REVIEW

Educational paperThe podocytopathies

Anja K. Büscher & Stefanie Weber

Received: 8 November 2011 /Accepted: 20 December 2011 /Published online: 13 January 2012# Springer-Verlag 2012

Abstract In the recent past, hereditary podocytopathieshave increasingly been recognized to be involved in thedevelopment of steroid-resistant nephrotic syndrome(SRNS). Mutations in podocyte genes substantially alterthe development and structural architecture of the podocyteincluding its interdigitating foot processes. These constitutethe basis of the slit diaphragm which is an essential part ofthe glomerular filtration barrier. Depending on the affectedprotein, the clinical course is variable with respect to onsetand severity of the disease as well as treatment options. Ingeneral, hereditary podocytopathies are associated with apoorer renal outcome than the non-genetic variants. In ad-dition, they require a different approach with respect to theapplied therapeutic strategies as most patients do not re-spond to immunosuppressive agents. Therefore, genetictesting of podocyte genes should be considered as a routinediagnostic tool for patients with SRNS because the identifi-cation of a genetic origin has a direct implication on clinicalcourse, renal outcome, and genetic counseling. In this edu-cational paper, we will give an overview over the podocytegenes identified so far to be involved into the pathophysi-ology of hereditary podocytopathies.

Keywords Pediatric nephrology . INF2 . Nephroticsyndrome .NPHS1 .NPHS2 . PLCe1 . Podocyte . TRPC6 .

WT1

Introduction

The glomerulus is a highly perfused capillary convolutesurrounded by mesangial cells. Forced by the intracapillarypressure the plasma is filtered through the glomerular barri-er, whose high permselectivity prevents the urinary loss ofmacromolecules in the normal state. It consists of threelayers: the fenestrated capillary endothelium, the glomerularbasement membrane (GBM), and the podocytes with theirinterdigitating foot processes. Within the last decade, theknowledge regarding the structure and function of thesehighly specialized epithelial cells has been constantly ex-tended, and it became evident that the podocyte plays a keyrole in the pathogenesis of proteinuria.

Podocytes are highly differentiated cells with a uniquearchitecture. They consist of a cell body, major processes,and foot processes. Podocytes develop out of the nephro-genic blastema during renal glomerular development and arethe first cells to be distinguished, forming a disk-like layerof epithelial cells. Subsequently, during the maturing pro-cess, which is associated with the loss of pluripotency andproliferation ability, podocytes develop their characteristicinterdigitating foot processes that are important for the for-mation of early cell–cell contacts. Adjacent foot processeswere demonstrated to form pores of about 40 nm in width,which are covered by an extracellular membrane with a“zipper-like” structure, the slit diaphragm. This slit dia-phragm which represents the only cell–cell contact betweenpodocytes, together with the highly dynamic foot processesof the podocyte is the central structure for the barrier func-tion of the glomerulus. In the past decades, genetic analysisof hereditary proteinuric diseases revealed a multitude oforchestrating proteins involved in this process (Table 1;

A. K. Büscher (*) : S. WeberPediatric Nephrology, Pediatrics II,University-Children’s Hospital Essen,Hufelandstraße 55,45122 Essen, Germanye-mail: anja.buescher@uk-essen.de

Eur J Pediatr (2012) 171:1151–1160DOI 10.1007/s00431-011-1668-2

Fig. 1). The main component of the slit diaphragm andresponsible for the zipper-like formation, is the proteinnephrin, whose large extracellular part links neighboringnephrin molecules through homophilic dimerization. Inter-acting with another membrane protein, podocin, and theadaptor protein CD2AP, nephrin is connected to the podo-cyte cytoskeleton. TRPC6 is a non-selective cation channelthat also co-localizes with the above-mentioned podocyteproteins and is hypothesized to regulate intracellular calci-um homeostasis of the podocyte thereby stabilizing thecomplex function network of the slit diaphragm. The struc-tural architecture of the podocyte foot processes is based onan actin cytoskeleton combined with abundant microfila-ments resulting in a firm but also highly dynamic formation.Two further podocytic proteins, α-actinin 4 and INF2, arelocated in proximity to these filaments stabilizing the cyto-skeleton and others, as laminin β2, promote the anchorageof the podocyte to the GBM. Other proteins have beendemonstrated to be involved in podocyte signaling

