COQ8B from isolated SRNS in adolescence to forms with intellectual disability and seizures [22]. In NPHS2, the allele in trans modifies age at onset, and p.Arg229Gln has been proposed as a modifier with a theoretical dominant-negative effect in heterozygous carriers [3, 51]. In WT1 disorder, penetrance is incomplete and age-dependent, and expressivity varies even within the same family [8]. In APOL1-related FSGS, environmental and genetic factors acting as a second hit are the main modifiers [68].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history of genetic SRNS compared with non-genetic SRNS

Age at onset and rate of progression depend on the gene and variant type [1]. The difference between genetic and non-genetic forms is nevertheless consistent across cohorts. The systematic review underpinning the IPNA recommendations found, in genetic forms, complete remission with immunosuppression in 2.7–3.0% and partial remission in 10.8–16%, progression to ESKD in 71–74% versus 4–29% in non-genetic forms, and median kidney survival of 45–48 months versus 58–205 months [3]. In the German study by Büscher and colleagues, comprising 231 systematically genotyped patients and a median observation period of 113 months (IQR 50–178), 66% of patients with genetic SRNS reached ESKD and only 3% achieved complete and 16% partial remission with ciclosporin A, whereas 78% of patients without a genetic cause entered remission after a median of 2.5 months, and 98% of those achieving complete remission with ciclosporin retained normal kidney function [70]. In the PodoNet registry (1354 patients with primary SRNS with onset between 3 months and 20 years), 10-year ESKD-free survival was 27% with a genetic diagnosis, 43% with resistance to intensified immunosuppression, 72% with partial remission and 94% with complete remission; DMS had 5-year kidney survival of 21% [71]. Sporadic multidrug-resistant disease had better kidney survival than genetic disease [71]. These figures describe patients treated in paediatric referral centres between the 1990s and the 2010s, with access to dialysis and transplantation, rather than untreated natural history.

3.2. Congenital nephrotic syndrome and NPHS1

The phenotype of NPHS1-related CNS is stereotyped: proteinuria from the first days of life, a large placenta (more than 25% of the newborn's weight), frequently increased nuchal translucency, elevated alpha-fetoprotein in amniotic fluid, fetal oedema or oligohydramnios, prematurity and meconium-stained fluid [2, 5]. Most CNS presenting in the first week of life has biallelic NPHS1 variants, although histology is not always ‘Finnish type’ [7]. Complications arise from protein loss: hypovolaemia, severe infections caused by encapsulated bacteria, large-vessel thrombosis, hypothyroidism, hypogammaglobulinaemia, hyperlipidaemia, vitamin D deficiency with secondary hyperparathyroidism, anaemia and severe growth retardation [2, 5]. In the Finnish 1965–1973 cohort, without dialysis or transplantation, mean survival was 7.6 months (0–26), infection was the immediate cause of death in 31%, and large-vessel thrombi were present in 11 of 58 post-mortem examinations [2, 24]. Since 1995, the approach using dialysis, nephrectomy and transplantation, followed by conservative management without routine nephrectomy, has allowed more than 90% of children to undergo transplantation, with kidney and overall survival similar to those of other transplanted children [2]. Most survivors progress to kidney failure within a few years [5].

3.3. NPHS2-related SRNS

Biallelic NPHS2 is the main genetic cause of CNS with onset after the first month, with no correlation between age at onset and variant type (truncating or missense) [7]. In childhood, patients with two pathogenic variants usually present before 6 years, with FSGS or non-specific diffuse mesangial proliferation on biopsy, and progress rapidly to ESKD [5]. In a study of 338 patients, NPHS2 variants were found in 43% of autosomal recessive familial SRNS and 10.5% of sporadic cases [5, 49]. Combinations with p.Arg229Gln produce later-onset disease, extending into adulthood [52]. Patients with NM_014625.4:c.412C>T, p.(Arg138Ter), had cardiac anomalies in 89% of cases, warranting cardiac assessment [7].

3.4. WT1 disorder, including the Denys-Drash and Frasier constellations

WT1 disorder combines SRNS of congenital, infantile or childhood onset, abnormalities of testicular development and Wilms tumour; CAKUT, gonadoblastoma and 46,XX gonadal dysgenesis are less common, and in adulthood most patients have early gonadal insufficiency [8]. Prevalence is unknown and fewer than 500 patients have been described, without founder variants or geographical bias [8]. Orphanet records approximately 300 cases or families with Denys-Drash syndrome and approximately 150 with Frasier syndrome [14, 15].

Table 3.1 — Frequency of findings in WT1 disorder. Source: GeneReviews [8].

Persistent proteinuria is the most common initial finding; it fluctuates initially and progressively worsens, with variable severity even within the same family, and patients with ESKD may be anuric [8]. SRNS may precede Wilms tumour by up to 4 years, coincide with it or arise up to 10 years after completion of oncological treatment; it leads to irreversible decline and ESKD, and CNS is more rapid, with ESKD within weeks to months [8]. Biopsy shows DMS mainly before 2 years and FSGS in older children, but histology is heterogeneous even with the same variant and does not correlate with clinical features [8]. Wilms tumour in heterozygotes with an exonic variant has an estimated risk of one tumour per 9 years at risk, a median of 1.3–1.6 years (0–4.5), and is bilateral in more than 50% of truncating variant carriers; survival is similar to that of Wilms tumour without a known cause [8]. Gonadoblastoma has an observed incidence of one tumour per 30 years at risk in 46,XY individuals with DSD or gonadal dysgenesis, and Sertoli cell tumours and other germ cell tumours have been described [8]. Diaphragmatic hernia has been described in fewer than 10 infants [8]. In Meacham syndrome, with diaphragmatic hernia, pulmonary dysplasia, complex heart disease and genitourinary anomalies, no patient with a confirmed WT1 variant and a diaphragmatic defect had complex heart disease, suggesting a multigenic cause [8, 72].

Denys-Drash constellation. This corresponds to the triad of Wilms tumour, DSD (severe in 46,XY individuals) and nephropathy presenting with hypertension and proteinuria and progressing to kidney failure, with DMS usually before 1 year [32, 73]. Median age at Wilms tumour diagnosis is 16 months; disease is usually de novo, and non-penetrance has been described in carrier parents [73]. In a historical series of 33 patients with severe hypospadias, a cause was found in 12, three of whom had Drash syndrome [74].

Frasier constellation. This is defined by a female phenotype with a 46,XY karyotype and streak gonads, frequent gonadoblastoma and glomerulopathy with childhood proteinuria, nephrotic syndrome and FSGS, with ESKD in adolescence or early adulthood; no Wilms tumour was described in the original study, even with prolonged follow-up [32]. Intronic KTS variants also cause isolated SRNS with FSGS and slow progression in genotypically and phenotypically female individuals, and 46,XY sex reversal with complete gonadal dysgenesis occurs with intronic KTS variants and exonic variants [7].

Isolated WT1 nephropathy. Some children with DMS or FSGS without other signs have constitutional WT1 variants, and vertical transmission of isolated SRNS occurs [8, 73].

After kidney transplantation, post-transplant lymphoproliferative disease (PTLD) has been described in 7–17% of patients with WT1 disorder, compared with a 25-year cumulative incidence of 3.6% (95% CI 2.7–4.8) in all transplanted children; it is not possible to state that risk is higher in WT1 disorder, and a French case–control study registered in 2026 has not yet started recruitment [8, 75].

3.5. PLCE1 and Pierson syndrome

Patients with PLCE1 have early nephrotic syndrome with DMS and progression to ESKD; incomplete penetrance has been described anecdotally, and some cases respond to steroids or ciclosporin, although most are resistant [7, 53]. In Pierson syndrome, CNS with DMS is accompanied by microcoria, a small fixed pupil due to hypoplasia of the ciliary and pupillary muscles, and cataracts and other lens and retinal anomalies [38]. Neurological disease is primary rather than a consequence of chronic kidney disease (CKD): among four surviving children aged 1.3–4.8 years receiving kidney replacement therapy, the three with biallelic truncating variants had severe hypotonia, psychomotor delay and blindness, whereas a girl with presumed residual function had milder kidney disease, normal development and preserved vision [76]. Orphanet records 98 described cases [16].

3.6. Autosomal dominant FSGS in adolescents and adults

TRPC6-related FSGS begins at a mean age of 22 years, and approximately half of patients reach kidney failure in the fourth decade [56, 57]. INF2-related disease manifests in adolescence or adulthood, sometimes with intermediate-conduction-velocity peripheral neuropathy and sensorineural deafness; it does not respond to steroids or immunosuppression, and transplantation has good outcomes [5, 60]. ACTN4-related disease often has non-nephrotic proteinuria and slow decline, with early, severe exceptions [5]. In nail-patella syndrome, renal involvement occurs in 30–50% of patients, with intermittent proteinuria at any age, which may remit, persist or progress to nephrotic syndrome; ESKD was estimated at up to 15%, 5% and less than 5% in different series, the last Japanese, and electron microscopy shows irregular GBM thickening with electron-lucent areas and collagen-like fibres [11]. In MYH9-related disease, nephropathy begins at a mean age of 27 years, 72% of cases are diagnosed before 35 years, and after a median of 36 months 64% of 61 patients with nephropathy had CKD and 43% ESKD [23].

3.7. Primary coenzyme Q10 deficiencies

Nephropathy usually presents with proteinuria in early childhood; many patients begin with SRNS that progresses to ESKD, followed by encephalomyopathy with seizures and stroke-like episodes, severe neurological disability and death, while others have isolated SRNS with onset in the first or second decade and slow progression [22]. In patients with COQ6, the kidney is affected first, at a median age of 1.2 years, with nephrotic proteinuria and FSGS; without treatment, approximately half have kidney failure by 5 years, deafness develops on average around 3 years and is progressive, and only approximately 11% have isolated renal involvement at diagnosis [77]. COQ8B causes SRNS in the first or second decade, characteristically in adolescence, with less prominent extrarenal manifestations [5, 22]. COQ2 produces isolated SRNS or SRNS with encephalomyopathy and multisystem disease, including hypertrophic cardiomyopathy, diabetes and liver failure [7, 22]. PDSS2 has been described in fewer than 10 patients, with Leigh syndrome, retinopathy, optic atrophy and deafness; neonatal forms with nephrotic syndrome, hypertrophic cardiomyopathy, encephalomyopathy and lactic acidosis are lethal [5, 7]. Severe multisystem forms respond poorly to treatment and are usually fatal in the neonatal period or first year [22].

3.8. Schimke immuno-osseous dysplasia

Schimke immuno-osseous dysplasia (SIOD) combines spondyloepiphyseal dysplasia with short-trunk short stature, nephropathy and T-lymphocyte deficiency [10]. In more than 100 patients with biallelic SMARCAL1, disproportionate short stature was present in approximately 99% (intrauterine growth restriction in 70%), nephropathy with proteinuria in 99% and FSGS in 83%, T-lymphocyte deficiency in approximately 80%, and recurrent or opportunistic infections in 60–80%; migraine-like headaches, transient ischaemic attacks (TIA) and stroke occurred in 47%, 41% and 43% [5]. Kidney disease manifests 1–5 years after growth retardation is detected and progresses to ESKD within 2–12 years; 1–8 years later, TIA and cerebral infarctions develop due to progressive arteriosclerotic stenoses, which are not halted by medication or kidney transplantation [6]. Hypothyroidism occurs in approximately half of patients, autoimmune disease in approximately 20%, and there is a risk of non-Hodgkin lymphoma and leukaemia [6, 10]. Mean age at death is 11 years; causes were infection (23%), stroke (13%), pulmonary hypertension or heart failure (13%), kidney failure (11%) and transplant complications (9%) [10]. Mild forms, presenting between 8 and 13 years, survive into adulthood [6].

