Advertisement

Pediatric Nephrology

, Volume 34, Issue 11, pp 2279–2293 | Cite as

Treatment of steroid-resistant nephrotic syndrome in the genomic era

  • Adam R. Bensimhon
  • Anna E. Williams
  • Rasheed A. GbadegesinEmail author
Review

Abstract

The pathogenesis of steroid-resistant nephrotic syndrome (SRNS) is not completely known. Recent advances in genomics have elucidated some of the molecular mechanisms and pathophysiology of the disease. More than 50 monogenic causes of SRNS have been identified; however, these genes are responsible for only a small fraction of SRNS in outbred populations. There are currently no guidelines for genetic testing in SRNS, but evidence from the literature suggests that testing should be guided by the genetic architecture of the disease in the population. Notably, most genetic forms of SRNS do not respond to current immunosuppressive therapies; however, a small subset of patients with monogenic SRNS will achieve partial or complete remission with specific immunomodulatory agents, presumably due to non-immunosuppressive effects of these agents. We suggest a pragmatic approach to the therapy of genetic SRNS, as there is no evidence-based algorithm for the management of the disease.

Keywords

Nephrotic syndrome SRNS Genetic SRNS Treatment Genetic SRNS 

Introduction

Nephrotic syndrome (NS) is the most common glomerular disorder in childhood, with an incidence that ranges from approximately 2 to 7/100,000 children per year and a global prevalence of approximately 16/100,000 children [1, 2]. It is diagnosed by a constellation of clinical signs and symptoms that include massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Childhood nephrotic syndrome is classified based on initial response to a standardized corticosteroid therapy into steroid-sensitive nephrotic syndrome (SSNS) or steroid-resistant nephrotic syndrome (SRNS). Despite the lack of a global consensus regarding the definition of steroid resistance, most experts agree that SRNS constitutes the failure to achieve remission after 4–6 weeks of daily corticosteroid therapy [3, 4]. The SSNS variant is the most common among children, accounting for about 80% of cases, while the SRNS variant accounts for the remaining 20% of cases and typically portends an unfavorable prognosis [5]. Most children with SRNS will progress to end-stage kidney disease (ESKD) within 5–10 years of diagnosis [6, 7].

The etiology of SRNS is unknown in the majority of children with the disease; however, data from genomic studies in the last 20 years suggest that most cases of SRNS are probably due to structural and functional defects of the podocyte, the glomerular visceral epithelial cell. Strikingly, the majority of the over 50 single-gene causes of hereditary NS are critical for the functional integrity of the podocyte; thus, most clinicians now refer to SRNS as a podocytopathy [8].

The prevalence of genetic SRNS is unknown due to the dearth of population-based studies. Reported prevalence varies between 4 and 30%, with a higher prevalence among inbred populations and a lower prevalence in heterogeneous outbred populations [9, 10, 11, 12, 13]. Sadowski et al. [9] studied 1783 unrelated families and found the prevalence of monogenic NS to be 29.5%; however, mutation prevalence varies widely between different regions of the world, with the highest prevalence in regions of the world where consanguinity is common. In addition, there is currently no data from Africa on disease burden due to monogenic NS. While genetic SRNS is being increasingly recognized, there is no standardized approach to the management of children with genetic NS. In addition, the relationship between genetic mutations and response to therapy has not been established, but it has been reported that the prevalence of resistance to corticosteroid therapy and other immunosuppressive agents is significantly higher in patients with genetic NS compared to those with non-genetic disease [14, 15], though there are isolated reports in the literature describing patients with monogenic SRNS who have responded to immunosuppressive therapies. To further compound the dilemma of treatment decision in genetic NS, there is accumulating evidence from pre-clinical studies that, in addition to their immunomodulating effects, the effects of immunosuppressive agents such as corticosteroids and calcineurin inhibitors in NS may be partially due to their stabilizing effects on the podocyte F-actin cytoskeleton, suggesting that these agents may be useful in the treatment of SRNS due to structural defects of the podocyte [16, 17, 18, 19].

In this review, we will address the indications for genetic testing in SRNS and discuss the implications of a positive and negative genetic test result on management decisions and long-term prognosis. We will discuss the current evidence available for making decisions on whether or not to use immunomodulatory therapy and/or other supportive agents in the management of SRNS. We will also suggest a practical approach to handling this clinical scenario in day-to-day practice.

Etiology and pathogenesis of SRNS

SRNS is a clinically heterogeneous condition that is associated with different morphologic changes on kidney biopsy. The most common pathologic variant associated with SRNS in children is focal segmental glomerulosclerosis (FSGS). FSGS is a pathologic finding that is characterized by focal glomerulosclerosis or tuft collapse, segmental hyalinosis, IgM deposits on immunofluorescence staining, and podocyte foot process effacement [20, 21]. Clinically, FSGS is characterized by rapid progression to ESKD within 5–10 years of diagnosis [6, 7]. It is increasingly being recognized that morphological changes in kidney biopsies of patients with FSGS are heterogeneous, and that the different morphologic types may be associated with different disease courses [22], though the detailed description of these variants is beyond the scope of this review. Other less common lesions that may cause SRNS include minimal change disease (MCD) and membranous and membranoproliferative glomerulopathy.

The molecular pathogenesis of FSGS and other SRNSs is not fully understood; however, there is evidence that SRNS is caused by defects in the glomerular filtration barrier (GFB), the charge and size-selective barrier that is made up of specialized fenestrated endothelial cells, the glomerular basement membrane (GBM), and glomerular epithelial cells (podocytes). Data emanating from studies of familial FSGS suggest that the podocyte is the most important component of the GFB in that majority of the more than 50 genes mutated in hereditary FSGS affect the structure and functions of the podocyte and its slit diaphragm [8, 23, 24]. These observations have given rise to the concept of FSGS being a podocytopathy. In addition to structural defects of the podocyte, putative soluble circulating factors resulting from immune dysregulation may also cause podocyte injury in patients with SRNS. Furthermore, maladaptive changes such as obesity, and conditions that result in reduced nephron number (e.g., congenital or acquired solitary kidney, or preterm birth), can cause and perpetuate podocyte injury [25, 26, 27, 28, 29, 30, 31, 32, 33]. It should be noted that soluble urokinase-type plasminogen activator receptor (suPAR), CD80, and other molecules have been linked to the etiology and pathogenesis of SRNS, pattern of therapy response, and risk of recurrence following kidney transplantation. However, the genetic basis of how these molecules modulate disease course in NS is unknown, and this topic will be the subject of another review.

Genetic SRNS

Monogenic SRNS

Monogenic SRNS can be of autosomal recessive (AR), autosomal dominant (AD), X-linked, or mitochondrial inheritance [34]. Typically, recessive inheritance is characterized by early onset of disease presentation and high penetrance and is sometimes associated with extra-renal manifestations. In contrast, dominant inheritance is associated with later onset of disease presentation and incomplete penetrance. Monogenic causes of SRNS are probably responsible for a small proportion of all cases of SRNS; however, data from studies of this small fraction of patients with SRNS has improved our understanding of disease pathobiology. The landmark discovery of nephrin (NPHS1) as the gene mutated in congenital nephrotic syndrome by Tryggvason and his colleagues [24] drew attention to the vital role of genetic and molecular analyses in understanding the pathogenesis of SRNS.