processes (e.g., PLCe1) and podocyte differentiation (e.g.,WT1). Mutations in the corresponding podocyte genesresult in the disintegration of this complex network withthe morphologic phenomenon of foot process efface-ment, loss of the slit diaphragm, and subsequent pro-teinuria. Depending on the mutated protein, podocytedamage is caused by the alteration of podocyte function,integrity, or the altered expression of podocyte-specificproteins due to alteration of nuclear transcriptional fac-tors. Moreover, as podocytes are also involved in syn-thesis of the GBM and the fenestration of endothelialcells (via secretion of VEGFa), local podocyte injurywas demonstrated not to affect the podocyte alone butalso adjacent structures with functional consequences forglomerular permeability. Therefore, there is increasingevidence that not the podocyte alone but the interactionbetween the three layers of the glomerular filtrationbarrier, the so-called crosstalk, is an important factorfor the pathophysiology of proteinuria.

Table 1 Hereditary forms of SRNS

Gene Locus OMIM Inheritance Protein Function Phenotype

Slit diaphragm

NPHS1 19q13.1 602716 AR Nephrin Structural basis of slitdiaphragm; podocytesignaling

CNS Finnish type; rarelylate-onset SRNS

NPHS2 1q25-31 604766 AR Podocin Linkage nephrin/cytoskeleton;targets nephrin to lipid rafts

CNS; early and lateonset SRNS

CD2AP 6p12.3 604241 AR/AD CD2 associated protein Adapter protein; anchorage ofslit diaphragm to actincytoskeleton

Adolescent/adulthood SRNS(FSGS)

TRPC6 11q21-22 603652 AD Transient receptorpotential cationchannel 6

Mediation of calcium influx;cell signaling

Predominately late-onset SRNS(FSGS); incompletepenetrance

PLCe1 10q23 608414 AR Phospholipase Cε1 Podocyte signaling Early-onset SRNS with DMSor FSGS

PTPRO(GLEPP-1)

12p12 600579 AR Protein tyrosinephosphatase receptortype O (glomerularepithelial protein 1)

Regulation of glomerularpressure and permselectivity

Infantile/adolescent SRNS(FSGS/MCN)

Cytoskeleton

ACTN4 19q13 604638 AD α-Actinin 4 Crosslinkage of f-actin Late-onset SRNS; incompletepenetrance

INF2 14q32 610982 AD Inverted formin 2 Actin-regulating protein;influence on actinpolymerization and-depolymerization

Adolescent/adulthood SRNS(FSGS)

LAMB2 3p21 150325 AR Laminin β2 Linkage podocyte/GBM Pierson syndrome; isolated DMS

MyoE1 15q21 601479 AR Myosin E1 Structural integrity ofpodocyte

Infantile SRNS (FSGS)

Nuclear protein

WT1 11p13 607102 AD Wilms tumor 1 Mediator of podocytedifferentiation

Denys-Drash-S., Frasier S.,WAGR S., isolated FSGS/DMS

LMX1B 9q34 602575 AD LIM-homeodomainprotein

Podocyte differentiation Nail-patella syndrome

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Clinically, mutations in different podocyte genes canbe discriminated by the histological changes in the kid-ney biopsy, which vary from minimal change nephropa-thy (MCN) to diffuse mesangial sclerosis (DMS) orfocal segmental glomerulosclerosing (FSGS), and theonset of the disease with disorders of early glomerulardevelopment manifesting prenatally, directly after birthor in early infancy, and disorders with late-onset ne-phrotic syndrome, typically manifesting in adulthood.However, the clinical course of patients with hereditarypodocytopathies differs in general from patients withnon-genetic disease with respect to renal survival as wellas response to therapy: The majority of patients progressto end-stage renal disease (ESRD) and show no or onlylittle response to immunsuppressive agents includingcalcineurin inhibitors [8].