3.9. SPLIS and Galloway-Mowat

In SPLIS, GeneReviews brings together 76 published and 12 unpublished patients. Frequencies were: SRNS 80%, primary adrenal insufficiency 65% (five with mineralocorticoid deficiency), hypothyroidism 35%, testicular failure in 33% of males, immunodeficiency 36%, developmental delay 31%, ichthyosis or acanthosis 31%, cranial nerve deficits 22% and sensorineural deafness 19% [9]. Renal involvement ranges from non-immune hydrops fetalis to adolescent nephrosis; the interval between first proteinuria and kidney failure was less than 1 to 60 months, with a median of 30 months, and the latest known onset was at 25 years [9]. Survival in non-transplanted patients with two complete loss-of-function variants was 28%; survival in p.Arg222Gln homozygotes, with a mean presentation age of 8 years, was 77% versus 44% with other variants; in Hutterites with p.Tyr416Cys it was 66.7% [9]. In 15 pregnancies, hydrops, adrenal calcifications and increased nuchal translucency were described, with four fetal deaths [9].

In WDR73-related GAMOS, a systematic review of 64 patients found a median age at onset of 2.5–6 months, psychomotor impairment in all, microcephaly in 85.9%, cerebellar atrophy in 85.3% of those investigated, ocular abnormalities in 84.4%, axial hypotonia in 81.3%, movement disorders in 62.5% and proteinuria in 57.8%; 95.3% were homozygotes [78]. Inter- and intrafamilial variability of renal involvement is considerable, and some patients have no kidney disease [7]. In Kuwait, five of eight patients from five families died between 5 and 10 years, mainly from ESKD [79].

3.10. APOL1-mediated kidney disease

With two risk alleles, the OR for FSGS was 17 (95% CI 11–26) and that for HIV-associated nephropathy (HIVAN) 29 (13–68) in one series, and the two alleles accounted for 18% of FSGS and 35% of HIVAN [80]. APOL1-associated FSGS begins earlier and progresses more rapidly, with similar steroid sensitivity [5]. The estimated lifetime risk of FSGS without HIV with two alleles is 4.25% (1:24), and that of HIVAN without antiretroviral therapy 50% (1:2), compared with 0.2% and 2.5% without risk alleles [46]. High-risk genotypes are also associated with nephropathies caused by other viruses, other glomerulopathies, transplant outcomes and pregnancy complications; in children, they are associated with SRNS and CKD progression, although paediatric studies are small [68]. In the CureGN network, 18% of participants with FSGS had two risk alleles [81]. HIVAN biopsy appearances are the same regardless of allele number, and APOL1 does not increase the risk of HIV immune complex disease [46].

4. Clinical Recognition and Warning Signs

4.1. When to suspect a genetic cause

The probability of a genetic cause decreases with age at onset and increases with family history and extrarenal manifestations [3]. In an international cohort of 1783 families with SRNS beginning before 25 years, a monogenic cause was found in 69.4% with onset at 0–3 months, 49.7% at 4–12 months, 25.3% between 1 and 6 years, 17.8% between 7 and 12 years and 10.8% between 13 and 18 years [25]. Absence of a family history does not exclude genetic SRNS, because most forms are recessive or de novo and some dominant forms have reduced penetrance [1]. A genetic cause should be suspected in: nephrotic syndrome within the first 12 months, particularly the first 3 months; primary steroid resistance, because secondary resistance, in an initially steroid-sensitive child, had no monogenic cause in British series [82]; consanguinity or relatives with proteinuria, haematuria or CKD of unknown cause; extrarenal findings; DMS on biopsy; adult FSGS with a family history, syndromic features or resistance to immunosuppression [3, 4, 46]. The 2023 French PNDS lists, from the first assessment of childhood nephrotic syndrome, the features that raise concern for a secondary or genetic form: impure presentation (severe hypertension, organic kidney failure, macroscopic haematuria), extrarenal manifestations, age under 1 year or over 12 years, parental consanguinity, a family history of nephrotic syndrome or other nephropathies, a dysimmune background and oedema of more than a few weeks' duration [30]. In these situations, and also below 2 years of age, in the presence of a complication or a familial form, the protocol requires the opinion of a paediatric nephrologist from the outset; steroid resistance requires immediate referral [30].

4.2. Recognition by age

Prenatal and neonatal. In CNS, prenatal signs include increased nuchal translucency, elevated alpha-fetoprotein in amniotic fluid, fetal oedema, oligohydramnios and a placenta exceeding 25% of the newborn's weight; at birth, oedema and abdominal distension [2, 24]. Non-immune hydrops fetalis and adrenal calcifications suggest SPLIS, and prenatal ventriculomegaly with corticomedullary cysts suggests CRB2 [7, 9]. Generalised oedema in early childhood should prompt urine dipstick testing for protein [83].

Infant and young child. Nephrotic syndrome with DMS suggests WT1, PLCE1 or LAMB2; a small fixed pupil suggests Pierson syndrome; microcephaly with severe delay suggests GAMOS; deafness, ataxia, seizures or encephalopathy suggest CoQ10 deficiency [7, 22].

Older child and adolescent. Disproportionate short stature with a short trunk suggests SIOD; a sitting-height/leg-length ratio below 0.83 makes SIOD very likely, while values above 1.01 suggest other causes of short stature in CKD [10]. Isolated adolescent SRNS is typical of COQ8B [5].

Adult. FSGS with a dominant family history suggests INF2, TRPC6, ACTN4 or collagen IV; peripheral neuropathy suggests INF2; macrothrombocytopenia suggests MYH9; nail dysplasia and a hypoplastic patella suggest LMX1B [1, 11, 23]. In people of African ancestry, FSGS or HIVAN raises the question of APOL1 [46].

4.3. Extrarenal clues

Table 4.1 — Extrarenal findings and suggested genes. Sources: ERKNet-ESPN consensus and GeneReviews [1, 7].

4.4. Emergency signs

In CNS and severe SRNS, signs of intravascular hypovolaemia (oliguria, acute kidney injury [AKI], prolonged capillary refill, tachycardia, hypotension, abdominal discomfort) require albumin and contraindicate diuretics because of the risk of thrombosis and AKI [2, 3]. Fever in an infant with CNS requires immediate empirical antibiotics, because C-reactive protein and leucocytes are not reliable indicators of sepsis in these patients [2]. Signs of venous or arterial thrombosis, infections caused by encapsulated bacteria and peritonitis are serious complications [2, 3]. In SPLIS, unrecognised adrenal insufficiency exposes patients to crises during intercurrent illness and surgery [9]. In SIOD, TIA and stroke, and in WT1 disorder an abdominal mass, require immediate assessment [8, 10].

4.5. Newborn and presymptomatic screening

There is no population newborn screening for genetic SRNS in the sources consulted. Presymptomatic detection takes place within the family: IPNA recommends offering urinalysis to siblings of a child with SRNS, even before the genetic test result, because recurrence risk in autosomal recessive forms is 25% [1, 3]. In CoQ10 deficiencies, siblings should be assessed as early as possible because of the benefit of early treatment [22]. A dried blood spot from newborn screening can serve as a sample for genetic testing in an infant who has received a transfusion or in whom sampling is difficult [7].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and operational definitions

IPNA developed its recommendations with a core group of 18 experts (paediatric nephrologists, renal geneticists, epidemiologists, an adult nephrologist and a pathologist), three patient representatives and a dietitian, a Delphi panel of 23 paediatric nephrologists with a consensus threshold above 70%, and a systematic review up to September 2019 addressing 9 PICO questions, for children older than 3 months and younger than 18 years; grading followed the American Academy of Pediatrics, with evidence levels A to D and X and strong, moderate, weak or discretionary recommendation strength [3]. Most recommendations are weak to moderate because of a lack of good-quality trials [3].

Table 5.1 — Definitions of childhood nephrotic syndrome according to IPNA 2020, adopted by KDIGO 2025. Sources [3, 4].

KDIGO 2025 adds CNI-responsive SRNS (partial remission at 6 months and/or complete remission at 12 months) and recommends collecting the first morning urine separately to exclude orthostatic proteinuria [4]. For WT1 disorder, GeneReviews uses the definition of persistent proteinuria lasting more than 3 months: 24 h urinary protein >100 mg/m²/day, UPCR ≥0.2 mg/mg (≥0.5 mg/mg below 2 years) or UPCR >20 mg/mmol (>50 mg/mmol below 2 years) [8].

Table 5.1a — Definitions of the 2023 French PNDS compared with IPNA 2020. Sources: PNDS «Syndrome néphrotique idiopathique de l’enfant» and IPNA [3, 30].

The PNDS considers prolonged remission to be the absence of relapse for 12 months, with or without treatment, and cure the absence of relapse for 2 years after stopping all specific treatment, without excluding late relapses [30]. In practice, the French definition delays the diagnosis of steroid resistance by just over a week relative to the 4 weeks of IPNA, but generally falls within the confirmation period that IPNA uses to request genetic testing [30].

There are no formal clinical criteria for genetic SRNS. Diagnosis rests on identifying a pathogenic or likely pathogenic variant (biallelic in recessive forms, heterozygous in dominant forms) in an associated gene, in a patient with a compatible phenotype; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [3, 8]. In CoQ10 deficiency and SPLIS, diagnosis requires biallelic variants and at least one suggestive finding [9, 22].

5.2. Initial assessment

IPNA recommends a detailed family history of renal and extrarenal manifestations, including consanguinity, and, in affected relatives, age at onset, course, drug response, kidney function and biopsy and genetic results (A, strong); a physical examination directed at skeletal, neurological, ocular, auditory and urogenital anomalies and secondary causes, especially infectious causes (A, strong); and quantification of proteinuria by UPCR before defining SRNS (A, strong) [3]. Secondary causes to exclude include infections (cytomegalovirus, HIV, hepatitis B, malaria, parvovirus B19, syphilis), sickle cell disease, lymphoma, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy, IgA nephropathy, systemic lupus erythematosus, collagen IV nephropathies, amyloidosis and thrombotic microangiopathy (TMA) [3]. Tuberculosis screening is recommended in endemic areas, and hepatitis B, hepatitis C, syphilis and HIV serology before immunosuppression [3]. The 2023 French PNDS systematically includes in the initial assessment dipstick testing, UPCR, total protein and albumin, electrolytes, creatinine and urea, complement measurement (C3, C4 and CH50, whose normality argues against post-infectious glomerulonephritis, lupus, MPGN and C3 glomerulopathy), varicella-zoster virus serology in children without previous clinical chickenpox and measles serology in those who have not received two doses of the vaccine [30]. In atypical situations or with extrarenal signs it adds antinuclear and anti-DNA antibodies, ANCA, hepatitis B and C and HIV serology, chest radiography and abdominal ultrasound if lymphoma is suspected, and anti-PLA2R antibodies above 12 years of age to exclude membranous nephropathy; coagulation tests (aPTT, PT, antithrombin, fibrinogen and D-dimers) are considered with marked oedema or other thrombotic risk factors [30]. Children who have stayed in areas endemic for strongyloidiasis receive ivermectin 200 µg/kg before corticosteroid therapy [30].

In CNS, the ERKNet-ESPN consensus adds growth, blood pressure and volume status; full blood count, sodium, chloride, magnesium, creatinine, urea, total protein, albumin, cholesterol, fasting triglycerides, glucose, thyroid-stimulating hormone (TSH) and free T4, IgG, ionised calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH) and 25-hydroxyvitamin D; abdominal and pleural ultrasound and echocardiography; as second-line investigations, assessment for dysmorphic features, ophthalmological examination, hearing, neurological and cognitive assessment with magnetic resonance imaging (MRI) if indicated, and serology for syphilis, toxoplasmosis, cytomegalovirus, rubella, measles, hepatitis B and C, herpes simplex, varicella-zoster, HIV and Bordetella pertussis; in specific settings, malaria, antinuclear antibodies, C3/C4, anti-neutral endopeptidase antibodies (anti-NEP), amino acids and mercury [2]. Ophthalmological examination and hearing assessment should be performed in all patients with CNS, and brain MRI in selected cases shows gyration abnormalities or cerebellar atrophy in GAMOS, atrophy and stroke-like lesions in CoQ10 nephropathies, ventriculomegaly in CRB2 glomerulopathy and subcortical abnormalities in SPLIS [7].

5.3. Indications for genetic testing: convergence and differences between guidelines

Table 5.2 — Indications for genetic testing and kidney biopsy according to current guidelines.