With the completion of the sequencing of the human genome and rapid improvements in high-throughput sequencing technology, the rate of discovery of genes causing monogenic SRNS has increased dramatically. Mutations in approximately 50 genes are now known to cause SRNS [9, 35, 36, 37, 38, 39, 40]; however, these genes are responsible for less than 20% of all cases of SRNS, suggesting that SRNS is genetically heterogeneous and there are still many unidentified genetic causes of the disease. The majority of SRNS genes are enriched in the podocyte and the slit diaphragm, as well as other components of the GFB. A list of genetic causes of SRNS and the localization of the genes in the GFB is shown in Table 1. Genes mutated in SRNS are generally rare in the genus population; however, data from different cohorts seems to suggest that mutations in NPHS1, NPHS2, and PLCE1 are the most common cause of autosomal recessive SRNS, while mutations in INF2, COL4A3, COL4A4, WT1, TRPC6, ACTN4, and LMX1B are responsible for most cases of autosomal dominant SRNS [11, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50]. It should be noted that the prevalence of mutations in these genes also varies widely between different regions of the world; for example, R138Q and R138X mutations in NPHS2 represent founder mutations in Central Europe [51]. More recently, Winkler et al. reported that NPHS2 V260E may also represent a founder mutation among blacks in South Africa (Cheryl Winkler, PhD, personal communication, 26 June 2018). Generally, patients with genetic SRNS progress more rapidly to ESKD than those with non-genetic disease [12]; however, the rate of disease recurrence post-transplantation in those with genetic disease is much lower than that in those with non-genetic disease. In some studies, recurrence risk in genetic SRNS was reported as less than 8% compared with 30% in patient populations with non-genetic causes [12, 14, 15, 52].
Table 1

Genetic causes of nephrotic syndrome

Gene

Protein

Mode of inheritance

Slit diaphragm genes

NPHS1

Nephrin

AR

NPHS2

Podocin

AR

PLCE1

Phospholipase C epsilon 1

AR

CD2AP

CD2-associated protein

AD, AR

TRPC6

Transient receptor potential channel C6

AD

CRB2

Crumbs family member 2

AR

FAT1

FAT atypical cadherin

AR

Transcription factors and nuclear genes

WT1

Wilms tumor protein 1

AD

LMX1B

LIM homeobox transcription factor 1-beta

AD

SMARCL1

SMARCA-like protein

AR

NUP93

Nuclear pore complex protein 93

AR

NUP107

Nuclear pore complex protein 107

AR

NUP205

Nuclear pore complex protein 205

AR

XPO5

Exportin 5

AR

E2F3

E2F transcription factor

AD

NXF5

Nuclear RNA export factor 5

X-linked recessive

PAX2

Paired box protein 2

AD

LMNA

Lamin A and C

AD

WDR73

WD repeat domain 73

AR

Cytoskeletal and membrane genes

ACTN4

Alpha-actinin 4

AD

INF2

Inverted formin 2

AD

MYO1E

Myosin 1E

AR

MAGI2

Membrane-associated guanylate kinase, inverted 2

AR

ANLN

Anillin actin binding protein

AD

PTPRO

Protein tyrosine phosphatase RO

AR

EMP2

Epithelial membrane protein 2

AR

CUBN

Cubilin

AR

PODXL

Podocalyxin

AD

ARHGAP24

Rho GTPase-activating protein 24

AD

ARHGDIA

Rho GDP dissociation inhibitor alpha

AR

DLC1

DLC1 Rho GTPase-activating protein

AR

KANK 1/2/4

Kidney ankyrin repeat-containing protein

AR

ITSN 1/2

Intersectin protein

AR

SYNPO

Synaptopodin

AD

TNS2

Tensin-2

AR

Mitochondrial, lysosomal, metabolic, and cytosolic genes

COQ2

Coenzyme Q2 4-hyroxybenzoate polyprenyl transferase

AR

COQ6

Coenzyme Q6 monooxygenase

AR

PDSS2

Prenyl-diphosphate synthase subunit 2

AR

ADCK4

AarF domain-containing kinase 4

AR

SCARB2

Scavenger receptor class B, member 2

AR

PMM2

Phosphomannomutase 2

AR

ALG1

Asparagine-linked glycosylation 1

AR

TTC21B

Tetratricopeptide repeat protein 21B

AR

CDK20

Cyclin-dependent kinase 20

AR

CFH

Complement factor H

AR

DGKE

Diacylglycerol kinase epsilon

AR

SPGL1

Sphingosine-1-phosphate lyase 1

AR

Glomerular basement membrane genes

LAMB2

Laminin subunit beta-2

AR

ITGB4

Integrin beta 4

AR

ITGA3

Integrin alpha 3

AR

COL4A 3/4/5

Type IV collagen alpha 3, 4, 5

AR, AD, X-linked

Endosomal regulator genes

GAPVD1

GTPase-activating protein and VPS9 domain 1

AR

ANKFY1

Ankyrin repeat and FYVE domain containing 1

AR

AR autosomal recessive, AD autosomal dominant

Polygenic SRNS

A full discussion of the role of polygenic inheritance in SRNS is beyond the scope of this review; however, it is worth noting that two variants in APOL1 gene [G1 allele (rs73885319 or rs60910145) and G2 allele (rs717853136)] were recently identified as being responsible for excess risk of FSGS and chronic kidney disease (CKD) in African Americans [53]. Heterozygosity for either of these alleles protects against sleeping sickness, thereby conferring a survival advantage similar to protection provided by sickle cell trait (hemoglobin AS) against malaria. However, when the G1 and G2 alleles are inherited in a homozygous or a compound heterozygous manner, these alleles confer a 7- to 17-fold increased odds for FSGS and a plethora of other forms of CKD in African Americans [53, 54]. In addition, variants in glypican-5 (GPC5) were reported to be associated with FSGS and MCD in Japanese adults [55]. It should be noted that variants in polygenic genes are not causal and they will result in disease only in the presence of additional modifier variants and environmental factors. For example, only about 25% of individuals with the high-risk APOL1 genotype will develop CKD in their lifetime.

The role of genetic testing in SRNS

Genetic testing in clinical practice is emerging as an invaluable diagnostic and prognostic tool in the management of children with SRNS. Mutation detection in patients with SRNS potentially allows for (1) a pragmatic approach to the use of different immunosuppressive agents and avoidance of side effects [56], (2) selection of targeted therapies that may induce remission and/or delay progression to ESKD [57], (3) prediction of clinical course and post-transplant disease recurrence [58], and (4) genetic counseling and possible antenatal screening [59]. In addition to these clinical benefits, the continued discovery of novel SRNS genes will further our understanding of the pathogenesis of SRNS, aid in the precise definition of disease phenotype, and allow for a personalized approach to therapy.

Genetic testing methods

With improvements in high-throughput sequencing technology, genetic testing is now widely available and is being deployed by clinicians in routine evaluation of children with SRNS. The most common methods used in the clinical setting are the sequencing of a panel of candidate genes using direct sequencing (Sanger sequencing) and targeted sequencing of candidates (TSC) using a next-generation sequencing platform. The latter approach is generally more practical, less laborious, and more cost-effective than direct sequencing, considering the fact that there are over 50 genes known to cause SRNS, and the number of causal mutations will likely continue to increase. The advantages of the TSC approach include (1) high yield of positive tests, especially in populations where mutation in a particular gene or set of genes is known to be common; (2) the ability to establish causality without extensive family studies; and (3) the ability to more easily manage data from this approach compared with whole exome sequencing (WES) or whole genome sequencing (WGS). The major limitation of the TSC approach is that mutations in novel genes cannot be identified, and a negative result does not necessarily rule out genetic SRNS since the individual may have a mutation in a yet-to-be-discovered novel gene.