The orchestrating genes

WT1

Wilms tumor (nephroblastoma) is one of the most commonsolid tumors of childhood, accounting for 8% of childhoodcancers. In 1990, the Wilms’ tumor suppressor gene (WT1)was first identified [60]. It locates on chromosome 11p13and encodes a zinc finger transcription factor regulating theexpression of various genes during kidney and urogenitaldevelopment. Mutations in WT1 were first identified inpediatric patients affected by a combination of Wilms’ tu-mor, aniridia, genitourinary malformations, and mental re-tardation called WAGR syndrome, bearing a deletion on the

short arm of chromosome 11, associated with complete loss-of-function of WT1 [22]. However, truncating WT1 muta-tions were also detected in patients with isolated Wilms’tumor [25]. Familial Wilms tumor forms seem to follow adominant pattern of inheritance, with dominant germlinemutations. Subsequently, WT1 mutations were also associ-ated with Denys-Drash syndrome (DDS) [51], Frasier syn-drome (FS) [3], and diffuse mesangial sclerosis (DMS) withisolated nephrotic syndrome (NS) [36]. The full picture ofDenys-Drash syndrome is characterized by early-onsetSRNS, male pseudohermaphroditism, gonadal dysgenesis,and the development of Wilms tumor (in more than 90% ofpatients). Age at onset of SRNS is commonly within the firstmonths of life [28]. Only in a very small subset of patients,CsA therapy has been shown to be effective inducing atleast partial remission [8, 21, 67]. Most patients rapidlyprogress to ESRD, and renal histology typically showsDMS [26] with foot process effacement in electron micro-socopy. After renal transplantation, recurrence of the diseasehas not been observed so far [49]. Most WT1 mutationsassociated with DDS are missense mutations, predominantlyaffecting exons 8 and 9 with the majority being de novomutations not observed in the parents. R394W is the mostfrequent mutation affecting a conserved amino acid of thezinc finger domains and therefore reducing the DNA bind-ing capacity of the WT1 protein [46]. Consistently, knock-inmice bearing the heterozygous R394W missense mutation,present with DMS and male genital anomalies [20]. Due tothe high risk of tumor development, preemptive bilateralnephrectomy is generally advised in patients with DDSand ESRD. Furthermore,WT1 analysis should be performedin all children with isolated DMS and early-onset NS to

Fig. 1 The slit diaphragm with orchestrating podocyte proteins

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detect mutation carriers not presenting with the full pictureof DDS but with an equal risk of tumor development. Theyshould be closely monitored by renal ultrasound (e.g., every6 months). In addition, karyotype analysis is recommendedin all girls with isolated DMS to detect a possible malepseudohermaphroditism. Besides dominant inheritance, iso-lated DMS can be associated with recessive WT1 mutationswith both the maternal and paternal allele being affected[36].

In 1997, heterozygous WT1 mutations have been associ-ated with FS [3]. These mutations represent donor splice-site mutations located in intron 9 of the WT1 gene, whichplays an important role for the generation of the KTS iso-form of the WT1 protein. This isoform contains three addi-tional amino acids (lysine–threonine–serine; KTS) and is ofhigh relevance for WT1 action during genitourinary andkidney development. In FS patients, the ratio of this (+)KTS isoform to the (−)KTS protein is markedly reduceddue to the splice-site mutations [3]. Similar to DDS, FS ischaracterized by a progressive glomerulopathy with SRNSand male pseudohermaphroditism [18]; however, there arespecific differences: The later onset of proteinuria, theslower deterioration of renal function with the developmentof ESRD not until the second or third decade of life andFSGS in renal biopsy [24]. In patients with XX karyotype,the genitourinary tract is normal, whereas a complete sexreversal with gonadal dysgenesis is observed in 46,XYpatients. Primary amenorrhea in conjunction with NS is atypical feature of these 46,XY patients and should promptmolecular analysis of WT1. While the risk to develop aWilms’ tumor is low in patients with FS, gonadoblastoma,developing from gonadal dysgenesis, is frequently ob-served. Therefore, gonadectomy is highly recommended inpatients with FS and 46,XY karyotype.

While the pathogenicity of WT1 mutations is beyond anydoubt, there is remarkable phenotypical heterogeneity:Splice-site mutations typical for FS may in some cases befound in patients with DDS [51] or isolated DMS [14], andpatients with typical DDS mutations may display with iso-lated FSGS or Wilms’ tumor without NS [39].