KDIGO 2021 lists reasons for testing an adult with FSGS as a strong family history, syndromic features, an atypical phenotype, resistance to immunosuppression, estimation of transplant recurrence risk, evaluation of a related living donor or suspected APOL1 risk variants, and prenatal diagnosis [46]. The North American Kidney Disease Outcomes Quality Initiative (KDOQI) commentary on KDIGO 2025 notes that, in the United States, access to testing is no longer the main barrier, which has shifted to interpretation, integration into treatment and counselling, and criticises the absence of practice points on integrating genetic results into decisions to initiate and maintain CNI [81]. The European Renal Association (ERA) Immunonephrology Working Group commentary considers European practice aligned with KDIGO, with an emphasis on genetic testing and cautious use of CNI [84].

5.4. Choice of method and sequence of tests

IPNA recommends a comprehensive NGS panel containing all known SRNS genes as the most cost-effective approach, except when the phenotype suggests a specific condition, when single-gene analysis is justified (B, moderate); variants should be classified according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, with segregation studies in selected cases (B, moderate), and pathogenic or likely pathogenic variants confirmed by Sanger sequencing; with a negative panel and high suspicion, consider exome or genome sequencing [3]. In CNS, the ERKNet-ESPN consensus prefers rapid exome sequencing or, if unavailable, an extended podocytopathy panel; the minimum set NPHS1, NPHS2, WT1, PLCE1 and LAMB2 identifies a genetic alteration in more than 80% of cases, and a dozen less common genes add approximately 5% [2, 7]. A clear syndromic phenotype (Denys-Drash, Pierson) or Finnish ancestry (Fin-major and Fin-minor variants) justifies targeted testing first [2, 7]. The preferred sample is whole blood collected in ethylenediaminetetraacetic acid (EDTA) or cord blood; if there has been a transfusion within the preceding 3 months or sampling is difficult, a buccal swab or dried blood spot from newborn screening may be used [7]. The indications for genetic testing in adults with chronic kidney disease of undetermined cause and the technical limitations of kidney gene panels are common to the hereditary nephropathies.

In WT1 disorder, some laboratories first sequence exons 8 and 9 and the intronic junctions, where more than 90% of variants are located; sequencing detects more than 90% of pathogenic variants and targeted deletion/duplication analysis less than 10% [7, 8]. Karyotyping (or fluorescence in situ hybridisation for SRY, or chromosomal microarray) should be performed in all children with CNS and ambiguous genitalia and in all phenotypically female children with a causal WT1 variant [7, 8]. Informed consent should anticipate findings with psychosocial implications, such as disclosure of a 46,XY karyotype [7].

5.5. Test limitations

A negative test does not exclude a genetic cause. Panels have greater read depth and do not generate incidental findings, but the gene list is limited and becomes outdated; composition, sensitivity by gene and methods vary between laboratories and over time, and some panels do not include new or rare genes or deletion/duplication analysis [1, 7]. Exome sequencing detects new genes but may miss complex rearrangements, small copy number variants (CNV), regulatory regions (promoters, deep introns), GC-rich regions (such as WT1 exon 1), the mitochondrial genome and duplicated regions with pseudogenes [7, 8]. The intronic WT1 KTS variants (NM_024426.6:c.1447+4C>T and c.1447+5G>A) lie outside exons and require coverage of intronic junctions [8]. Parental mosaicism may not be detected in leucocyte DNA [1]. The 10–30% diagnostic rate obtained with exome sequencing in children with SRNS measures the proportion of patients diagnosed within a cohort rather than the analytical sensitivity of the method [3]. Genes frequent in one population may be rare in another [3]. In TRPC6-related disease, a truncating variant should not be interpreted as causal [5]. For APOL1, the genotype indicates a risk rather than a diagnosis [5].

5.6. Interpretation and report content

The report should state the gene, versioned reference transcript (preferably MANE Select), HGVS designation at coding DNA and protein levels, zygosity, phase of variants in recessive forms when established by segregation, and ACMG/AMP class [3]. WT1 nomenclature requires particular attention, because the same variant has different names in different transcripts and the historical protein numbering (p.Arg394Trp) differs from the current numbering (p.Arg467Trp) [8, 48]. In NPHS2, the report should interpret p.Arg229Gln in relation to the variant in trans [7]. For a VUS, family segregation and, in LAMB2, laminin β2 immunohistochemistry in kidney tissue may support interpretation [3, 5]. In hereditary defects showing remission under immunosuppression, IPNA recommends reviewing whether the variant is indeed pathogenic (A, strong) [3]. Public variant lists include ClinVar, LOVD and HGMD, and ERKNet has a virtual case consultation system [7].

5.7. Kidney biopsy and histology

Biopsy excludes other diagnoses, confirms podocytopathy (minimal change disease, FSGS or DMS) and grades tubular atrophy, interstitial fibrosis and glomerulosclerosis as prognostic markers; it should be performed before starting CNI, except in a clear monogenic form unresponsive to immunosuppression [3]. In the PodoNet registry, histology was FSGS in 56%, minimal change disease in 21% and mesangioproliferative glomerulonephritis in 12% [85]. In WT1 disorder, histology is heterogeneous and does not correlate with clinical features, so kidney biopsy is no longer a first-line investigation [8]. In CoQ10 nephropathies, biopsy shows FSGS, focal mesangial sclerosis or collapsing glomerulopathy, and enlarged dysmorphic mitochondria in podocytes on electron microscopy are highly suggestive, but their absence does not exclude the diagnosis [7]. In ACTN4-related disease, α-actinin-4 immunofluorescence is segmental and granular [5]. In nail-patella syndrome, the GBM has a ‘moth-eaten’ appearance with collagen-like fibres [11].

5.8. Additional biomarkers

In CoQ10 deficiency, molecular testing is the usual diagnostic method. Biochemistry is reserved for cases without a molecular diagnosis or with a VUS: measurement of CoQ10 in skeletal muscle, the preferred test, and activities of complexes I+III and II+III in frozen muscle homogenate, reduced with normal individual complexes [22, 63]. Plasma CoQ10 reflects diet and is not useful; genetically proven patients may have normal CoQ10 in muscle, fibroblasts and leucocytes; and biochemistry does not distinguish primary from secondary deficiencies [22, 69]. Serum lactate may be elevated in severe neonatal forms, but a normal value does not exclude the diagnosis [22]. In SPLIS, plasma sphingolipids (sphingosine-1-phosphate and the sphingosine/sphinganine ratio) are increased [9, 64].

Anti-nephrin antibodies distinguish autoimmune from genetic podocytopathy. In a study of 539 patients, they were present in 44% of adults with minimal change disease, 9% of adults with primary FSGS and 52% of children with idiopathic nephrotic syndrome, and in 69% and 90% of patients with active disease without immunosuppression who had minimal change disease and paediatric idiopathic nephrotic syndrome, respectively [86, 87]. ERA considers that variability in sensitivity and specificity and lack of standardisation require validation before widespread clinical use [84]. In NPHS1-related CNS, anti-nephrin antibody measurement by enzyme-linked immunosorbent assay (ELISA) is used to investigate post-transplant recurrence rather than for diagnosis [5].

5.9. Practical algorithm

In a child with nephrotic syndrome without complete remission after 4 weeks of PDN, the confirmation period (weeks 4–6) is used to start RAASi, request genetic testing and, if indicated, biopsy, ideally with results within the next 2 weeks [3]. If testing identifies a monogenic form, CNI are not started and PDN is withdrawn; if the result is unavailable at the end of the confirmation period, CNI are started and reassessed when it arrives [3]. In a child with a pathogenic variant who has achieved remission under immunosuppression, the decision to continue or withdraw is made after variant review and counselling [3]. In an infant with CNS, comprehensive genetic testing is performed immediately, before any biopsy, with karyotyping if there are atypical genitalia [2, 7]. In an adult with FSGS, testing is selective and guided by family history, resistance to treatment and the need to plan transplantation [46]. The original algorithms are available in the figures of the IPNA guidelines (https://pmc.ncbi.nlm.nih.gov/articles/PMC7316686/figure/Fig2/) and the ERKNet-ESPN genetic consensus (https://pmc.ncbi.nlm.nih.gov/articles/PMC7608398/figure/Fig1/), whose legends were read in the full text [3, 7]. The 2023 French PNDS follows the same logic: when a genetic cause is identified, only antiproteinuric treatment is continued, because immunosuppressants bring no benefit; without a genetic cause, second-line treatment is the combination of a CNI (ciclosporin, or tacrolimus outside its marketing authorisation in France) with prednisone [30]. The summary for the attending physician acknowledges that ideally the genetic result would be known before starting treatment, but that the turnaround time of the test, at least 15 days and often longer, rarely makes this possible in paediatric and especially neonatal forms [30]. For non-responsive forms, the protocol refers the strategy to a paediatric nephrologist and allows immunoadsorption, plasmapheresis or other immunotherapies after discussion at a multidisciplinary team meeting [30].

5.10. Prenatal and preimplantation diagnosis

When familial variants are known, prenatal diagnosis and preimplantation genetic testing (PGT) are technically possible and should be discussed in each family's financial, social and legal context [7, 8]. Ultrasound and biochemical markers of CNS (nuchal translucency, amniotic alpha-fetoprotein, large placenta, oedema) are non-specific and do not replace molecular testing [2].

6. Differential Diagnosis

6.1. Differential diagnosis between the genetic forms themselves

Table 6.1 — Differential diagnosis between the main forms of genetic SRNS. Sources: [1, 5, 7–10, 22].

6.2. Secondary and non-genetic causes

Exclusion of secondary causes is part of the initial assessment of all SRNS: infections, sickle cell disease, lymphoma, membranous nephropathy, MPGN, C3 glomerulopathy, IgA nephropathy, lupus, amyloidosis and TMA [3]. Doppler ultrasound helps recognise CAKUT and vascular thrombosis [3]. Presumed immune-mediated non-genetic SRNS is distinguished mainly by response to CNI, absence of pathogenic variants and, in some patients, presence of anti-nephrin antibodies [70, 86]. Secondary steroid resistance, after an initial steroid-sensitive phase, had no monogenic cause in the British cohort and responds better to rituximab (64% complete response versus 26% in primary SRNS in the RaDaR registry) [81, 82].

In CNS, the differential includes congenital infections and alloimmune membranous nephropathy. Re-emerging congenital syphilis is treated with penicillin G 50,000 U/kg intravenously (IV) every 12 h in the first week, every 8 h after the first week and every 6 h after the first month, or with benzathine penicillin G 50,000 U/kg intramuscularly every 24 h for 10–15 days (neonatal and infant doses; no maximum dose defined in the source); congenital cytomegalovirus infection is asymptomatic in more than 90% of cases and causes CNS only exceptionally, and is treated with ganciclovir 6 mg/kg every 12 h for 15–21 days followed by valganciclovir 15 mg/kg every 12 h for 6 weeks, with a target 0–24 h area under the curve (AUC) of 40–50 µg·h/ml; rare cases with toxoplasmosis, hepatitis B and rubella have been described, and no CNS due to HIV [2]. A patient with presumed infectious CNS may have a genetic cause and should be tested [2]. In congenital alloimmune membranous nephropathy, a mother lacking neutral endopeptidase because of MME variants becomes sensitised to the fetal protein; antibodies increase in successive pregnancies, with transient proteinuria or severe CNS with kidney failure in subsequent children. Anti-NEP antibodies should be sought in the child and mother in the presence of kidney failure at presentation, transient proteinuria resolving within weeks, affected siblings or membranous nephropathy on biopsy; treatment is mainly symptomatic [2].

6.3. Genetic phenocopies with persistent proteinuria

Table 6.2 — Genetic phenocopies of SRNS. Source: GeneReviews [1].

6.4. Additional metabolic and syndromic differential diagnoses

Inborn errors with nephrotic syndrome include respiratory chain defects, DGKE deficiency, SPLIS and pre-ribosomal RNA processing defects caused by DKC1 and NOP10 variants, which combine cataracts, enterocolitis, deafness and SRNS [66, 88]. DGKE deficiency causes autosomal recessive aHUS in the first year of life, with repeated episodes of microangiopathic haemolytic anaemia, thrombocytopenia and AKI; filtration recovers, but hypertension, microhaematuria and proteinuria persist, with nephrotic syndrome 3–5 years after onset, CKD in the second decade and no response to anti-complement therapy [89]. MELAS syndrome caused by m.3243A>G may combine FSGS with diabetes and deafness [63]. Galloway-Mowat disorders are distinguished from CoQ10 deficiencies by molecular diagnosis [66].