The other approach that is less commonly used in clinical practice is WES, where enrichment strategies are used to sequence only the protein-coding regions of the gene (exome), which accounts for only 1% of the entire human genome, or WGS, where both the coding and the non-coding regions are sequenced. The advantages of WES and WGS are that they are all inclusive and mutations may be detected in both candidate and novel genes, especially with the availability of informative pedigrees. However, compared with TSC, WES and WGS are more expensive, and they are more likely to generate uninterpretable data especially when informative pedigrees are not available. In addition, this approach may identify potential pathogenic variants that are irrelevant to SRNS but have potential consequences on the health and well-being of the patients.

Indications for genetic testing

While various genetic testing modalities are now widely available, there are no guidelines for when or on whom genetic testing should be done. However, if we view genetic testing like any other diagnostic test, clinicians should consider whether the test result is apt to alter the management of the patient or better inform discussion of disease prognosis and genetic counseling [34]. If testing will provide any of this information, genetic testing is probably indicated.

Based on the variable prevalence of genetic SRNS in different populations, the approach to genetic testing will depend on where the clinician is practicing. For example, in regions of the world where inbreeding is highly prevalent or in populations where there is high prevalence of a particular founder mutation, one can make a case for routine genetic testing for all children with SRNS by sequential TSC followed by WES or WGS if no mutation is detected (Fig. 1a). On the other hand, in an outbred population where the likelihood of a positive test is low, genetic testing may be limited to children with onset of disease in infancy, family history of SRNS or CKD, and syndromic SRNS (Fig. 1b) [9, 13, 34]. A strong point in support of the latter approach is a recent finding from our group that mutation detection rate in patients with a family history of SRNS and/or CKD is about 40% compared with a 6% rate of detection in those without a family history of CKD (Varner et al., manuscript in preparation).
Fig. 1

Approach to genetic testing in SRNS. a Approach to genetic testing in population with high prevalence of SRNS such as an inbred population or populations with founder mutations. b Approach to genetic testing in an outbred population

Approaches to management of SRNS

Specific therapy

Corticosteroids

The initial treatment for all children presenting with NS generally includes daily corticosteroid therapy for 6 weeks followed by alternate-day therapy for another 6 weeks, for a total of 3 months of treatment [4]. Steroid resistance is defined as a failure to achieve remission following 6 weeks of daily therapy. It should be noted that more than 90% of children who are steroid-sensitive will achieve remission within 4 weeks of therapy initiation [60]. In contrast, adult literature seems to suggest that longer duration of therapy may be needed before classifying an adult as being steroid-resistant [61, 62, 63, 64]. The mechanisms of action of corticosteroids in NS are not fully elucidated; however, the premise for their use is based on the evidence that NS is an immunological disease and corticosteroids act by suppressing T lymphocyte-mediated responses [25]. In addition to immunomodulatory effects, there are pre-clinical data to suggest that corticosteroids may have non-immunologic effects on the F-actin cytoskeleton of the podocyte [17]. In a study to determine the effects of glucocorticoids on podocytes, Xing et al. [65] showed that dexamethasone upregulates the expression of nephrin and tubulin-α in cultured human and murine podocytes, suggesting a direct effect of glucocorticoids on the podocyte actin cytoskeleton and regulation of critical slit diaphragm proteins. More recently, Zhao et al. [18] demonstrated that α-actinin 4 (ACTN4) interacts with the glucocorticoid receptor (GR) in the nucleus of human podocytes. Glucocorticoids have also been shown to protect and enhance recovery of cultured podocytes from puromycin aminonucleoside (PAN)-induced injuries via actin filament stabilization and protection from apoptosis [66, 67]. Recently, Mallipattu et al. [68] demonstrated that in vitro treatment with dexamethasone induced a rapid increase in Krüppel-like factor 15 (KLF15) expression in human and murine podocytes. KLF15 is a kidney-enriched zinc finger transcription factor that has been shown to be required for restoring podocyte differentiation markers in cultured murine and human podocytes subjected to stress [69]. Overall, these data suggest that in addition to the effects of corticosteroids on T cell function, they may also have direct effects on the podocyte cytoskeleton and slit diaphragm, indicating that corticosteroids may be useful in the treatment of some forms of genetic NS. There are few reports in the literature describing children with monogenic NS who have achieved complete or partial remission following corticosteroid therapy (Supplementary Table 1) [70, 71, 72]. Based on published data, there is currently no justification for extended corticosteroid therapy in children with genetic SRNS.

Second-line immunomodulatory agents

In patients with SRNS, most clinicians will elect to use second-line non-glucocorticoid agents to induce complete or partial remission, as induction of even partial remission can delay disease progression. Commonly used agents include calcineurin inhibitors (CNIs), anti-proliferative agents such as mycophenolate mofetil (MMF), and biologics like anti-CD20 (rituximab). A brief description of the mechanism of action of these agents and the rationale for their use in SRNS is provided below.

Calcineurin inhibitors

The two CNIs routinely used to treat NS are cyclosporine A (CsA) and tacrolimus (also known as FK506). The immunosuppressive properties of CsA and tacrolimus result from inhibition of calcineurin, a calcium- and calmodulin-dependent phosphatase [73, 74]. Both agents inhibit calcineurin, CsA by binding to cyclophilin, and FK506 by binding to protein 12 to form the FKBP12 complex, which ultimately inhibits calcineurin [73, 74]. Inhibition of calcineurin results in suppression of the transcription of interleukin-2 and subsequent T cell activation [75, 76]. A number of randomized clinical trials have suggested improved remission rates following CNI therapy in patients with SRNS. The most comprehensive study to date is the National Institutes of Health (NIH)-sponsored multicenter randomized trial of 192 children and young adults with steroid-resistant FSGS who received either CsA or a combination of MMF and pulse dexamethasone. In this study, 65% of patients in the CsA arm achieved remission compared with 42% of those in MMF/dexamethasone arm. Though the difference in remission was not significant, this study demonstrated that both treatments are useful in the management of children with SRNS [77]. In addition to immunosuppressive effects, the anti-proteinuric effects of CNIs may also be mediated by intra-renal hemodynamic changes and also by inhibition of calcineurin-mediated degradation of synaptopodin and stabilization of the podocyte actin cytoskeleton [17]. In another study, CNIs were shown to stabilize the podocyte actin cytoskeleton by upregulation of cofilin-1 expression [78]. These studies suggest that, like glucocorticoids, the non-immunomodulatory effects of CNIs may also ameliorate the clinical manifestations of genetic SRNS that are due to structural defects of podocytes and other components of the GFB. Despite these potential effects on the GFB, a small case series from the literature seemed to suggest that the majority of children with genetic SRNS will not respond to CNI-based therapy [56, 79, 80]. In a study of 91 children with SRNS, Buscher et al. [79] reported that 55% of children with non-genetic SRNS achieved complete remission and 13% were in partial remission following treatment with CNIs compared with 0% complete remission and 29% partial remission in children with genetic SRNS who presented after the age of 3 months. A similar pattern has been reported in other studies [14, 15, 56, 70, 81, 82, 83, 84, 85, 86]. A summary of studies reporting on the use of CNIs and other therapeutic agents in children with genetic SRNS can be found in Supplementary Table 1. The major challenge in the use of CNIs and other second-line agents in the treatment of children with genetic SRNS is that there are no clinical or genetic predictors of response to therapy, nor is there a guideline on when to stop therapy in unresponsive patients.