NPHS1

NPHS1 maps to chromosome 19q13 [42] and encodes forthe protein nephrin. Nephrin is a member of the immuno-globin superfamily and is exclusively expressed in podo-cytes [63]. It comprises a single putative transmembranedomain, a short intracellular N terminus and a long extra-cellular C terminus, which bridges the intercellular spacebetween the podocyte foot processes contributing to theporous structure of the slit diaphragm [42] and therewiththe glomerular filtration barrier (Fig. 1). Apart from itsstructural relevance, nephrin is discussed to have an

important role in intracellular signaling pathways, maintain-ing, together with other podocyte proteins as podocin,CD2AP and TRPC6, the functional integrity of the podocyte[33, 34]. In the 1990s, NPHS1 gene mutations were firstdemonstrated to be associated with “Finnish type” CNS[41], an autosomal-recessive inherited nephrotic syndromewith congenital onset (CNS) first described in the Finnishpopulation. Typically, Finnish type CNS is characterized by asevere clinical course with onset of the disease in utero orwithin the first 3 months of life [58] and a characteristic renalhistology with immature glomeruli, mesangial cell hypercellu-larity, glomerular foot process effacement, and pseudocysticdilations of the proximal tubules. Therapeutical options arerestricted to albumin infusions, indomethacin therapy, “phar-macological nephrectomy”with ACE inhibitors or angiotensinreceptor inhibitor, and, ultimately, uni- or bilateral nephrecto-my [13, 32, 43, 55]. In particular, two truncating mutationswere identified to exist almost exclusively and with highfrequency within the Finnish population suggesting two inde-pendent underlying founder effects: L41fsX90 (Fin major,truncating the majority of the protein) and R1109X (Fin minor,truncating only a short C-terminal part) [41]. Meanwhile, morethan 90 different NPHS1 mutations have been described, scat-tered along the whole gene, most of them being private muta-tions. Besides protein-truncating nonsense and frameshiftmutations, splice-site, and missense variants were identified.

Concordant with the broadening spectrum of NPHS1mutations, recent studies proved that the clinical courseassociated with NPHS1 mutations is not, as assumed initial-ly, restricted to “classical CNS”. NPHS1 mutations werealso identified to be disease-causing in patients with milderdisease, adult-onset, and the histological finding of FSGS[53, 64]. This attenuated clinical course may be explainedby the pathogenicity of the underlying mutations, predom-inately missense mutations with minor modifications of theprotein not altering protein trafficking or dimerization sug-gesting retained protein function [53].

NPHS2

NPHS2 was mapped by linkage analysis in eight familieswith autosomal recessive SRNS to chromosome 1q25-q31[19]. NPHS2 encodes for podocin, a 42-kD integral mem-brane protein with a hair-pin like structure, expressed inboth fetal and mature glomeruli at the slit diaphragm(Fig. 1) of the podocyte [5]. Interacting with both nephrinand CD2AP, podocin appears to link nephrin to the podo-cyte cytoskeleton. In patients affected by recessive muta-tions in NPHS2, formation of the slit diaphragm is impaired,and the typical foot process effacement is visible. Theseobservations suggest that podocin has an important functionfor maintaining the glomerular filtration barrier. Up to now,more than 30 pathogenic mutations have been described in