Alport syndrome is the most frequent genetic differential diagnosis of adolescent and adult FSGS; in X-linked Alport syndrome, proteinuria never precedes haematuria, and biopsy shows GBM thickening and splitting [1, 62]. In a Brazilian study of transplanted children, COL4A3–5 variants of uncertain interpretation raised the question of isolated FSGS or a misdiagnosed Alport spectrum [90]. In Wilms tumour, the probability of a germline WT1 variant is 0–5% in the absence of a genitourinary anomaly, DMS, nephrogenic rests or bilaterality; stromal-predominant histology or rhabdomyoblastic differentiation and intralobar nephrogenic rests suggest WT1 syndrome, while aniridia suggests an 11p13 deletion [5, 73].

6.5. APOL1 and HIV-associated FSGS

In a person of West African ancestry with HIVAN, it remains uncertain whether APOL1 should be routinely genotyped; host susceptibility factors include APOL1 G1/G2 and, less firmly established, sickle cell trait and ABCC2/4 variants [46]. An APOL1 result does not exclude a monogenic form, and many commercial SRNS panels include G1 and G2 [81].

7. Treatments and Risk Management Strategies

7.1. Principles: supportive treatment and withdrawal of ineffective immunosuppression

No treatment corrects genetic podocytopathy. The objectives are to reduce proteinuria, control blood pressure and nephrotic complications, delay CKD progression, avoid toxicity from ineffective immunosuppressants and prepare for kidney replacement therapy [1, 3]. IPNA recommends not starting CNI and withdrawing PDN in patients with evidence of monogenic SRNS (B, moderate), offering screening of all known podocytopathy genes to guide immunosuppression decisions (X, strong), counselling about the high risk of ESKD in hereditary or multidrug-resistant forms (X, strong), and withdrawing ineffective immunosuppression while maintaining non-immunosuppressive treatment, including RAASi (X, strong) [3]. In patients with a hereditary defect who achieved partial or complete remission under immunosuppression, it recommends reviewing variant pathogenicity (A, strong) and deciding whether to continue after counselling about benefits (symptom relief, possibly slower progression), risks (toxicity, infections) and costs (A, strong) [3]. KDIGO 2025 states that genetic forms of SRNS invariably progress, over a variable period, to kidney failure and should be managed conservatively, although some variants show some response to immunosuppression, particularly CNI [4].

Divergence regarding a CNI therapeutic trial in monogenic SRNS. Guidelines advise against immunosuppression in monogenic forms, but the data are not homogeneous. In a retrospective study from 37 centres, 122 children with a pathogenic genotype and 19 with a possibly pathogenic genotype treated with CNI for at least 3 months had a partial or complete response in 27.6% at 6 months and 22.5% at the last visit; at least partial response at 6 months was associated with lower risk of kidney failure (hazard ratio [HR] 0.25; 95% CI 0.10–0.62), and higher serum albumin at CNI initiation was the only predictor of remission (OR 1.16; 95% CI 1.08–1.24) [91]. The authors advocate a CNI therapeutic trial in monogenic SRNS as well [91]. In the PodoNet registry, 11% of 74 children with a podocyte variant achieved at least partial remission with intensified immunosuppression [4]. In the British cohort, complete response occurred in 4% of monogenic cases versus 25% of patients without a variant [92]. Responses to steroids and low-dose CNI described in WT1 and PLCE1 are variable [4, 39, 53]. In a retrospective study with patient selection, a response rate of 22–28% cannot distinguish the CNI effect from haemodynamic reduction of proteinuria or natural history, and there is no randomised trial in monogenic SRNS. The KDOQI commentary criticises KDIGO's lack of guidance on this integration [81].

7.2. Inhibition of the renin–angiotensin–aldosterone system

IPNA recommends starting an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) as soon as SRNS is diagnosed (B, moderate), aiming for the maximum tolerated approved doses (C, weak) [3]. It prefers drugs with non-renal metabolism, such as ramipril and ARBs, which do not accumulate in kidney impairment (D, weak) [3]. The antiproteinuric effect of ACEi is dose-dependent, with reductions of approximately 30%, and ACEi–ARB combination therapy is discouraged because of the risk of AKI and death [3]. They should not be started, or should be withdrawn, in volume depletion, AKI, hyperkalaemia or frequent vomiting and diarrhoea (X, strong), with caution in CKD stage 4; in adolescent girls, contraception is mandatory because of fetopathy associated with renin–angiotensin system blockade (X, strong) [3]. In patients with a monogenic form, RAASi are maintained until advanced CKD when they are no longer tolerated [3].

In CNS, the ERKNet-ESPN consensus recommends RAASi only from 4 weeks of post-term age, to avoid interfering with tissue growth and prevent prolonged hypotension and oliguric AKI; it prefers captopril in young infants because of its short half-life and does not recommend combining ACEi and ARBs [2]. In CNS, the effect is moderate: in a retrospective study, albumin increased by a median of 6 g/l and some patients reduced infusion frequency; in older children and adults, proteinuria reductions are 30–50% [2]. No ACEi or ARB has an approved indication for SRNS; antiproteinuric use is off-label and based on guidelines. The IPNA supplementary table with maximum doses by drug was not obtained; the doses below come from the CNS consensus and United States hypertension labels.

Table 7.1 — RAASi doses with sources.

The enalapril label describes preparation of a 1.0 mg/ml oral suspension from tablets [93]. The main adverse effects are hypotension, AKI and hyperkalaemia; RAASi, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) should be withheld during vomiting or diarrhoea episodes [2, 3].

7.3. Immunosuppression while awaiting the genetic result and in SRNS without a genetic cause

Although genetic SRNS is not a candidate for immunosuppression, CNI doses are relevant because treatment often starts before the genetic result is available and because a negative test reclassifies the patient [3]. IPNA recommends ciclosporin or tacrolimus as first-line immunosuppressive treatment for SRNS after confirmation (B, moderate), and KDIGO 2025 recommends the same drugs as initial second-line therapy (1C) [3, 4]. CNI should be withheld or deferred if eGFR is below 30 ml/min/1.73 m², or if there is AKI or uncontrolled hypertension (X, strong) [3]. In the 2023 French PNDS, the phase preceding the declaration of steroid resistance in children follows a fixed regimen: PDN 60 mg/m²/day (maximum 60 mg/day) as a single morning dose for 4 weeks; if proteinuria persists, three infusions of methylprednisolone 1 g/1.73 m² (or 500 mg/m²), in hospital, over 4 to 6 hours, with monitoring of blood pressure and heart rhythm because of the risk of bradycardia, continuing oral PDN at the same dose between infusions; prednisolone may replace prednisone at the same dose [30]. Once resistance without a genetic cause is confirmed, the PNDS recommends CNI with prednisone, considers the benefit of alkylating agents and MMF unproven, and defines neither CNI doses nor trough targets, which therefore follow Table 7.2 [30].

Table 7.2 — CNI regimens in childhood SRNS: divergence between IPNA 2020 and KDIGO 2025.

Drug selection takes adverse effects into account: tacrolimus is preferable if the cosmetic effects of ciclosporin (hypertrichosis, gingival hyperplasia) are unacceptable, and ciclosporin if there is a risk of diabetes [3, 4]. Evidence from trials of CNI as first-line treatment shows remission of approximately 75% with ciclosporin versus 22% with placebo, no treatment or methylprednisolone (relative risk [RR] 3.50; 95% CI 1.04–9.57), no difference between tacrolimus and ciclosporin (RR 1.05; 95% CI 0.87–1.25), and superiority of CNI over IV cyclophosphamide (78% versus 40%; RR 1.98; 95% CI 1.25–3.13); older studies probably included unidentified monogenic forms [3]. In the FSGS-CT trial, comprising 138 children and young adults with steroid-resistant FSGS, ciclosporin did not differ from mycophenolate mofetil (MMF) with pulse dexamethasone, but the trial was designed for 500 patients and was underpowered [4]. MMF (1200 mg/m²/day in 2 doses for 1 year) is used to maintain remission after CNI [3, 4]. Without a response to CNI and without genetic or syndromic disease, IPNA proposes enrolment in a trial and, if unavailable, rituximab (375 mg/m² per infusion, 1–2 infusions over 2 weeks, until CD19 <5/µl or <1%; no maximum dose defined in the source), with complete remission of approximately 30% in observational series, whereas KDIGO 2025 assigns it a limited or no role in SRNS [3, 4]. Ofatumumab was used off-label in 2 studies [3]. Cyclophosphamide is not recommended by KDIGO 2025, and IPNA allows it only when CNI are unavailable (D, weak) [3, 4].

Table 7.3 — Adverse effects of immunosuppression and prevention. Source: IPNA 2020 [3].

CNI nephrotoxicity is recognised on biopsy by arteriolar hyalinosis, smooth muscle vacuolisation, ischaemic glomerular collapse, juxtaglomerular apparatus hyperplasia and striped interstitial fibrosis; repeat biopsy should be considered for an unexplained fall in eGFR, increased proteinuria or CNI exposure exceeding 2 years [3].

7.4. Congenital nephrotic syndrome: conservative management according to the ERKNet-ESPN consensus

The 2021 ERKNet-ESPN consensus is based on expert opinion rather than a formal guideline: a core group of 9 members, including a patient representative, an external multidisciplinary group with an ethicist and a Delphi panel of 35 paediatric nephrologists analysed 1367 search results, with no randomised trial [2]. It recommends management by a multidisciplinary team in a tertiary centre (neonatology, paediatric nephrology, nursing, renal dietitian, surgery, psychology and social work) and early presentation to a transplant centre [2]. Treatment is adapted to severity and aims to maintain intravascular euvolaemia and nutrition, prevent complications and preserve central and peripheral vessels for future dialysis access, avoiding peripherally inserted central catheters and unnecessary punctures [2]. The defined goals are normal growth, nutrition and development, preservation of vascular access, absence of thrombosis, severe infections, oedema and anaemia, normal blood pressure, euthyroidism, minimal hospital admissions and good quality of life [2]. Almost all doses below represent off-label paediatric use and come from the consensus.

Albumin and fluids. IV fluids and normal saline should be avoided and concentrated high-calorie formulas used [2]. Albumin is guided by clinical signs of hypovolaemia (oliguria, AKI, prolonged capillary refill, tachycardia, hypotension, abdominal discomfort) or poor weight gain, rather than serum albumin; severe disease may require 1–4 g/kg/day, to be reduced, spaced out or stopped in stable patients or with CKD progression [2]. Practice varies between centres giving infusions only when indicated and centres giving regular infusions, with no difference in long-term outcomes in retrospective studies [2]. Home administration by parents after training is feasible and safe, and outpatient management is preferable when possible [2]. If a central venous catheter is unavoidable, prophylactic anticoagulation is recommended while it remains in place [2].

Diuretics. Furosemide, 0.5–2 mg/kg IV at the end of each albumin infusion, should be omitted only in marked hypovolaemia or hyponatraemia [2]. Outside this setting, diuretics are reserved for intravascular overload (good peripheral perfusion, high blood pressure with oedema) with preserved kidney function: furosemide 0.5–2 mg/kg/dose IV or orally up to 6 times daily (maximum 10 mg/kg/day), without exceeding 6 mg/kg/day for more than 1 week, with infusions over 5–30 minutes because of ototoxicity, and withdrawal in anuria [2]. In stable patients, oral furosemide 2–5 mg/kg/day may be combined with a thiazide or a potassium-sparing diuretic; the consensus prefers amiloride to spironolactone, because urinary proteases, such as plasmin, directly activate the epithelial sodium channel (ENaC) independently of the mineralocorticoid receptor [2].

Antiproteinuric agents. After 4 weeks of post-term age, captopril is used at the doses in Table 7.1 and, in stable patients, ramipril or candesartan [2]. Indometacin may be an adjunct if the response is insufficient, escalating from 0.5 to 3 mg/kg/day after 4 weeks post-term, with an H2 antagonist or proton pump inhibitor; celecoxib is an alternative, and both are withdrawn if there is no benefit within 2–4 weeks or in CKD stages 4–5 [2].