Mycophenolate mofetil

MMF is an anti-proliferative agent that is used extensively for immunosuppression in solid organ transplantation and has also been increasingly used for treatment of SRNS [15, 87, 88]. MMF acts through its active metabolite mycophenolic acid (MPA) as a non-competitive inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), which preferentially inhibits B and T lymphocyte proliferation. Its mechanism of action in the treatment of glomerular disease is not fully understood, but it has been shown in both human and experimental studies that MMF may act by suppressing lymphocyte proliferation and antibody production. MMF also decreases interleukin-2, interleukin-4, and adhesion molecule expression in the kidney [89, 90, 91, 92]. Limited clinical data suggest that MMF may induce complete or partial remission in steroid- and CsA-resistant FSGS without causing the side effects of nephrotoxicity that are seen with CNIs [93, 94]. In the NIH trial described above, a combination of MMF and dexamethasone was found to be as effective as CsA in the treatment of SRNS [77]. To date, there are no reports in the literature on the use of MMF in children with genetic SRNS.

Rituximab

Rituximab is a genetically engineered chimeric monoclonal antibody, containing murine variable regions and a human IgG1 constant domain directed against the CD20 antigen expressed on the surface of B lymphocytes [95]. There are a few case series in the literature to show that rituximab may induce partial and complete remission in some children with SRNS [96, 97, 98, 99, 100, 101]. The mechanisms of action of rituximab in both SSNS and SRNS are unknown; however, it has been shown that rituximab directly modulates and protects podocytes from injury by preserving sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) expression, suggesting that rituximab may modulate podocyte function independent of its immunomodulatory effects [102]. There are currently no reports to show that rituximab may be useful in the treatment of genetic SRNS.

Agents targeting pathways that are dysregulated by specific mutations

One of the promises of the genomic revolution is that identification of genetic causes and genetic risk factors for SRNS will lead to a better understanding of disease pathogenesis, identification of novel diagnostic tools, and the development of targeted therapeutic agents. Despite the fact that multiple genetic causes of NS have been identified, there is a significant lag in the utilization of this information to identify targeted therapies for NS [103]. There are multiple reasons for this lag, including but not limited to a lack of high-fidelity cell lines to study podocytes in culture [103]. The mouse- and human-derived podocyte cell lines that are currently used for biochemical characterization of disease-causing mutations have provided some insight into pathways that are defective in patients with genetic NS; however, they have some major limitations because they lack essential podocyte characteristics that may be important to achieving a full understanding of the mechanisms of podocyte injury [103]. For example, these cell lines do not form slit diaphragm cross-bridges in vitro, thereby limiting our understanding of the structural and signaling alterations induced by disease-causing mutations [103]. In addition, mouse models that are often used to study these mutations in vivo do not accurately recapitulate phenotypes seen in humans [103]. Furthermore, pathway analyses are not automated, and they are often laborious and frequently require investigators with different skill sets to carry out. Despite these limitations, some of these discoveries have led to identification of targeted therapies, novel therapeutic targets, or existing agents that may be repurposed for the treatment of SRNS.

Coenzyme Q10 supplementation

Coenzyme Q (CoQ) is a small lipophilic molecule that is synthesized ubiquitously in the inner mitochondrial membrane and is involved in many essential cellular processes, especially in the mitochondria [104]. The molecule is composed of a quinone group and a polyisoprenoid tail of variable length, depending on the species [105]. In humans, CoQ with 10 isoprenoid subunits is found abundantly in the mitochondria and is named coenzyme Q10 (CoQ10) or ubiquinone [106]. Aside from being an essential component of the mitochondrial electron transport chain, CoQ10 is required for pyrimidine nucleoside biosynthesis and is one of the most potent lipophilic antioxidants [104, 107]. Biosynthesis of CoQ10 requires at least 16 different genes (PDSS1, PDSS2, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9, COQ10A, COQ10B, FDX1L, FDXR, and ALDH3A1) [108, 109, 110]. Mutations in some of these genes cause primary CoQ deficiency, a severe but treatable, mitochondrial cytopathy [111]. In contrast to most mitochondrial respiratory chain disorders, for which no effective treatment exists, children with primary CoQ10 deficiency respond to oral supplementation [112]. Mutations in COQ6 and COQ2 have been reported to cause syndromic and isolated SRNS [57, 111, 113]. Since the products of these genes have been identified as being important in the synthesis of CoQ10, there are reports on the use of CoQ10 supplementation in the treatment of children with SRNS due to mutation in these genes [114]. Montini et al. [112] described two siblings with missense mutations in COQ2, one of whom was already in ESKD at presentation and the other sibling presented with NS and was treated with oral CoQ10 supplementation. This individual achieved partial remission and has stable renal function after 5 years of follow-up [112]. Other reports have found the same pattern; however, treatment is only effective prior to the development of ESKD [57, 113, 115]. In another study, Heeringa et al. [57] reported that up to 50% of children with COQ6 mutations achieved complete or partial remission with CoQ10 supplementation with or without an angiotensin-converting enzyme inhibitor (ACEi). More recently, mutations in the aarF domain-containing kinase 4 (ADCK4) gene were reported as a cause of SRNS [116]. ADCK4 interacts with components of the CoQ10 biosynthesis pathway, and patients with ADCK4 mutations have been reported to have reduced cellular CoQ10 content [116]. In one study, a child with a homozygous frameshift mutation in ADCK4 and SRNS was successfully treated with CoQ10 supplementation [116]. These studies clearly illustrate the power of genomics in the identification of therapies based on the underlying mechanisms of disease.

Vitamin B12

Mutations in the cubilin (CUBN) gene have been reported in children with intermittent proteinuria [117]. Cubilin is a coreceptor for the intestinal vitamin B12-intrinsic factor complex, and it is also essential for tubular reabsorption of protein in the proximal tubule [118]. It is therefore conceivable that treatment with vitamin B12 may ameliorate proteinuria associated with CUBN mutation. However, there are no reports in the literature demonstrating the benefit of vitamin B12 supplementation in the treatment of proteinuria due to CUBN mutations.

Other agents

In addition to identification of specific molecules that may be replaced to reverse phenotypes induced by genetic SRNS, some SRNS-associated genetic mutations have also been shown to be viable therapeutic targets. For example, mutations in the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) can cause autosomal dominant FSGS through aberrant calcium ion conductance in podocytes [103, 119]. Therefore, modification of TRPC6 enzymatic activity may represent a novel therapeutic approach in the treatment of FSGS. Indeed, there are already published proof-of-principle data to show that pharmacological targeting of TRPC6 and other TRPCs is feasible for treating diseases that are associated with TRPC overactivity [120, 121]. More recently, in a study designed to identify pathways that are perturbed in FSGS due to mutations in the ANLN gene, we showed that dysregulation of the PI-3K/AKT/mTOR/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum (ER) stress are responsible for the aberrant podocyte phenotype seen in cell lines overexpressing mutant ANLN [122]. Furthermore, we identified existing compounds and novel compounds that may reverse the abnormal podocyte phenotype, showing that rational therapeutic targets for familial FSGS can be identified through rigorous biochemical characterization of dysregulated podocyte phenotypes [122].