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NPHS2. Initially, NPHS2 mutations were described inpatients with infantile SRNS and rapid progression to ESRD[5]. Subsequently, however, it was found that defects inpodocin can be responsible for SRNS manifesting at anyage from birth to adulthood [9, 10]. Patients generally do notrespond to intensified immunosuppressive therapy regimensbased on CsA [8], and in light of the severe side effects, thistreatment should be avoided. Only single cases have beenreported, in whom at least a partial remission inductioncould be achieved under CsA treatment [62]. FollowingRTx extremely low rates of disease recurrence were ob-served [31, 37, 71]. Renal histology typically shows FSGS,however, some patients present with only MCN in the initialbiopsy. A partial genotype–phenotype correlation is appar-ent: While the R138Q mutation is typically associated withearly-onset NS, other missense mutations (e.g., V180M,R238S) are predominantly found in patients with a lateronset of SRNS [71]. A frequent single-nucleotide polymor-phism (PM) in the NPHS2 gene (R229Q) is prevalent inheterozygous state in approximately 3% of the normal popu-lation (range, 0.5–7%, depending on the genetic background)[17]. R229Q is present in compound heterozygosity with apathogenic NPHS2 mutation on the second allele in somepatients with FSGS/SRNS. NS manifests late in these indi-viduals, suggesting a reduced pathogenicity when comparedwith true/non-polymorphic NPHS2 mutations. R229Q istherefore considered a non-neutral PM enhancing the suscep-tibility to FSGS in association with a second mutant NPHS2allele [70]. Moreover, in a large study of more than 1,500individuals of the general population, the R229Q PM wassignificantly associated with the prevalence of microalbumi-nuria, a risk factor for developing chronic renal insufficiencyand cardiovascular events [52]. In vitro studies havedemonstrated that R229Q podocin shows decreased bind-ing to its interacting protein partner nephrin [70]. Thesefindings underline the functional importance of podocinfor the glomerular filtration barrier, with even subtlechanges of the amino acid sequence impairing its properfunction. The knock-out of Nphs2 in mice is associatedwith a phenotype highly reminiscent of the human diseasewith podocyte foot process effacement, nephrotic range pro-teinuria, and chronic renal failure [61].

ACTN4

In 1998, ACTN4 encoding for α-actinin 4, an actin-bundlingprotein of the cytoskeleton, was mapped to chromosome19q13 [47]. ACTN4 is highly expressed in podocytes. Inhumans, ACTN4 mutations were identified as the underlyingpathogenic cause in three families with autosomal dominantFSGS [38]. Clinically, the affected family members pre-sented with proteinuria of adolescent onset progressing tochronic renal insufficiency during adulthood with ESRD in

several cases. The identified missense mutations led to non-conservative amino acid substitutions affecting the bindingdomain of actinin 4. Hence, in vitro studies demonstrated anincreased binding to filamentous actin for the mutant proteincompared with wild-type actinin 4 together with the forma-tion of large aggregates of the mutant protein itself andimpaired migration properties [48, 75]. Renal histologyrevealed a segmental and irregular granular staining patternin the capillary walls of preserved glomeruli of ACTN4mutants [38, 75]. However, Kaplan et al. observed incom-plete penetrance in these families with some mutation car-riers not developing a renal phenotype suggesting otheradditional (genetic or non-genetic) factors to be involvedin the pathogenesis of ACTN4 associated FSGS [38]. Insummary, ACTN4 mutations were proposed to interfere withthe regulation of the actin cytoskeleton of glomerular podo-cytes in this group of patients, thereby altering the functionof the podocyte foot processes. However, mutations inACTN4 represent a rare cause of hereditary FSGS, account-ing for approximately 4% of familial FSGS [72].

TRPC6

In 1999, TRPC6 was mapped to chromosome 11q21-q22 asthe second locus for autosomal dominant FSGS after theidentification of ACTN4 [74]. TRPC6 encodes for the tran-sient receptor cation channel TRPC6 which is highlyexpressed in podocytes at the level of the slit diaphragmand is thought to mediate calcium influx into cells (Fig. 1).Altered calcium signaling conferred by TRPC6 mutations isimplicated in the disruption of glomerular cell function.Initially, a dominant missense mutation was identified in alarge Caucasian family of British heritage with 31 affectedfamily members, 28 of whom developed ESRD, the otherspresenting with proteinuria [73]. In the meantime, severalother pathogenic mutations have been reported, most ofwhich associated with late-onset FSGS with mild to ne-phrotic range proteinuria progressing to ESRD [59]. How-ever, the studies indicate an incomplete penetrance of theidentified mutations with several unaffected mutation car-riers. Moreover, in the recent past, TRPC6 mutations havebeen detected in patients with early-onset disease [23]. Invitro, several missense mutations were demonstrated to in-crease the current amplitudes of TRPC6, consistent with again-of-function effect of the mutations [59, 73]. Moreover,podocyte-specific overexpression of wild-type or mutantTRPC6 in transgenic mice led to a proteinuric phenotype withhistologic criteria of FSGS [44] and, vice versa, the knock-down of TRPC6 reduced the susceptibility to proteinuricagents as angiotensin II in mice [15]. However, the exact roleof this cation channel in the pathophysiology of proteinuricdiseases remains to be elucidated.