Nutrition and growth. The consensus recommends a high-energy (130 kcal/kg/day), high-protein (4 g/kg/day), low-salt diet (<0.5 g/day below 6 months; <1 g/day between 7 and 12 months; <2 g/day between 1 and 3 years; <3 g/day above 3 years), with tube feeding or gastrostomy if intake is insufficient; fluid restriction should not compromise caloric intake [2]. Growth hormone (somatropin), 0.045–0.05 mg/kg/day subcutaneously from 6 months, is indicated if height is below the 3rd centile, growth velocity below the 25th centile and eGFR 60 or lower, or if height is below the 10th centile with velocity persistently below the 25th centile (more than 3 months in infants, more than 6 months in children), after malnutrition and acidosis have been corrected [2].

Endocrinology and mineral metabolism. Levothyroxine treats hypothyroidism due to urinary loss of thyroxine-binding proteins [2]. Ionised calcium, 25-hydroxyvitamin D and PTH are monitored; colecalciferol or calcifediol and calcium 250–500 mg/day are supplemented if 25-hydroxyvitamin D or ionised calcium is low or PTH high, and magnesium and calcium to prevent very low levels [2]. Statins are considered with fasting low-density lipoprotein (LDL) cholesterol persistently above 160 mg/dl (4.1 mmol/l), or above 130 mg/dl (3.4 mmol/l) with other risk factors [2].

Thrombosis. Preventive anticoagulation should be considered in all patients with CNS and especially in high-risk states (acute illness, dehydration, a central venous catheter, thrombocytosis >750,000/µl) [2]. Before inserting a central catheter, antithrombin III 50 U/kg is given, and low-molecular-weight heparin (LMWH) may be ineffective because of low antithrombin [2]. In Finland, prolonged warfarin (international normalised ratio 2–2.5) has been used in patients with central catheters without a substantial increase in bleeding, according to unpublished data; benefit has not been demonstrated in a trial, and a retrospective study showed no change in thrombosis incidence with warfarin, heparin or aspirin [2]. Aspirin should be used cautiously because of AKI risk [2].

Infections and immunoglobulins. Infections are the main cause of death in CNS because of urinary loss of IgG and complement factors [2]. Routine antibiotic prophylaxis is not recommended, but immediate antibiotics on suspicion are; IV immunoglobulin is justified with low IgG and recurrent or severe infections, bearing in mind that up to 50% of infused IgG is lost within 30 hours [2]. Vaccination follows the schedule for healthy children, with vaccines against encapsulated bacteria, varicella and annual influenza; antibody titres are uninformative with nephrotic proteinuria or after immunoglobulin [2]. After varicella exposure in an unimmunised infant, IV varicella-zoster immunoglobulin or oral aciclovir 10 mg/kg 4 times daily for 7 days is given, starting 7–10 days after exposure; active varicella is treated with high-dose IV aciclovir for 7–10 days [2].

Anaemia. This results from urinary losses of erythropoietin, iron, transcobalamin and transferrin (making transferrin saturation and ferritin unreliable), vitamin B12 or copper deficiency and ACEi toxicity; it is treated with iron and erythropoietin, often at higher doses, and, if it persists after 4 weeks, copper, caeruloplasmin and B12 are investigated [2].

Nephrectomy, dialysis and transplantation. The classic Finnish protocol consisted of bilateral nephrectomy and dialysis at approximately 7–9 kg (6–12 months of age) and transplantation at 10 kg, with dialysis mortality of 6–11% [2]. The consensus does not recommend routine early nephrectomy; it suggests unilateral or bilateral nephrectomy if severe complications persist (poor weight gain, thrombosis, difficulty maintaining euvolaemia) despite optimised treatment, and recommends bilateral nephrectomy before transplantation if nephrotic syndrome persists or there is a dominant pathogenic WT1 variant [2]. Peritoneal dialysis is the modality of choice because it preserves central venous access, with outcomes comparable to those in other diseases; haemodialysis is an alternative [2]. Transplantation is definitive treatment, and parental kidney donation is generally accepted in autosomal recessive forms [2]. Referral for kidney replacement therapy should occur around 6 months and, at the latest, with eGFR below 30 ml/min/1.73 m² [2].

Immunosuppression in CNS. This is not recommended in CNS; biopsy and a trial of immunosuppression are considered only in selected cases with negative genetic testing and secondary-cause screening and a biopsy without DMS, bearing in mind that spontaneous remissions have been described [2, 5].

7.5. SRNS complications outside the neonatal period

Oedema. IPNA recommends avoiding excessive salt (C, weak), not routinely restricting fluids (C, weak), and using furosemide for severe oedema and, for refractory oedema, metolazone, thiazides or potassium-sparing diuretics (C, moderate); diuretics should not be given with signs of intravascular depletion because of the risk of thrombosis and AKI (X, strong) [3]. A fractional sodium excretion below 0.2% suggests an ‘underfilled’ patient, and hypertension with a fraction above 0.2% suggests an ‘overfilled’ patient [3]. In refractory oedema, symptomatic hypovolaemia or a prerenal crisis, 20–25% albumin, 0.5–1 g/kg IV over 4–8 hours, is combined with furosemide 1–2 mg/kg IV midway and/or at the end, with blood pressure and heart rate monitoring every 30 minutes initially (X, strong) [3].

Infections and vaccination. Approximately 60% of nephrotic syndrome-associated deaths are attributed to infection, 30–50% of which are pneumococcal [3]. IPNA does not recommend routine antibiotic prophylaxis (C, weak), but recommends co-trimoxazole for 3–6 months after rituximab (C, weak), in infants from 4 weeks and children at 5–10 mg/kg/day of trimethoprim or 150 mg/m²/day, as one or two doses, 3 times weekly, up to 320 mg/day; in adolescents, 80–160 mg/day or 160 mg 3 times weekly, with a 50% reduction if eGFR is below 30 and contraindication below 15 [3]. It recommends completing pneumococcal, meningococcal, Haemophilus and, if possible, varicella vaccination (A, strong), annual inactivated influenza vaccine (A, strong) and no live vaccines under daily immunosuppression (X, strong); in a susceptible child exposed to varicella, specific immunoglobulin within 10 days (A, strong) or, if unavailable, oral aciclovir 10 mg/kg 4 times daily for 7 days, starting 7–10 days after exposure (C, moderate) [3]. IgG replacement is justified only with low IgG and recurrent or severe infections (D, weak) [3].

Thrombosis. The incidence of thromboembolic events in children with nephrotic syndrome is approximately 3% [3]. Mobilisation and avoidance of central catheters are recommended (X, strong), without routine prophylactic anticoagulation; LMWH or an oral anticoagulant after previous venous thromboembolism and to be considered with additional factors, and thrombophilia screening with risk factors (C, weak) [3].

Lipids, mineral metabolism, thyroid and blood pressure. In persistent multidrug-resistant SRNS with fasting LDL cholesterol above 130 mg/dl (3.4 mmol/l), lipid-lowering treatment beginning with lifestyle is considered (C, weak); there is no evidence for statins, and a randomised trial did not significantly reduce lipids [3]. Colecalciferol or ergocalciferol is recommended if 25-hydroxyvitamin D is below 30 ng/ml (C, moderate), calcium if there is hypocalcaemia, magnesium if there is symptomatic hypomagnesaemia, and levothyroxine if TSH is above 10 mU/l with low free T4, monitoring cases with TSH between 4.5 and 10 and normal free T4 (A, strong) [3]. Hypertension is treated above the 95th centile, with a target below the 75th centile without proteinuria and the 50th centile with proteinuria (A, strong) [3].

Table 7.3a — Supportive measures of the 2023 French PNDS applicable to SRNS in the nephrotic phase, compared with IPNA. Sources [3, 30].

The PNDS doses are indicative, and the protocol asks that each centre's practices be confirmed with a paediatric nephrologist [30]. In patients with chronic SRNS, the PNDS adds monitoring of thyroid function and lipids to symptomatic treatment [30].

Lifestyle. IPNA recommends physical activity, a healthy diet with home-prepared meals from fresh ingredients, containing less salt and inorganic phosphorus, and avoidance of smoking and electronic cigarettes (C, moderate) [3].

7.6. Targeted treatments and entity-specific management

Coenzyme Q10 (ubidecarenone) in primary CoQ10 deficiencies. This is the only targeted treatment with a demonstrated effect on kidney disease in genetic SRNS. High-dose oral CoQ10 may halt kidney disease and prevent neurological disease when started early, with biallelic COQ2, COQ6, COQ8B or PDSS2 variants, but does not reverse established severe neurological or renal damage, and response is highly variable [22]. In the international cohort of Drovandi and colleagues, 116 treated patients with biallelic COQ2, COQ6 or COQ8B variants, followed for a median of 2 years, had a sustained 88% reduction in proteinuria at 12 months, with complete remission more frequent in COQ6-related disease; in 41 patients younger than 18 years with CKD stages 1–4, compared with an untreated cohort matched for genotype, age, kidney function and proteinuria, 5-year kidney failure-free survival was 62% versus 19%, and adverse effects were rare and mild [26]. In Turkey, 28 patients with biallelic ADCK4 (COQ8B) treated for a median of 11.5 months reduced proteinuria from 1008 (IQR 281–1567) to 363 (IQR 175–561) mg/m²/day, with preserved eGFR [96]. In 12 Korean children with COQ6, 42.9% had stable or improved hearing with CoQ10, with genotype-dependent benefit, and cochlear implants had favourable outcomes in those who progressed [97]. These data are observational, with historical controls or uncontrolled, and there are no randomised trials.

The optimal dose is not established. The ERKNet-ESPN consensus gives a starting dose of 15–30 mg/kg/day in 3 doses, which may be increased to 50 mg/kg/day, and emphasises that leucocyte CoQ10 levels may be normal and are not useful for treatment monitoring [7]. GeneReviews indicates a range of 5–50 mg/kg/day, with soluble formulations apparently more bioavailable [22, 98], and a textbook of metabolic diseases gives at least 30 mg/kg/day in children and up to 3 g/day in adults [63]. The case series by Starr and colleagues proposes 30–50 mg/kg/day as the starting dose [69]. The dose and formulation used in the Drovandi cohort were not obtained. No CoQ10 product has FDA authorisation or a European public assessment report (EPAR) from the European Medicines Agency (EMA) for this indication; it is marketed as a food supplement, without regulation of dose, formulation and quality as a medicinal product [5]. Use is therefore off-label and should be lifelong [26]. Ubiquinol (the reduced form) has greater bioavailability, but there are no dose and efficacy data; idebenone and other short-chain quinone analogues are ineffective, and clinical deterioration has been described; therapies with quinone ring precursors (4-hydroxybenzoic, 2,4-dihydroxybenzoic and vanillic acids) and lipid nanodispersions are at the cell or animal stage [5, 22, 69]. CoQ10 crosses the blood–brain barrier poorly [5]. ACEi may be combined with CoQ10 in patients with proteinuria [22]. In CNS with signs of mitochondrial disease, the ERKNet-ESPN consensus suggests a trial of CoQ10 even before the genetic result, to be withdrawn if there is no improvement in kidney function or substantial reduction in proteinuria within 4–6 weeks [2].

Pyridoxine in SPLIS. GeneReviews indicates vitamin B6 (pyridoxine) 10 mg/kg/day in 2 doses, up to 200 mg/day, based on the authors' experience rather than trials, possibly more effective in p.Arg222Gln homozygotes; excess pyridoxine causes neuropathy overlapping that of SPLIS itself, so baseline and periodic nerve conduction studies are recommended [9, 99]. Adrenal insufficiency is treated with glucocorticoid, mineralocorticoid and sodium as needed, with stress doses during intercurrent illness, emergencies and the perioperative period; hypothyroidism with levothyroxine; and micropenis may justify testosterone [9]. Avoidance of nephrotoxic agents, live vaccines and non-irradiated blood products is recommended [9]. Regarding transplantation, 14 patients underwent transplantation between 3 and 22 years, of whom 4 died; there was one recurrence, difficult vascular anatomy and severe complications (neurological catastrophe, encapsulating peritonitis), so potential benefit must be weighed against the risk of fibrotic and neurological complications [9].