Supportive therapy

There are multiple publications to show that supportive measures such as the use of angiotensin receptor blockade to reduce proteinuria, aggressive blood pressure control, and the use of lipid-lowering agents are useful in both non-genetic and genetic SRNS to slow progression of disease [123, 124].

Kidney transplantation

Monogenic SRNS portends a highly unfavorable long-term prognosis, as ~ 50% of patients will develop ESKD requiring dialysis and kidney transplantation within 10 years of diagnosis [15]. Fortunately, several studies have shown that the risk of disease recurrence post-transplantation in patients with genetic SRNS is low compared with those with non-genetic SRNS [125, 126]. Ding et al. [52] reported a recurrence rate of 0% (0/25) in genetic SRNS compared with 30% (26/86) in those with non-genetic SRNS. We reported the same pattern in a large cohort of North American children with ESKD due to FSGS who received kidney transplantation over 10 years [127]. Because the risk of post-transplant recurrence is very low in genetic SRNS, deceased donor and living-related donor (LRD) transplant can be planned with great optimism after excluding the disease-causing mutations in living donors.

Scrupulous planning, however, will be required prior to embarking on LRD kidney transplantation from family members of patients with known single gene defects, regardless of the mode of inheritance [34]. In autosomal recessive conditions for example, the effect of reducing renal mass by 50% (i.e., acquired solitary kidney) in a heterozygous carrier is unknown, and the risk of developing kidney disease in that setting as a result of modifier genes and/or environmental factors is also not clear. In autosomal dominant conditions, family members should not be considered as LRD candidate until the mutation has been ruled out in the donor because of variable penetrance associated with AD gene and the existence of asymptomatic carriers who may develop kidney disease following reduction of kidney mass by 50%, or the potential of implanting a kidney that may not function optimally in the recipient [128]. Thus, we do not support the use of LRD donation from families with known hereditary disease and unknown gene defects. If the gene defect is known, LRD kidneys should only be accepted if the mutation has been ruled out in the potential donor.

Treatment guidelines for non-genetic and genetic SRNS

Children with SRNS are often challenging to manage because many of the agents used are often not effective in majority of patients. In fact, the single most important predictor of response to most of these agents is the initial response to corticosteroid therapy. As described above, about 60% of patients with SRNS will achieve partial or complete remission following use of immunomodulatory agents other than glucocorticoids; however, there are no robust clinical or laboratory predictors of response to these agents. Despite this lack of predictors, there are guidelines for the therapy of non-genetic SRNS based on accumulated clinical experience and expert opinions; an example is the Kidney Disease Improving Global Outcomes (KDIGO) guideline (Fig. 2) [3]. The overall goal of most of these treatment approaches is to use a combination of immunomodulatory and supportive agents to achieve complete or partial remission in order to delay progression of disease and development of ESKD. Because overall experience with treatment of genetic SRNS is limited, there are no such treatment guidelines for children with genetic SRNS. As described in previous sections, most cases of genetic SRNS are due to defective proteins that are important for maintaining the functional and structural integrity of the podocyte and other components of the slit diaphragm. It is therefore logical to assume that most of the immunomodulatory agents will not be effective in the treatment of genetic SRNS; in fact, most limited small series support this approach, as over 90% of patients with genetic SRNS have been reported to be unresponsive to different immunomodulatory agents. Thus, the approach of most clinicians is to offer only supportive therapy and measures to slow progression of CKD in these children. Importantly, there are pre-clinical data and limited case series that suggest that immunomodulatory agents may be beneficial in the treatment of genetic SRNS, as discussed in the preceding paragraphs. Therefore, we approach the treatment of children with genetic SRNS in a pragmatic way by discussing the uncertainty of benefits of therapy with parents and also by having a low threshold for discontinuing these therapies to minimize side effects. Figure 3 shows the approach that we typically use in the treatment of children with genetic SRNS. There is a need for randomized trials to evaluate the usefulness of existing agents in the treatment of genetic SRNS.
Fig. 2

Approach to management of a child with non-genetic steroid-resistant nephrotic syndrome (SRNS)

Fig. 3

Suggested approach to management of a child with genetic steroid-resistant nephrotic syndrome (SRNS)

Conclusions

Over the past 20 years, advances in genomics have dramatically improved our understanding of the molecular pathogenesis of NS. Studies have revealed that genetic SRNS cases make up only a small fraction of SRNS in outbred populations and that genetic SRNS is heterogeneous. Diagnosis of genetic SRNS may allow for a more personalized approach to therapy and informed discussion of long-term prognosis and post-kidney transplantation outcome with families. There are currently no guidelines for genetic testing in SRNS; however, based on the published literature, the decision to carry out genetic testing should be based on the genetic architecture of the disease in the population where the clinician is practicing. We suggest a pragmatic approach to the therapy of genetic SRNS, as there is no evidence-based algorithm for the management of the disease. There is a need for international collaborative studies to define the genetic architecture of SRNS and approach to its therapy.

Notes

Funding

The National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants 5R01DK098135 and 5R01DK094987 to RAG, ARB, and AEW are supported by the Duke Pediatric Research Scholars (DPRS) program.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

467_2018_4093_MOESM1_ESM.docx (92 kb)
Supplementary Table 1 (DOCX 91 kb)