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INF2

Recently, linkage analysis revealed another locus for auto-somal dominant FSGS on chromosome 14q containingINF2 [7]. INF2 encodes a member of the formin family ofactin-regulating proteins with the ability to accelerate bothactin polymerization and depolymerization in vitro [29](Fig. 1). All identified disease-segregating mutations weremissense variants and were located within its diaphanousinhibitory domain inhibiting actin depolymerization [12].Clinically, the affected individuals presented with moderateproteinuria during adolescence and adulthood, the histolog-ical finding of FSGS (in combination with prominent actinbundles), and progression to ESRD [7]. Mutational analysisof a large cohort of 78 patients (54 families) with autosomaldominant FSGS revealed that a non-negligible proportion ofthe disease is due to INF2 mutations (17%), whereas insporadic cases the allele frequency is extremely low(0.006) [6]. INF2 is highly expressed in glomerular podo-cytes, and consistently, electron microscopy of renal bi-opsies of affected patients demonstrated prominent actinbundles besides irregular morphology of podocyte footprocesses. In addition, transfection studies with wild-typeand mutant protein revealed differences regarding thesubcellular localization of INF2 and the distribution pat-tern of actin filaments [7]. As the podocytes, especiallytheir interdigitating foot processes are complex, actin-rich, and highly dynamic structures, the dysregulationof the podocyte cytoskeleton due to INF2 mutations islikely to alter podocyte function regarding the mainte-nance of the filtration barrier. Besides, most of the iden-tified mutations were located in a region assumed to beimportant for the interaction with IQ motif-containingGTPase-activating protein 1 (IQGAP1), a protein knownto interact with other podocyte proteins as nephrin andPLCe1 [30, 45], providing additional evidence for theimportance of formin proteins for podocyte function.

Clinical presentation

Podocytopathies typically present with, often nephrotic-range, proteinuria. Nephrotic syndrome (NS) is defined asthe association of severe proteinuria (>40 mg/m2/h), hypo-albuminemia (<2.5 g/dl), and, optionally, edema and hyper-lipidemia. Patients with NS can be separated into twocategories on the basis of their response to standard steroidtreatment, i.e., steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) [35]. (Steroid resistance: failureof remission induction after 4 weeks of prednisone60mg/m2/day). Themajority of patients with podocytopathiesas the underlying cause of NS suffer from the steroid-resistantform of the disease. In the kidney biopsy, SRNS is associated

with the histological features of FSGS in approximately 75%of patients, whereas 20% demonstrate minimal-change NS(MCNS) [57]. FSGS is a histological finding that impliesthe presence of sclerotized areas affecting only a certainproportion of the glomeruli of the kidney (focal) as wellas only a certain part of each glomerulus (segmental).With progression of the disease, the sclerosis may ex-pand, changing into a more diffuse and global pattern.Besides sclerosis, alterations of podocytes with effacementof podocyte foot processes are common findings in FSGS.Patients suffering from SRNS (and therewith patients withpodocytopathies) often exhibit a poor renal survival withprogression to ESRD. This applies particularly for patientswith hereditary podocytopathies with 71% of the patientsprogressing to ESRD over an observation period of 8 yearscompared with 29% of the patients with non-hereditarySRNS [8].