SIOD. Ciclosporin, tacrolimus or steroids may temporarily delay renal progression in some patients [6, 10]. Kidney transplantation is performed with mild immunosuppression, and neither nephropathy nor arteriosclerosis recurs in the graft; in patients with renal and immune decline before the end stage, combined kidney and haematopoietic stem cell transplantation (HSCT) may be considered, with reduced-intensity conditioning because of genotoxic sensitivity and short telomeres [5, 10]. Pneumocystis prophylaxis, colony-stimulating factors, aciclovir for recurrent herpes and avoidance of live vaccines form part of management; pentoxifylline, aspirin, dipyridamole, warfarin and heparin have produced temporary improvement in ischaemic events, and ergotamine and sumatriptan are contraindicated with vaso-occlusive disease or ischaemic events [5, 10].

WT1 disorder. IPNA and GeneReviews recommend RAASi and avoidance of immunosuppressants, which are ineffective and potentially toxic; nephropathy does not recur after transplantation [3, 8]. Most centres require a weight of 10 kg and/or at least 1 year after completion of Wilms tumour treatment before transplantation [8]. Wilms tumour is treated according to oncological protocols, with nephron-sparing surgery when possible, and prophylactic bilateral nephrectomy should be considered in ESKD (at transplantation or peritoneal dialysis catheter insertion), especially with truncating variants [7, 8]. Bilateral gonadectomy is indicated in 46,XY individuals with a female phenotype and complete gonadal dysgenesis because of gonadoblastoma risk, and in abnormalities of testicular development the decision is taken by a DSD team, without consensus on timing [7, 8, 100]. Diaphragmatic hernia should be repaired before starting peritoneal dialysis [8]. Sex assignment and surgical decisions are the responsibility of a multidisciplinary DSD team in a tertiary centre, including a geneticist, endocrinologist, urologist, oncologist and psychologist [7, 100].

Other entities. In Pierson syndrome, the team includes ophthalmology, genetics, neurology and rehabilitation, and anticholinesterases should not be given empirically to a patient with LAMB2 and muscle weakness [7, 55]. In GAMOS, the approach is multidisciplinary, with speech and language therapy and psychological support, and palliative care is considered according to severity; there is no disease-modifying treatment, and ESKD determines survival [5, 7]. INF2-related disease does not respond to steroids or immunosuppressants, and the nephrologist should examine for neuropathy, just as the neurologist assessing intermediate CMT should request urinalysis and kidney function [5]. In nail-patella syndrome, ACEi treat hypertension and may slow proteinuria, chronic NSAIDs should be avoided, and transplantation has favourable outcomes [11]. In MYH9-related disease, nephropathy is treated with ACEi and/or ARBs, dialysis and transplantation, and eltrombopag is used in preparation for surgery [23]. In ACTN4-related disease, one case retained stable function for 7 years with early initiation of RAASi [5]. In APOL1-associated FSGS, the existing kidney disease is treated and, in HIVAN, HIV infection, the most important modifiable second hit [5].

7.7. Kidney transplantation, recurrence and donor selection

Transplantation corrects the podocyte defect in all genetic forms of SRNS [1]. Graft recurrence is the main prognostic difference between genetic and non-genetic forms: 24% versus 0% in a Brazilian cohort and 50% versus 7% in a European cohort [3]. In KDIGO 2025, estimated recurrence is 0–5% in genetic nephrotic syndrome, approximately 40% in nephrotic syndrome overall and more than 80% in secondary SRNS [4, 5]. In the British cohorts, no monogenic patient had recurrence, compared with 47.8% of patients with primary resistance without a variant and 73% of patients without a variant who did not respond to immunosuppression [82, 92]. In a study of 338 patients, 32 transplanted patients with two NPHS2 variants had a single late FSGS recurrence [49]. In the Spanish and Brazilian series, no causal variant carrier had recurrence [90, 101]. IPNA identified recurrence risk factors as the non-genetic form, initial steroid resistance (OR 30; 95% CI 6.6–135.9) and progression to ESKD within less than 48 months (OR 11.7; 95% CI 1.53–89.1); recurrence in a first transplant is associated with recurrence in 60–80% or more in the next [3].

IPNA recommends genetic testing before transplantation to inform recurrence risk (B, moderate) and offering transplantation regardless of cause (B, moderate); it recommends measuring proteinuria before transplantation in patients with residual function and considering medical or surgical nephrectomy if transplantation takes place before resolution of nephrotic syndrome [3]. Recurrence may develop within 24 hours and is monitored by UPCR from the day of transplantation: daily during hospitalisation, weekly for 4 weeks, monthly for 1 year and then quarterly (C, moderate) [3].

Alloimmune recurrence in NPHS1-related CNS. Almost all children with CNS and recurrent nephrotic proteinuria after transplantation are Fin-major homozygotes, lacking nephrin in the native kidney; they develop de novo glomerulopathy in 25–35% of cases, and at least 70% of these have anti-nephrin antibodies through alloimmunisation against graft nephrin [2]. Proteinuria may develop at any time, with initially normal function, mild biopsy changes and negative immunofluorescence [2]. In the Finnish series, recurrence occurred in 13 of 45 children (25% of 51 grafts), all Fin-major/Fin-major, with loss of 6 grafts [102]. In a subsequent series of 77 grafts in 65 patients (1986–2006), plasmapheresis combined with cyclophosphamide reduced graft loss to 1 in 9 episodes, and with remission long-term function was not significantly impaired [103, 104]. Treatment described as successful combines daily plasmapheresis, methylprednisolone pulses and oral cyclophosphamide or rituximab [2]. Outside Finland, a single patient with anti-nephrin antibodies has been described (homozygous truncating variant NM_004646.4:c.565G>T, p.(Glu189Ter)), and early or late recurrence occurs in 1–2% of patients with biallelic NPHS2 variants, particularly NM_014625.4:c.412C>T, p.(Arg138Ter), and c.413G>A, p.(Arg138Gln), without identified antibodies [2]. In this setting, immunosuppression, which has no role in native disease, treats an alloimmune complication [5].

Selection of related living donors. IPNA recommends genetic testing of related living donors in genetic SRNS (X, strong) and excludes carriers of a pathogenic variant in a dominant gene, with or without symptoms (X, strong) [3]. A heterozygous carrier of a recessive variant may donate after counselling, except for the genes COL4A3, COL4A4 and COL4A5 (C, weak), and an asymptomatic VUS carrier only after extensive assessment and without an alternative (C, weak) [3]. GeneReviews makes testing mandatory in autosomal dominant or X-linked families and in WT1, COL4A3/4/5 and NPHS2 disorders [1]. Parents should receive genetic counselling before donation, because in recessive forms a parent may themselves have a biallelic genotype, particularly in NPHS2 with p.Arg229Gln, and because incomplete WT1 penetrance may conceal a carrier parent [1, 7]. After recurrence in the first graft, a second related living donor is discouraged (B, moderate) [3].

Donors and recipients with a high-risk APOL1 genotype. Kidneys from donors with two risk alleles fail more frequently than those from donors without risk, whereas recipient genotype did not correlate with graft survival [46, 105]. In a retrospective United States cohort of living donors who donated between 2000 and 2008, assessed a median of 18.5 years later, 15.3% of the 445 Black donors had a high-risk genotype, with greater risk of eGFR below 45 ml/min/1.73 m² (RR 2.31; 95% CI 1.16–4.61) [106]. A United States Delphi panel of 27 members, 70% of whom were Black, recommended asking about African ancestry rather than race, testing only after discussion with the donor, encouraging without requiring disclosure to relatives and the recipient, and using the result in shared decision-making and never for unilateral programme decisions, rejecting a ban on donation based on genotype [107]. A 2025 United States practice document restricts genetic testing of transplant candidates to cases in which it changes management or the assessment of an at-risk donor [108]. The prospective APOLLO study evaluates transplant outcomes from donors with risk genotypes [109].

7.8. Sparsentan: indication, dosing and safety

Sparsentan (Filspari®) is a dual endothelin and angiotensin II receptor antagonist [27]. In the United States, initial authorisation, on 17 February 2023, was for adult primary IgA nephropathy; the efficacy extension approved on 13 April 2026 (supplement 6) added the indication of reducing proteinuria in adults and children aged 8 years or older with FSGS without nephrotic syndrome [27]. The indication is defined by disease rather than gene; the DUPLEX trial included patients with biopsy-proven FSGS or a genetic variant known to cause FSGS, but did not routinely perform genetic testing or present genetic subgroups [27, 110]. Application to genetic SRNS is therefore an extrapolation, and restriction to patients without nephrotic syndrome excludes most typical paediatric presentations.

Dosing in FSGS depends on weight: above 50 kg, 400 mg orally once daily, increasing to 800 mg after 14 days if tolerated; at 50 kg or less, 200 mg once daily, increasing to 400 mg after 14 days; in adult IgA nephropathy, 200 mg then 400 mg [27]. RAASi and endothelin antagonists are withdrawn before initiation; after interruption, treatment may be resumed at 50% of the dose and retitrated after 14 days [27]. The 200 and 400 mg tablets are taken whole before breakfast or the evening meal; if they cannot be swallowed, they may be crushed and suspended in half a glass of water immediately before administration [27]. The label has a boxed warning for hepatotoxicity and embryo-fetal toxicity, and the drug is available in the United States only through a risk evaluation and mitigation strategy (REMS) programme [27]. Aminotransferase (ALT/AST) elevation above 3 times the upper limit of normal (ULN) occurred in up to 3.5% of patients, without liver failure; aminotransferases and bilirubin are measured before initiation and every 3 months, treatment is not started with values above 3 times ULN, is interrupted with values between 3 and 8 times ULN, and is permanently discontinued above 8 times ULN or with bilirubin above 2 times ULN, international normalised ratio above 1.5 or symptoms [27]. It is contraindicated in pregnancy and in combination with ARBs, endothelin antagonists or aliskiren; pregnancy must be excluded before initiation and effective contraception is required before, during and until 2 weeks after treatment, informing prepubertal girls and their guardians [27]. Other adverse effects are hypotension, AKI, hyperkalaemia and fluid retention; strong CYP3A inhibitors should be avoided [27]. Safety and efficacy are not established below 8 years in FSGS, and the trial included 35 paediatric patients aged 9 years or older [27].

7.9. Comparison of regulatory status

Table 7.4 — Regulatory status of drugs indicated or used in genetic SRNS and related diseases (October 2026).

7.10. Clinical trials and therapeutic studies

Table 7.5 — Trials and therapeutic studies relevant to genetic SRNS and FSGS.

The results of these studies cannot be compared with each other: they differ in population (FSGS of mixed aetiology, APOL1 genotypes without a histological diagnosis, children with CoQ10 deficiency), endpoint (proteinuria, UACR, eGFR), duration and design. No randomised trial included a defined monogenic SRNS group. Relative reductions in proteinuria must be read against baseline proteinuria: in AMPLIFIED cohort 1, baseline UACR was 0.28 g/g [111]. DUPLEX was negative for the primary kidney function endpoint, and United States approval rests on a surrogate endpoint in a subgroup [27, 112]. KDIGO 2025 cites partial remission of 44.3% versus 23.2% for DUPLEX, values differing from the 42.0% versus 26.0% in the main publication because they represent a different analysis [4, 112]. BI 764198 results have very wide confidence intervals, show no dose–response relationship and do not include the proportion of patients with a TRPC6 variant [118]. CoQ10 and CNI studies are observational and subject to selection bias and confounding by indication [26, 91].

7.11. Developments over the last 6–12 months and level of evidence

Regulatory authorisation. On 13 April 2026, the FDA approved the sparsentan extension for FSGS without nephrotic syndrome from 8 years; in the European Union, the indication remains restricted to adult IgA nephropathy [27, 28].