References

  1. 1.
    Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood. Lancet 362:629–639CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    McKinney PA, Feltbower RG, Brocklebank JT, Fitzpatrick MM (2001) Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK. Pediatr Nephrol 16:1040–1044CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cattran DC, Feehally J, Cook T, Liu ZH, Fervenza FC, Mezzano SA, Floege J, Nachman PH, Gipson DS, Praga M, Glassock RJ, Radhakrishnan J, Hodson EM, Rovin BH, Jha V, Troyanov S, Li PKT, Wetzels JFM (2012) Kidney disease: improving global outcomes (KDIGO) glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Intl Suppl 2:139–274CrossRefGoogle Scholar
  4. 4.
    Ehrich JH, Brodehl J (1993) Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J Pediatr 152:357–361CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Children ISoKDi (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564CrossRefGoogle Scholar
  6. 6.
    Smith JM, Stablein DM, Munoz R, Hebert D, McDonald RA (2007) Contributions of the transplant registry: the 2006 annual report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Pediatr Transplant 11:366–373CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hildebrandt F (2010) Genetic kidney diseases. Lancet 375:1287–1295CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wiggins RC (2007) The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 71:1205–1214CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, Group SS, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lovric S, Fang H, Vega-Warner V, Sadowski CE, Gee HY, Halbritter J, Ashraf S, Saisawat P, Soliman NA, Kari JA, Otto EA, Hildebrandt F, Nephrotic Syndrome Study Group (2014) Rapid detection of monogenic causes of childhood-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 9:1109–1116CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E, Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T, Ozkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Ozcakar ZB, Sallay P, Cakar N, Galanti M, Terzic J, Aoun B, Caldas Afonso A, Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F, PodoNet Consortium (2015) Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E, Ding WY, Nabhan MM, Kerecuk L, Hegde S, Hughes D, Marks S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M, Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB, Welsh GI, Saleem MA (2017) Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 91:937–947CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sampson MG, Gillies CE, Robertson CC, Crawford B, Vega-Warner V, Otto EA, Kretzler M, Kang HM (2016) Using population genetics to interrogate the monogenic nephrotic syndrome diagnosis in a case cohort. J Am Soc Nephrol 27:1970–1983CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Buscher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, Kemper MJ, Tonshoff B, Hoyer PF, Konrad M, Weber S, German Pediatric Nephrology Association (GPN) (2016) Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 11:245–253CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Trautmann A, Schnaidt S, Lipska-Zietkiewicz BS, Bodria M, Ozaltin F, Emma F, Anarat A, Melk A, Azocar M, Oh J, Saeed B, Gheisari A, Caliskan S, Gellermann J, Higuita LMS, Jankauskiene A, Drozdz D, Mir S, Balat A, Szczepanska M, Paripovic D, Zurowska A, Bogdanovic R, Yilmaz A, Ranchin B, Baskin E, Erdogan O, Remuzzi G, Firszt-Adamczyk A, Kuzma-Mroczkowska E, Litwin M, Murer L, Tkaczyk M, Jardim H, Wasilewska A, Printza N, Fidan K, Simkova E, Borzecka H, Staude H, Hees K, Schaefer F, PodoNet Consortium (2017) Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol 28:3055–3065CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ding WY, Saleem MA (2012) Current concepts of the podocyte in nephrotic syndrome. Kidney Res Clin Pract 31:87–93CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhao X, Khurana S, Charkraborty S, Tian Y, Sedor JR, Bruggman LA, Kao HY (2017) Alpha actinin 4 (ACTN4) regulates glucocorticoid receptor-mediated transactivation and transrepression in podocytes. J Biol Chem 292:1637–1647CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I, Burchette J, Wu G, Homstad A, Sparks MA, Gomez J, Jiang R, Alonso A, Lavin P, Conlon P, Korstanje R, Stander MC, Shamsan G, Barua M, Spurney R, Singhal PC, Kopp JB, Haller H, Howell D, Pollak MR, Shaw AS, Schiffer M, Winn MP (2014) Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. J Am Soc Nephrol 25:1991–2002CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    D’Agati VD, Fogo AB, Bruijn JA, Jennette JC (2004) Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 43:368–382CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    D’Agati VD, Kaskel FJ, Falk RJ (2011) Focal segmental glomerulosclerosis. N Engl J Med 365:2398–2411CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Fogo AB (2015) Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol 11:76–87CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Buscher AK, Weber S (2012) Educational paper: the podocytopathies. Eur J Pediatr 171:1151–1160CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354:1387–1401CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Karp AM, Gbadegesin RA (2017) Genetics of childhood steroid-sensitive nephrotic syndrome. Pediatr Nephrol 32:1481–1488CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–560CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Coward RJ, Foster RR, Patton D, Ni L, Lennon R, Bates DO, Harper SJ, Mathieson PW, Saleem MA (2005) Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, podocin, and CD2 associated protein in cultured human podocytes. J Am Soc Nephrol 16:629–637CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zimmerman SW (1984) Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol 22:32–38PubMedPubMedCentralGoogle Scholar
  29. 29.
    Davin JC (2016) The glomerular permeability factors in idiopathic nephrotic syndrome. Pediatr Nephrol 31:207–215CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Weisinger JR, Kempson RL, Eldridge FL, Swenson RS (1974) The nephrotic syndrome: a complication of massive obesity. Ann Intern Med 81:440–447CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD (2001) Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 59:1498–1509CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bhathena DB, Julian BA, McMorrow RG, Baehler RW (1985) Focal sclerosis of hypertrophied glomeruli in solitary functioning kidneys of humans. Am J Kidney Dis 5:226–232CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schreuder MF, Langemeijer ME, Bokenkamp A, Delemarre-Van de Waal HA, Van Wijk JA (2008) Hypertension and microalbuminuria in children with congenital solitary kidneys. J Paediatr Child Health 44:363–368CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gbadegesin RA, Winn MP, Smoyer WE (2013) Genetic testing in nephrotic syndrome—challenges and opportunities. Nat Rev Nephrol 9:179–184CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bierzynska A, Soderquest K, Koziell A (2014) Genes and podocytes—new insights into mechanisms of podocytopathy. Front Endocrinol (Lausanne) 5:226Google Scholar
  36. 36.
    Ebarasi L, Ashraf S, Bierzynska A, Gee HY, McCarthy HJ, Lovric S, Sadowski CE, Pabst W, Vega-Warner V, Fang H, Koziell A, Simpson MA, Dursun I, Serdaroglu E, Levy S, Saleem MA, Hildebrandt F, Majumdar A (2015) Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet 96:153–161CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K, Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI, Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y, Nakashima M, Saitsu H, Ohashi K, Imamoto N, Ryo A, Ogata K, Iijima K, Matsumoto N (2015) Biallelic mutations in nuclear pore complex subunit NUP107 cause early-childhood-onset steroid-resistant nephrotic syndrome. Am J Hum Genet 97:555–566CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst WL, Gee HY, Ashraf S, Lawson JA, Shril S, Airik M, Tan W, Schapiro D, Rao J, Choi WI, Hermle T, Kemper MJ, Pohl M, Ozaltin F, Konrad M, Bogdanovic R, Buscher R, Helmchen U, Serdaroglu E, Lifton RP, Antonin W, Hildebrandt F (2016) Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nat Genet 48:457–465CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gee HY, Zhang F, Ashraf S, Kohl S, Sadowski CE, Vega-Warner V, Zhou W, Lovric S, Fang H, Nettleton M, Zhu JY, Hoefele J, Weber LT, Podracka L, Boor A, Fehrenbach H, Innis JW, Washburn J, Levy S, Lifton RP, Otto EA, Han Z, Hildebrandt F (2015) KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. J Clin Invest 125:2375–2384CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJ, Christian M, Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA, RADAR the UK SRNS Study Group (2013) Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 8:637–648CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S, Lovric S, Ashraf S, Rao J, Hermle T, Jobst-Schwan T, Widmeier E, Majmundar AJ, Schneider R, Gee HY, Schmidt JM, Vivante A, van der Ven AT, Ityel H, Chen J, Sadowski CE, Kohl S, Pabst WL, Nakayama M, Somers MJG, Rodig NM, Daouk