Therapeutical options

Immunosuppression

The therapy of patients with a steroid-resistant form of NS ingeneral is demanding. Numerous immunosuppressive agentshave shown some efficacy in a subset of SRNS patients. Theseagents include cyclosporine (CsA), cyclophosphamide, aza-thioprine, and mycophenolate mofetil, often in combinationwith glucocorticoids [54]. In many centers, CsA is used, andseveral studies showed CsA-induced remission rates of up to70% in pediatric SRNS patients [11, 56]. CsA is a calcineurininhibitor that suppresses the immune response by downregu-lation of various cytokine genes, and its antiproteinuric prop-erties were so far attributed to this immunosuppressive action[68]. However, some SRNS patients proved to be insensitiveto immunosuppressive treatment, and these patients have beensupposed to suffer from a hereditary podocytopathy patho-physiologically explained by the presence of intrinsic defectsin podocyte architecture and function. Based on these obser-vations, it was discussed to spare patients with hereditarypodocytopathies from intensified immunosuppressive treat-ment regimens. However, recently, several centres reportedpartial remissions induced by CsA in patients with a provengenetic basis of the disease. Ruf et al. reported a large cohortof 190 SRNS patients, 29 of whom with mutations in NPHS2and treatment with CsA or cyclophosphamide. Of these, fiveindividuals exhibited partial response upon this treatment[62]. In addition, few patients with pathogenic mutations inWT1 and PLCe1 have been demonstrated to respond to im-munosuppressive therapy regimens including CsA [21, 30].The pathophysiology of remission induction in this subset ofpatients remains unclear so far, and besides effects on vascularperfusion and the immune system, direct effects on the

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podocyte architecture are discussed. Faul et al. demonstrated adirect effect of CsA on the stabilization of the podocyte actincytoskeleton by inhibiting the degradation of synaptopodin,thus suggesting a benefit of CsA treatment also for patientswith hereditary SRNS [16]. However, these observations re-main rare and apply only for a minority of patients. Systematicanalyses demonstrated that remission rates following CsAtherapy are significantly lower in patients with genetic diseasecompared with non-hereditary SRNS (17% vs. 68%) and thatlow remission rates were associated with significantly worserenal survival (29% vs. 71%) [8]. In this study, remissioninduction in hereditary disease was restricted to partial re-sponse in few patients affected by WT1 mutations. Togetherwith the observations of Gellermann et al. [21] reportingpartial remission in two patients affected by WT1 mutationsthe impression arises that CsA therapy in a subset of WT1mutation carriers might reduce proteinuria to a certain extend[67]. But, in light of the various side effects of this immuno-suppressive therapy that has to be maintained for years tosustain the beneficial effect, intensified immunosuppressivetherapy regimens generally should be avoided in patients withhereditary SRNS (possibly with the exception of WT1 muta-tion carriers).

Renal transplantation

Resistance to intensified immunosuppressive therapy inpatients with NS is commonly associated with progressionto ESRD requiring dialysis and/or renal transplantation(RTx). SRNS patients with a renal histology of FSGS havea non-negligible risk for a recurrence of the disease afterRTx with approximately 30% in pediatric patients [1, 66].They present with nephrotic range proteinuria early afterRTx (mean time, 14 days post-transplant) [69], which isoften sensitive to plasmapheresis and cyclophosphamidetreatment [2, 40]; however, it is associated with a negativeimpact on graft survival in both children and adults [27]. Inidiopathic FSGS, a circulating plasma factor derived from Tcell dysfunction is discussed to participate in the pathogen-esis of proteinuria recurrence [65]. This factor may beresponsible for an increase in podocyte integrin-linked ki-nase activity leading to podocyte detachment from theGBM. In hereditary podocytopathies with the clinical pre-sentation of FSGS, recurrence of the disease following RTxis less frequent (less than 10%); however, these patients arenot entirely protected from post-transplant recurrence ofproteinuria, even in the long-term mutations [4, 31, 37, 50,62, 71]. The origin of post-transplant recurrence in thesepatients is largely unknown with the exception of patientswith NS-related NPHS1 mutations. These patients, especial-ly if affected by a truncating Fin major mutation, have ahigh risk of post-transplant recurrence of NS equally tothose with idiopathic FSGS. Analogous to the situation in

Alport syndrome, these patients develop anti-nephrin anti-bodies directed against the wild-type protein residing in thetransplanted kidney [50] resulting in the development of ade novo glomerulonephritis. Treatment options of post-transplant NS in these patients are scarce with a subset ofpatients responding to cyclophosphamide [50].