Press release. On 22 September 2026, Vertex disclosed the main AMPLIFIED results (inaxaplin 45 mg once daily for 13 weeks), which it describes as phase 2b, with a UACR reduction of 42.7% in APOL1-mediated disease with modest proteinuria and of 17.3%, non-significant, with type 2 diabetes, without related serious adverse events, with headache in 7.3% and five asymptomatic, transient transaminase elevations [111]. These data had not been published in a peer-reviewed journal or posted on ClinicalTrials.gov at the time of consultation [116]. The same release announced completion of AMPLITUDE recruitment, whose 48-week interim analysis, expected in early 2027, may support an application for accelerated approval in the United States; no application has been submitted [111, 123].

Registry results. BI 764198 results were posted on ClinicalTrials.gov in January 2026, with no peer-reviewed publication identified [118].

Published studies. In 2026, publications included the cohort of living donors with high-risk APOL1 genotype [106], the GUARDD-US trial on return of APOL1 genotype [122], the KDOQI and ERA commentaries on KDIGO 2025 [81, 84], paediatric reviews of APOL1 and ongoing SRNS trials [68, 124], and creation of United States ICD-10-CM codes for APOL1-mediated kidney disease [47]. The 2026 Brazilian reviews of APOL1 synthesise limited national data [105, 125].

Registered trials. APPRECIATE (anti-APOL1 antisense oligonucleotide), MZE829 and EPPIK trials are ongoing, as is the international SPLIS observational registry (SPLIS-OSPRI), recruiting since April 2025 [113, 120, 121, 126]. GeneReviews for WT1 disorder identifies no specific investigational therapies [8]. Absence of other targeted trials in the sources consulted does not demonstrate that none exist.

7.12. Agents and practices to avoid

In confirmed monogenic forms without a previous response, prolonged PDN and CNI should be avoided [3]. Combining ACEi and ARBs is not recommended [2, 3]. Diuretics are dangerous in intravascular depletion [3]. Live vaccines are contraindicated under daily immunosuppression, in SIOD and in SPLIS [3, 9, 10]. Nephrotoxic agents and chronic NSAIDs should be avoided, except supervised indometacin in CNS [2, 9, 11]. Acetylcholinesterase inhibitors should be avoided in Pierson syndrome [55]. In SIOD, ergotamine and sumatriptan are contraindicated [5]. Idebenone should not replace CoQ10 [22]. Sparsentan is not combined with ARBs, endothelin antagonists or aliskiren [27].

7.13. Pregnancy, lactation, perioperative care and transition

In WT1 disorder, kidney disease may progress during pregnancy, and the pregnant woman should be referred early to a perinatal centre experienced in CKD [8]. RAASi and sparsentan are teratogenic and require effective contraception in adolescent girls and women of childbearing potential [3, 27]. High-risk APOL1 genotype is associated with pregnancy complications [68]. The sources consulted describe no lactation data for these drugs in genetic SRNS. Perioperatively, patients with SPLIS and adrenal insufficiency need stress-dose glucocorticoids and adrenal assessment before major procedures [9]; in patients with WT1 disorder and diaphragmatic hernia, repair precedes peritoneal dialysis, and a chest radiograph should be performed before catheter insertion [8]; in CNS, central catheter insertion requires antithrombin and anticoagulation [2]. Transition to adult care is particularly relevant in childhood-onset forms extending into adulthood, such as WT1 KTS variants, COQ8B and combinations with NPHS2 p.Arg229Gln, and in the early gonadal insufficiency of WT1 disorder, which requires endocrine follow-up [7, 8]. In France, the 2023 PNDS recommends starting transition preparation early in adolescents with persistent nephrotic syndrome, using the ORKiD filière programme, which uses questionnaires to assess knowledge and autonomy before transfer to adult nephrology [30]. Therapeutic education begins at the first consultation with an information booklet for the child and parents and covers proteinuria monitoring by dipstick, treatments, adherence (especially in adolescence), the risks of self-medication and the vaccination schedule; normal schooling is the rule, with an individualised care plan (projet d’accueil individualisé, PAI) when needed, regular adapted physical activity and psychological support [30].

7.14. Current guidelines and differences between societies

Table 7.6 — Register of guidelines and consensus statements used.

The main divergence between IPNA and KDIGO 2025 concerns starting dose and trough targets for CNI, methylprednisolone pulses and the place of rituximab, rather than the principle that genetic forms should be managed conservatively [3, 4]. The divergence between guidelines and retrospective literature on a CNI therapeutic trial in monogenic SRNS remains to be resolved in a trial [81, 91]. In adults, KDIGO 2021 is more restrictive regarding genetic testing than paediatric guidelines [46]. The 2023 French PNDS diverges from the other guidelines on five points [30]. First, it declares steroid resistance only 8 days after three methylprednisolone pulses given at the end of 4 weeks of PDN, whereas IPNA declares it at 4 weeks and uses weeks 4–6 to confirm it and to request genetic testing; KDIGO 2025 also includes pulses, but before CNI and not as a condition of the definition [3, 4]. Second, it considers the benefit of MMF in SRNS unproven, whereas IPNA and KDIGO 2025 use it to maintain remission after CNI [3, 4]. Third, for varicella exposure it proposes aciclovir 3 times daily, started within 7 days of contact and continued for 7–10 days, and specific immunoglobulin within 48–96 h, whereas IPNA proposes 4 daily doses for 7 days, started 7–10 days after exposure, and immunoglobulin within 10 days [3]. Fourth, 20% albumin is given at 1 g/kg over 3–6 h, compared with 0.5–1 g/kg over 4–8 h in IPNA [3]. Fifth, it allows antiplatelet therapy with lysine acetylsalicylate in moderate forms, an option IPNA does not mention [3]. The PNDS does not address rituximab in SRNS or set CNI doses and targets; on these points IPNA and KDIGO 2025 apply (Table 7.2). Nor does the PNDS describe gene-by-gene genetic testing or the order of genetic testing and biopsy, which follow IPNA and the ERKNet-ESPN consensus [30].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

Genetic SRNS follows autosomal recessive inheritance (most forms), autosomal dominant inheritance (for example, WT1, INF2, TRPC6, ACTN4, LMX1B) or, rarely, X-linked inheritance (TBC1D8B, LAGE3); specific syndromes (WT1, Alport, CoQ10, Schimke, CMT) require their own counselling [1].

Table 8.1 — Recurrence risks by scenario. Sources: [1, 7, 8, 22].

In recessive forms, heterozygotes are asymptomatic and not at risk, and may be kidney donors [1]. In dominant forms, most variants are de novo, but probands with an affected parent are more frequent in COL4A3/4/5 and INF2; an apparently negative family history may result from non-recognition, reduced penetrance, early death or late onset [1]. In WT1 disorder, monozygotic twins with CNS have been described whose father, asymptomatic at 41 years, had the same variant, and, in Brazil, two families with vertical transmission of WT1-associated isolated SRNS [8]. Parental gonadal or somatic and gonadal mosaicism has been described [8].

8.2. Cascade testing and surveillance of relatives

Carrier and presymptomatic testing require identification of the familial variants [1]. First-degree relatives, including siblings, should be offered urinalysis for proteinuria as early as possible, without awaiting molecular confirmation in the proband; those with proteinuria are assessed by a nephrologist, and those without it remain at risk because of variable expressivity and reduced or age-dependent penetrance, and should undergo genetic testing when a molecular diagnosis is available [1, 3]. Family testing is mandatory in dominant forms and entities with considerable intra- and interfamilial variability and reduced or age-dependent penetrance, such as COL4A3/4/5, NPHS2 and WT1 [1]. Benefits of early identification include avoiding ineffective therapies, starting RAASi, controlling hypertension, cautious use of diuretics, vaccines, vitamin D and thyroid hormone, starting targeted treatment (CoQ10) and organising extrarenal surveillance (endocrine, oncological, immune and neurological); relatives with a negative test may be discharged from surveillance [1]. In CoQ10 deficiencies, siblings should be tested as early as possible and, when the proband's diagnosis is biochemical only, CoQ10 may be measured in siblings' fibroblasts; DNA banking is recommended when there is no molecular diagnosis [22]. In SPLIS and SIOD, early testing of at-risk siblings is also recommended [9, 10]. Asymptomatic at-risk relatives should be referred to a nephrogenetics centre [1].

8.3. Testing asymptomatic minors

The ERKNet-ESPN consensus considers that testing asymptomatic siblings for the familial variant in CNS should be considered only in WT1-associated glomerulopathy, the only dominant disease with variable expressivity and incomplete penetrance that may present as CNS, always preceded by counselling [2]. In WT1 disorder, GeneReviews recommends testing older and younger asymptomatic at-risk relatives to organise surveillance for glomerulopathy, Wilms tumour and gonadoblastoma [8]. IPNA recommends siblings' urinalysis without waiting for genetic testing [3].

8.4. Prenatal and preimplantation diagnosis and family planning

Families with a history of CNS or prenatal signs should receive prompt genetic counselling [2, 7]. Prenatal diagnosis and PGT are possible when familial variants are known, and views on their use may differ between professionals and families [7, 8]. Family planning should be discussed before pregnancy, and affected or at-risk young adults should be counselled about risks to offspring [8]. In WT1 disorder, infertility associated with abnormalities of testicular development and early gonadal insufficiency influence reproductive options [8]. In families with severe CNS, the decision between intensive treatment and palliative care is shared and family-centred, and withholding treatment may be legitimate with severe comorbidities or limited resources [2].

8.5. APOL1 counselling

APOL1 genotype carries no Mendelian recurrence risk and does not predict kidney failure in a healthy carrier [5]. Outside transplantation, the rationale for testing asymptomatic people is weak [5]. In the GUARDD-US trial, return of the genotype to hypertensive adults of African ancestry did not alter systolic blood pressure at 3 months, with a 4.1 mmHg reduction in the subgroup with uncontrolled blood pressure [122]. In living donor assessment, testing follows discussion and supports shared decision-making [107].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

The incidence of idiopathic nephrotic syndrome is approximately 1–3 per 100,000 children younger than 16 years per year, of whom approximately 15% are steroid-resistant [1, 3]. The KDOQI commentary places steroid resistance between 5% and 20% of primary paediatric nephrotic syndromes [81]. There is no validated population prevalence for hereditary SRNS; Orphanet records worldwide point prevalence as unknown [12]. Most figures are proportions with a genetic cause in cohorts of referred patients, which depend on age at onset, family history, the proportion of syndromic cases and number of genes analysed, and cannot be read as prevalences [3].

Table 9.1 — Proportion with a monogenic cause in SRNS cohorts.

In Europe, NPHS2, WT1 and NPHS1 are the most common genetic causes, with 42%, 16% and 13% of genetic cases in PodoNet, and NPHS2 accounts for approximately 20–30% of sporadic SRNS in patients of European ancestry [3]. Genes frequent in one population may not be frequent in another [3].

9.2. Founder populations and geographical variation

Finland. The incidence of Finnish-type CNS was 12.2 per 100,000 births (approximately 1:8200) between 1965 and 1973 [24]. This is a phenotypic rate, predating molecular diagnosis, in a founder population and should not be generalised; there is no reliable incidence outside Finland [5]. Orphanet gives a birth prevalence of 1–5/10 000 in Finland, citing another Finnish article from 1973 (Hallman and colleagues) rather than Huttunen's [13, 24]. The carrier frequency of NPHS2 p.Arg229Gln is 7% in Finns [1].

Europe. The NPHS2 variant p.Arg138Gln is a European founder variant [7].

African ancestry and APOL1. High-risk genotype occurs in approximately 13% of African Americans and approximately 10–15% of Black people in the United States, according to different sources; risk alleles have been found only on African chromosomes, and their frequency in people of European ancestry is unknown [1, 5, 68]. In the GUARDD-US trial, 14.1% of 6754 hypertensive adults of self-reported African ancestry had two alleles [122], and in the living donor cohort 15.3% of Black donors [106]. KDIGO's lifetime risk estimate derives from African American data [46].

Brazil. A 2026 integrative review identified 10 Brazilian studies among 306 articles on APOL1; G1 and G2 alleles are present in Afro-Brazilians and associated with CKD, lupus nephritis and early initiation of kidney replacement therapy, but studies in admixed populations are lacking [125]. A Brazilian transplantation review recommends genotyping potential living donors [105]. The São Paulo cohort of transplanted children found a hereditary cause in 8.4%, with NPHS2 the most frequent gene and no post-transplant recurrence in hereditary cases [90]. The Campinas families with vertical transmission of WT1-related SRNS were described in section 8 [8]. The IPNA voting panel included a paediatric nephrologist from São Paulo representing the Latin American Association of Pediatric Nephrology (ALANEPE) [3].