G, Baum M, Stein DR, Ferguson MA, Traum AZ, Soliman NA, Kari JA, El Desoky S, Fathy H, Zenker M, Bakkaloglu SA, Muller D, Noyan A, Ozaltin F, Cadnapaphornchai MA, Hashmi S, Hopcian J, Kopp JB, Benador N, Bockenhauer D, Bogdanovic R, Stajic N, Chernin G, Ettenger R, Fehrenbach H, Kemper M, Munarriz RL, Podracka L, Buscher R, Serdaroglu E, Tasic V, Mane S, Lifton RP, Braun DA, Hildebrandt F (2018) Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 13:53–62CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gbadegesin RA, Lavin PJ, Hall G, Bartkowiak B, Homstad A, Jiang R, Wu G, Byrd A, Lynn K, Wolfish N, Ottati C, Stevens P, Howell D, Conlon P, Winn MP (2012) Inverted formin 2 mutations with variable expression in patients with sporadic and hereditary focal and segmental glomerulosclerosis. Kidney Int 81:94–99CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Brown EJ, Schlondorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, Higgs HN, Henderson JM, Pollak MR (2010) Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 42:72–76CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Barua M, Brown EJ, Charoonratana VT, Genovese G, Sun H, Pollak MR (2013) Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int 83:316–322CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Boyer O, Benoit G, Gribouval O, Nevo F, Tete MJ, Dantal J, Gilbert-Dussardier B, Touchard G, Karras A, Presne C, Grunfeld JP, Legendre C, Joly D, Rieu P, Mohsin N, Hannedouche T, Moal V, Gubler MC, Broutin I, Mollet G, Antignac C (2011) Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol 22:239–245CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso AS, Jiang R, Lindsey TB, Wu G, Sparks MA, Smith SR, Webb NJ, Kalra PA, Adeyemo AA, Shaw AS, Conlon PJ, Jennette JC, Howell DN, Winn MP, Gbadegesin RA (2014) Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int 86:1253–1259CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lipska BS, Iatropoulos P, Maranta R, Caridi G, Ozaltin F, Anarat A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B, Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, Davitaia T, Wasilewska A, Drozdz D, Szczepanska M, Jankauskiene A, Higuita LM, Ardissino G, Ozkaya O, Kuzma-Mroczkowska E, Soylemezoglu O, Ranchin B, Medynska A, Tkaczyk M, Peco-Antic A, Akil I, Jarmolinski T, Firszt-Adamczyk A, Dusek J, Simonetti GD, Gok F, Gheissari A, Emma F, Krmar RT, Fischbach M, Printza N, Simkova E, Mele C, Ghiggeri GM, Schaefer F, PodoNet Consortium (2013) Genetic screening in adolescents with steroid-resistant nephrotic syndrome. Kidney Int 84:206–213CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F, Arbeitsgemeinschaft fur Paediatrische Nephrologie Study Group (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:e907–e919CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hinkes B, Vlangos C, Heeringa S, Mucha B, Gbadegesin R, Liu J, Hasselbacher K, Ozaltin F, Hildebrandt F, APN Study Group (2008) Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:365–371CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, Loirat C, Ozaltin F, Hashmi S, Ulmer F, Cleper R, Ettenger R, Antignac C, Wiggins RC, Zenker M, Hildebrandt F (2008) Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291–1297CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Niaudet P (2004) Podocin and nephrotic syndrome: implications for the clinician. J Am Soc Nephrol 15:832–834CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C, Antignac C, Boyer O, Saleem MA (2014) Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 25:1342–1348CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Freedman BI, Kopp JB, Langefeld CD, Genovese G, Friedman DJ, Nelson GW, Winkler CA, Bowden DW, Pollak MR (2010) The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. J Am Soc Nephrol 21:1422–1426CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M, Maeda S, Nakamura Y, Noiri E (2011) Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43:459–463CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F, Arbeitsgemeinschaft Fur Padiatrische Nephrologie Study Group (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rotig A, Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Muller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocana C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nurnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C (2004) NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66:571–579CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Gigante M, Greco P, Defazio V, Lucci M, Margaglione M, Gesualdo L, Iolascon A (2005) Congenital nephrotic syndrome of Finnish type: detection of new nephrin mutations and prenatal diagnosis in an Italian family. Prenat Diagn 25:407–410CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    (1981) Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A report of the International Study of Kidney Disease in Children. Kidney Int 20:765–771Google Scholar
  61. 61.
    Black DA, Rose G, Brewer DB (1970) Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J 3:421–426CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Rydel JJ, Korbet SM, Borok RZ, Schwartz MM (1995) Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am J Kidney Dis 25:534–542CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Banfi G, Moriggi M, Sabadini E, Fellin G, D’Amico G, Ponticelli C (1991) The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study. Clin Nephrol 36:53–59PubMedPubMedCentralGoogle Scholar
  64. 64.
    Korbet SM, Schwartz MM, Lewis EJ (1994) Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis 23:773–783CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Xing CY, Saleem MA, Coward RJ, Ni L, Witherden IR, Mathieson PW (2006) Direct effects of dexamethasone on human podocytes. Kidney Int 70:1038–1045CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE (2005) Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int 68:2473–2483CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Wada T, Pippin JW, Marshall CB, Griffin SV, Shankland SJ (2005) Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins. J Am Soc Nephrol 16:2615–2625CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Mallipattu SK, Guo Y, Revelo MP, Roa-Pena L, Miller T, Ling J, Shankland SJ, Bialkowska AB, Ly V, Estrada C, Jain MK, Lu Y, Ma’ayan A, Mehrotra A, Yacoub R, Nord EP, Woroniecki RP, Yang VW, He JC (2017) Kruppel-like factor 15 mediates glucocorticoid-induced restoration of podocyte differentiation markers. J Am Soc Nephrol 28:166–184CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Mallipattu SK, Liu R, Zheng F, Narla G, Ma’ayan A, Dikman S, Jain MK, Saleem M, D’Agati V, Klotman P, Chuang PY, He JC (2012) Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation. J Biol Chem 287:19122–19135CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O’Toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Gee HY, Ashraf S, Wan X, Vega-Warner V, Esteve-Rudd J, Lovric S, Fang H, Hurd TW, Sadowski CE, Allen SJ, Otto EA, Korkmaz E, Washburn J, Levy S, Williams DS, Bakkaloglu SA, Zolotnitskaya A, Ozaltin F, Zhou W, Hildebrandt F (2014) Mutations in EMP2 cause childhood-onset nephrotic syndrome. Am J Hum Genet 94:884–890CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA, Tan W, Hermle T, Warejko JK, Shril S, Airik M, Jobst-Schwan T, Lovric S, Braun DA, Gee HY, Schapiro D, Majmundar AJ, Sadowski CE, Pabst WL, Daga A, van der Ven AT, Schmidt JM, Low BC, Gupta AB, Tripathi BK, Wong J, Campbell K, Metcalfe K, Schanze D, Niihori T, Kaito H, Nozu K, Tsukaguchi H, Tanaka R, Hamahira K, Kobayashi Y, Takizawa T, Funayama R, Nakayama K, Aoki Y, Kumagai N, Iijima K, Fehrenbach H, Kari JA, El Desoky S, Jalalah S, Bogdanovic R, Stajic N, Zappel H, Rakhmetova A, Wassmer SR, Jungraithmayr T, Strehlau J, Kumar AS, Bagga A, Soliman NA, Mane SM, Kaufman L, Lowy DR, Jairajpuri MA, Lifton RP, Pei Y, Zenker M, Kure S, Hildebrandt F (2018) Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun 9:1960CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Flanagan WM, Corthesy B, Bram RJ, Crabtree GR (1991) Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352:803–807CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR (1993) Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol 13:4760–4769CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    O’Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O’Neill EA (1992) FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357:692–694CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Clipstone NA, Crabtree GR (1992) Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357:695–697CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, Moxey-Mims MM, Hogg RJ, Watkins SL, Fine RN, Hogan SL, Middleton JP, Vehaskari VM, Flynn PA, Powell LM, Vento SM, McMahan JL, Siegel N, D’Agati VD, Friedman AL (2011) Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int 80:868–878CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Li X, Zhang X, Li X, Wang X, Wang S, Ding J (2014) Cyclosporine A protects podocytes via stabilization of cofilin-1 expression in the unphosphorylated state. Exp Biol Med (Maywood) 239:922–936CrossRefGoogle Scholar