Living-related donor transplantation is generally consid-ered the therapy of first choice in pediatric patients with ESRDas well in patients with SRNS. However, in patients withhereditary podocytopathies, especially with recessive inheri-tance, several special aspects have to be considered. Essen-tially, prospective data on the outcome of living-related donortransplantation in patients with hereditary podocytopathies islacking so far. Experience is limited to the description ofsingle cases with this donor/recipient constellation [31]; how-ever, this data does not support a restriction in affected chil-dren. But, as neither the performance of the heterozygousdonor organs in recipients with recessive disease, nor theprognosis for the remaining single kidney in the donor hascarefully been evaluated, cautious surveillance of both donorand recipient is advisable. The parents of the affected childrenwith recessive podocytopathies carry one mutant allele whichis as well present in the transplanted kidney. Possibly, thesekidneys might be more susceptible to develop proteinuria inthe presence of other pathogenic factors (e.g., arterial hyper-tension, salt-rich diet). This applies for both the recipient ofthe transplanted kidney and for the donor. So far, the questionwhether the prognosis of the remaining single kidney in theheterozygous parental donor is impaired by the gene mutationremains to be elucidated. However, animal models do notsupport this hypothesis so far. In dominant disease, only oneparent is carrier of the pathogenic sequence variant. In thiscase, genetic testing will help to delineate mutation carrierswithin the family. In case of a de novo mutation in the patient,both parents are equally suitable for living donor transplanta-tion from a genetic point of view.

Genetic counseling

Genetic counseling should be offered to patients withhereditary FSGS/SRNS and their families because ofa considerable risk of recurrence (25% in recessivedisease and 50% in dominant disorders). However,counseling is complicated by several imponderabilia asincomplete penetrance and variable expressivity of thedisease which applies especially for autosomal-dominantFSGS. Hence, individuals carrying the same mutationmay be affected to a varying extent with an obviouslymild phenotype in some family members and ESRD inothers. In general, the nature of hereditary SRNS isdemonstrated to be more severe than idiopathic diseasewith limited treatment options and worse renal survival.

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In some cases, genotype–phenotype correlations mayfacilitate counseling, supplying additional informationfor the affected patients which may specify the expectedclinical course. This has been shown in NPHS2-associ-ated disease, where some mutations have been demon-strated to lead to early-onset and aggravated disease,whereas others were shown to be less pathogenic. Be-sides the influence on SRNS phenotype, proof of hered-ity may alter the patients’ future life in different aspects:Patients with WT1 mutations have a high risk for thedevelopment of uni- or bilateral nephroblastoma sug-gesting preventive bilateral nephrectomy. Moreover,WT1 mutations associated with Frasier syndrome maypresent with male pseudohermaphroditism with itsimplications on sexual identity and, in case of XYkaryotype, have a high risk for the development ofgonadoblastomas. Furthermore, patients with recessivedisease will transmit a heterozygous mutation to theirown prospective children. As long as the other parentdoes not carry a mutation himself, all offsprings will behealthy. In case of a dominant FSGS, the pathogenicmutation will be transmitted in 50%, with the mutationcarriers being clinically affected to a various extent dueto incomplete penetrance in many cases.

Conclusions

Hereditary podocytopathies are increasingly recognized asthe underlying cause of SRNS, especially if the clinicalcourse is aggravated by the development of ESRD andresistance to intensified immunosuppressive therapy. In therecent past, the panel of genes involved in SRNS pathogen-esis has been expanded considerably; however, the majorityof cases still can be attributed to pathogenic mutations inWT1 and NPHS2. Moreover, in patients with onset of thedisease in early childhood (less than 6 years of age), muta-tions in NPHS1 or, if associated with renal histology ofDMS, in PLCE1 and LAMB2 have to be considered asdisease-causing. On the contrary, in SRNS with an onsetof the disease in adolescence (>6 years of age) or evenadulthood, mutations in TRPC6, CD2AP, ACTN4, andINF2 are more prevalent. However, these age-dependentclassifications may serve as orientation guide but do notclaim to be exhaustive. Therefore, in individual cases, mu-tational screening has to be expanded. Overall, genetictesting of podocyte genes should be considered as a routinediagnostic tool in both pediatric and adult SRNS patients asthe identification of a genetic origin of the disease mayallow the specification of the prospective clinical courseand may therefore have a direct implication on therapyregimen and family counseling.

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