Portugal. The sources consulted contain no Portuguese data on genetic SRNS.

Other founder populations. In SPLIS, p.Tyr416Cys is a founder variant in Dariusleut Hutterites, with a carrier frequency of 6.67% (10/150), compared with an allele frequency of 0.00000739 in gnomAD Europeans; prevalence estimated using gnomAD is 0.015 per 100,000 (95% CI 0.010–0.021), higher in Turks (0.046) and Iranians (0.078), with a worldwide estimate of 11,707 patients [9, 127]. In Kuwait, WDR73 is the most common cause of GAMOS, with the regional founder variants NM_032856.5:c.287G>A, p.(Arg96Lys), and c.767G>A, p.(Arg256Gln) [79]. In Turkey, ADCK4 (COQ8B) is among the most common causes of albuminuria or CKD of unknown cause beginning in adolescence [96]. The carrier frequency of NPHS2 p.Arg229Gln is 3% in the multiethnic general population and 0.01% in East Asians [1].

9.3. Frequency of rare forms

Table 9.2 — Orphanet and GeneReviews data for the grouped entities.

9.4. Special populations

In infants, management is dominated by protein loss and preservation of vascular access [2]. In adults, genetic testing is selective and dominant forms and collagen IV forms predominate [1, 46]. In people of African ancestry, APOL1 genotype modifies individual risk and donor assessment, without justifying decisions by racial category [5, 107]. In HIV infection, antiretroviral treatment is the main modifiable measure [5]. In limited-resource settings without access to genetics or histology, IPNA allows immediate initiation of CNI [3].

9.5. Reference networks and patient organisations

ERKNet is the European reference network for rare kidney diseases, including SRNS and CNS, and developed the CNS consensus statements with ESPN; it has a virtual case consultation system [7, 29]. The PodoNet registry collects demographic, causal and prognostic data on CNS and SRNS [1]. In the United States and Canada, the NEPTUNE network (Nephrotic Syndrome Study Network, 26 centres) studies FSGS, minimal change disease and membranous nephropathy, and the CureGN network includes patients from 68 North American and 3 European centres [1, 81]. In the United Kingdom, the RaDaR registry covers rare kidney diseases [8]. Patient organisations include NephCure Kidney International, the American Kidney Fund, the Kidney Foundation of Canada, Kidney Care UK and the Nephrotic Syndrome Trust (NeST, United Kingdom), the last represented in the development of the IPNA recommendations [1, 3, 8, 128, 129]. In France, idiopathic nephrotic syndrome of childhood is managed by the rare disease reference centre for idiopathic nephrotic syndrome (Paris), the reference centres for rare kidney diseases NEPHROGONE (Lyon) and SORARE (Toulouse) and competence centres, within the ORKiD health filière, which provides a patient card and the transition programme; the disease qualifies for full coverage under the long-term illness scheme ALD 19 («néphropathies chroniques graves et syndrome néphrotique primitif ou idiopathique») [30]. The specific patient association is the Association des Malades atteints de Syndrome Néphrotique (AMSN), alongside France Rein and the Association pour l’Information et la Recherche sur les maladies Rénales Génétiques (AIRG), which have a broader scope; contact details are available on Orphanet and the ORKiD website [30].

10. Illustrative Clinical Case

In 2018, Starr and colleagues described three boys with COQ2-related nephropathy followed in Seattle and collaborating centres [69]. The first patient, an Asian American boy, presented at 9 months with severe nephrotic syndrome, with serum albumin of 0.6 g/dl and UPCR of 197 mg/mg. Infectious and metabolic screening was negative, and brain MRI and electroencephalogram were normal. Kidney biopsy showed focal mesangial sclerosis and collapsing glomerulopathy, with approximately 20% of glomeruli showing global or segmental sclerosis, and electron microscopy showed extensive foot process effacement and clusters of dysmorphic mitochondria with aberrant cristae. Initial treatment included ACEi and indometacin, and volume overload required haemofiltration and albumin. A 27-gene panel identified two COQ2 variants: NM_015697.9:c.1159C>T, p.(Arg387Ter), already described as pathogenic, and the novel NM_015697.9:c.973A>G, p.(Thr325Ala) (in the MANE transcript NM_001358921.2: c.1009C>T, p.(Arg337Ter), and c.823A>G, p.(Thr275Ala)). Ubiquinone was started at 30 mg/kg/day 5 weeks after diagnosis and increased to 50 mg/kg/day 3 weeks later. Baseline leucocyte CoQ10 was normal (121 pmol/mg protein; reference 66–183) and rose to 233 at 3 weeks. Within 4 weeks, proteinuria decreased and albumin increased, and infusions were no longer required; at 20 months, kidney function was stable, albumin was 3.4 g/dl and proteinuria stable on ACEi and ubiquinone [69].

The other two patients show the limits and variability of response. The second, a Caucasian boy, had severe SRNS at 10 years with ESKD within less than 1 year; biopsy showed collapsing FSGS with 40% global sclerosis and abnormal mitochondria, and the COQ2 variants were NM_015697.9:c.683A>G, p.(Asn228Ser), and c.881C>T, p.(Thr294Ile) (MANE NM_001358921.2: c.533A>G, p.(Asn178Ser), and c.731C>T, p.(Thr244Ile)). Ubiquinone, started 8 months after diagnosis, had no effect, and transplantation, approximately 2 years after diagnosis, had no recurrence. The third, of mixed European ancestry, had nephrotic syndrome at 2 years unresponsive to 3 months of steroids, treated with ciclosporin and hydrochlorothiazide; he had the variants NM_015697.9:c.683A>G, p.(Asn228Ser), and c.176dup, p.(Ala60ArgfsTer33) (MANE NM_001358921.2: c.533A>G, p.(Asn178Ser), and c.26dup, p.(Ala10ArgfsTer33)), and with ubiquinol at 30 to 50 mg/kg/day, started 9 months after diagnosis, UPCR fell below 1.0 mg/mg, ciclosporin and the thiazide were withdrawn without relapse, and albumin normalised after 1 year. None of the three had NPHS1, NPHS2 or WT1 variants [69].

Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC5990461/figure/F1/) brings together, in twelve panels, the histology of the three patients with trichrome, periodic acid–Schiff and Jones silver stains and electron microscopy with the abnormal mitochondria; the description presented is based on the figure legend and article text [69]. The case illustrates three lessons. First, normal leucocyte CoQ10 does not exclude primary deficiency, and diagnosis must be molecular [22, 69]. Second, response depends on early treatment and the state of renal damage, consistent with observations in the Drovandi cohort and GeneReviews [22, 26]. Third, the management in the report does not constitute routine practice: the 30–50 mg/kg/day dose comes from a case series, use of ubiquinol diverges from GeneReviews, which does not recognise dose and efficacy data for it, and the third patient received ciclosporin before molecular diagnosis, which current guidelines seek to avoid through genetic testing during the confirmation period [3, 22, 69].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Genetic SRNS has a worse renal prognosis than non-genetic SRNS but a better prognosis after transplantation. In the PodoNet registry, 10-year ESKD-free survival was 27% in patients with a genetic diagnosis, compared with 94% in those achieving complete remission; risk factors for ESKD were lack of response to immunosuppression, genetic diagnosis, FSGS or DMS on initial biopsy, age, albumin and CKD stage at onset [71]. In genetic forms, progression to ESKD occurred in 66–74% and median kidney survival was 45–48 months [3, 70]. SRNS is the second most frequent cause of ESKD in the first two decades of life [25]. Graft recurrence is exceptional in monogenic forms, apart from anti-nephrin alloimmunisation in Fin-major homozygotes [2, 92].

Prognosis differs by entity. In CNS, more than 90% of children reach transplantation, with survival similar to that of other transplanted children [2]. In WT1 disorder, 50% of carriers of missense variants in DNA-binding residues have ESKD by 2.5 years, while KTS variants lead to ESKD in adolescence; survival after Wilms tumour is similar to that of tumour without a known cause [8]. In CoQ10 deficiencies treated early, 5-year kidney failure-free survival was 62% [26]. In SIOD, mean age at death is 11 years [10]. In SPLIS, survival ranges from 28% in non-transplanted carriers of two complete loss-of-function variants to 77% in p.Arg222Gln homozygotes [9]. In TRPC6-related FSGS, approximately half of patients reach kidney failure at a median age of 33 years [56]. In MYH9-related disease, annual progression to ESKD was 6.79 per 100 patients with nephropathy [23]. In nail-patella syndrome, the presence and severity of proteinuria predict progression [11]. In KDIGO 2021, nephrotic syndrome in FSGS was associated with 10-year kidney survival of 57%, compared with 92% with lower proteinuria [46].

11.2. Surveillance

Table 11.1 — Surveillance by entity.

For WT1 disorder, Table 11.1 repeats the same Wilms tumour ultrasound surveillance interval given in section 7 (every 3 months until 7 years); alternative oncological strategies exist, such as the British and North American approaches [73]. For nail-patella syndrome, a dysmorphology textbook suggests renal and ophthalmological examination every 2 years in adults, whereas GeneReviews recommends renal surveillance at least annually [11, 67]. In SRNS of genetic aetiology, the aim of follow-up is early detection of progression and complications and timely preparation for transplantation, rather than assessment of response to immunosuppression [2, 3].

12. Summary and Final Considerations

Genetic SRNS encompasses more than 60 monogenic diseases of the glomerular filtration barrier sharing a presentation, nephrotic proteinuria unresponsive to glucocorticoids, and a therapeutic behaviour: poor response to immunosuppression, frequent progression to ESKD and rare graft recurrence. The probability of a genetic cause is highest in CNS, in which NPHS1, NPHS2, WT1, PLCE1 and LAMB2 account for more than 80% of cases, and decreases with age at onset to 10–15% in adult FSGS, in which INF2, TRPC6 and collagen IV predominate.

The IPNA and KDIGO paediatric guidelines recommend genetic testing in all children with primary SRNS, and the ERKNet-ESPN consensus places it before biopsy in all CNS; in adults, KDIGO 2021 keeps it selective. Testing uses a comprehensive panel or exome, with attention to intronic WT1 regions, phasing of NPHS2 variants with p.Arg229Gln and historical WT1 nomenclature, and a negative result does not exclude a genetic cause. The result changes management: it avoids biopsy in many cases, leads to withdrawal of PDN and avoidance of CNI initiation, guides surveillance for Wilms tumour and gonadoblastoma in WT1 disorder and extrarenal manifestations in syndromic forms, identifies forms treatable with CoQ10, informs post-transplant recurrence risk and determines which relatives may be donors.

Treatment rests on RAASi, control of blood pressure and nephrotic complications and, in CNS, detailed conservative management (clinically guided albumin, nutrition, prevention of thrombosis and infection, preservation of vascular access), followed by peritoneal dialysis and transplantation. The only targeted treatments with clinical data are CoQ10 in primary CoQ10 deficiencies, with observational evidence and non-standardised doses, and pyridoxine in SPLIS, based on the authors' experience. Retrospective literature suggests that a minority of patients with monogenic SRNS respond to CNI, which guidelines have not yet integrated. Sparsentan was authorised in the United States in 2026 for FSGS without nephrotic syndrome from 8 years, without a European equivalent or specific data in genetic forms. In kidney disease mediated by APOL1, a risk allele rather than a Mendelian cause, inaxaplin reduced proteinuria in phase 2 studies, one known only through a press release, and the phase 2/3 trial will have an interim analysis in 2027; the genotype is currently relevant mainly in living donor assessment, through shared decision-making.

The available epidemiological data are proportions in referral cohorts rather than population prevalences, and Portuguese data and Brazilian data beyond the São Paulo cohorts and APOL1 reviews are lacking. Follow-up of these patients is undertaken by paediatric nephrology and genetics teams integrated into networks such as ERKNet, with family genetic counselling and planned transition to adult care.

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