  79. 79.
    Buscher AK, Kranz B, Buscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Broking E, Wingen AM, John U, Kemper M, Monnens L, Hoyer PF, Weber S, Konrad M (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:2075–2084CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L, Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E, Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M, Romagnani P (2015) Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol 26:230–236CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Klaassen I, Ozgoren B, Sadowski CE, Moller K, van Husen M, Lehnhardt A, Timmermann K, Freudenberg F, Helmchen U, Oh J, Kemper MJ (2015) Response to cyclosporine in steroid-resistant nephrotic syndrome: discontinuation is possible. Pediatr Nephrol 30:1477–1483CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Stefanidis CJ, Querfeld U (2011) The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations. Eur J Pediatr 170:1377–1383CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Gellermann J, Stefanidis CJ, Mitsioni A, Querfeld U (2010) Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. Pediatr Nephrol 25:1285–1289CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Wasilewska AM, Kuroczycka-Saniutycz E, Zoch-Zwierz W (2011) Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations. Eur J Pediatr 170:389–391CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Megremis S, Mitsioni A, Mitsioni AG, Fylaktou I, Kitsiou-Tzelli S, Stefanidis CJ, Kanavakis E, Traeger-Synodinos J (2009) Nucleotide variations in the NPHS2 gene in Greek children with steroid-resistant nephrotic syndrome. Genet Test Mol Biomarkers 13:249–256CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Malina M, Cinek O, Janda J, Seeman T (2009) Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation. Pediatr Nephrol 24:2051–2053CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Gargah TT, Lakhoua MR (2011) Mycophenolate mofetil in treatment of childhood steroid-resistant nephrotic syndrome. J Nephrol 24:203–207CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    de Mello VR, Rodrigues MT, Mastrocinque TH, Martins SP, de Andrade OV, Guidoni EB, Scheffer DK, Martini Filho D, Toporovski J, Benini V (2010) Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome. Pediatr Nephrol 25:453–460CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Ziswiler R, Steinmann-Niggli K, Kappeler A, Daniel C, Marti HP (1998) Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis. J Am Soc Nephrol 9:2055–2066PubMedPubMedCentralGoogle Scholar
  90. 90.
    Hauser IA, Renders L, Radeke HH, Sterzel RB, Goppelt-Struebe M (1999) Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion. Nephrol Dial Transplant 14:58–63CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Penny MJ, Boyd RA, Hall BM (1998) Mycophenolate mofetil prevents the induction of active Heymann nephritis: association with Th2 cytokine inhibition. J Am Soc Nephrol 9:2272–2282PubMedPubMedCentralGoogle Scholar
  92. 92.
    Allison AC, Kowalski WJ, Muller CJ, Waters RV, Eugui EM (1993) Mycophenolic acid and brequinar, inhibitors of purine and pyrimidine synthesis, block the glycosylation of adhesion molecules. Transplant Proc 25:67–70PubMedPubMedCentralGoogle Scholar
  93. 93.
    Cattran DC, Wang MM, Appel G, Matalon A, Briggs W (2004) Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis. Clin Nephrol 62:405–411CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Montane B, Abitbol C, Chandar J, Strauss J, Zilleruelo G (2003) Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol 18:772–777CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Salama AD, Pusey CD (2006) Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol 2:221–230CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Gulati A, Sinha A, Jordan SC, Hari P, Dinda AK, Sharma S, Srivastava RN, Moudgil A, Bagga A (2010) Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol 5:2207–2212CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Prytula A, Iijima K, Kamei K, Geary D, Gottlich E, Majeed A, Taylor M, Marks SD, Tuchman S, Camilla R, Ognjanovic M, Filler G, Smith G, Tullus K (2010) Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25:461–468CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Ito S, Kamei K, Ogura M, Udagawa T, Fujinaga S, Saito M, Sako M, Iijima K (2013) Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome. Pediatr Nephrol 28:257–264CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Bagga A, Sinha A, Moudgil A (2007) Rituximab in patients with the steroid-resistant nephrotic syndrome. N Engl J Med 356:2751–2752CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23:1117–1124CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K, Ito S (2014) Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol 29:1181–1187CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L, Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C, Ikehata M, Rastaldi MP, Reiser J, Burke GW 3rd (2011) Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 3:85ra46CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Hall G, Gbadegesin RA (2015) Translating genetic findings in hereditary nephrotic syndrome: the missing loops. Am J Physiol Renal Physiol 309:F24–F28CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Turunen M, Olsson J, Dallner G (2004) Metabolism and function of coenzyme Q. Biochim Biophys Acta 1660:171–199CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Tran UC, Clarke CF (2007) Endogenous synthesis of coenzyme Q in eukaryotes. Mitochondrion (7 Suppl):S62–S71Google Scholar
  106. 106.
    Crane FL (2007) Discovery of ubiquinone (coenzyme Q) and an overview of function. Mitochondrion (7 Suppl):S2–S7Google Scholar
  107. 107.
    Bentinger M, Brismar K, Dallner G (2007) The antioxidant role of coenzyme Q. Mitochondrion (7 Suppl):S41–S50Google Scholar
  108. 108.
    Doimo M, Desbats MA, Cerqua C, Cassina M, Trevisson E, Salviati L (2014) Genetics of coenzyme q10 deficiency. Mol Syndromol 5:156–162CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Desbats MA, Vetro A, Limongelli I, Lunardi G, Casarin A, Doimo M, Spinazzi M, Angelini C, Cenacchi G, Burlina A, Rodriguez Hernandez MA, Chiandetti L, Clementi M, Trevisson E, Navas P, Zuffardi O, Salviati L (2015) Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure. Eur J Hum Genet 23:1254–1258CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Payet LA, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F (2016) Mechanistic details of early steps in coenzyme Q biosynthesis pathway in yeast. Cell Chem Biol 23:1241–1250CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Acosta MJ, Vazquez Fonseca L, Desbats MA, Cerqua C, Zordan R, Trevisson E, Salviati L (2016) Coenzyme Q biosynthesis in health and disease. Biochim Biophys Acta 1857:1079–1085CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 358:2849–2850CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, Ghiggeri GM, Murer L, Barisoni L, Pastore A, Muda AO, Valente ML, Bertini E, Emma F (2007) COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol 18:2773–2780CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Ozaltin F (2014) Primary coenzyme Q10 (CoQ 10) deficiencies and related nephropathies. Pediatr Nephrol 29:961–969CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Starr MC, Chang IJ, Finn LS, Sun A, Larson AA, Goebel J, Hanevold C, Thies J, Van Hove JLK, Hingorani SR, Lam C (2018) COQ2 nephropathy: a treatable cause of nephrotic syndrome in children. Pediatr Nephrol.  https://doi.org/10.1007/s00467-018-3937-z
  116. 116.
    Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschke P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Bockenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179–5189CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Ovunc B, Otto EA, Vega-Warner V, Saisawat P, Ashraf S, Ramaswami G, Fathy HM, Schoeb D, Chernin G, Lyons RH, Yilmaz E, Hildebrandt F (2011) Exome sequencing reveals cubilin mutation as a single-gene cause of proteinuria. J Am Soc Nephrol 22:1815–1820CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Amsellem S, Gburek J, Hamard G, Nielsen R, Willnow TE, Devuyst O, Nexo E, Verroust PJ, Christensen EI, Kozyraki R (2010) Cubilin is essential for albumin reabsorption in the renal proximal tubule. J Am Soc Nephrol 21:1859–1867CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308:1801–1804CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Urban N, Hill K, Wang L, Kuebler WM, Schaefer M (2012) Novel pharmacological TRPC inhibitors block hypoxia-induced vasoconstriction. Cell Calcium 51:194–206CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Zhou Y, Castonguay P, Sidhom EH, Clark AR, Dvela-Levitt M, Kim S, Sieber J, Wieder N, Jung JY, Andreeva S, Reichardt J, Dubois F, Hoffmann SC, Basgen JM, Montesinos MS, Weins A, Johnson AC, Lander ES, Garrett MR, Hopkins CR, Greka A (2017) A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358:1332–1336CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Hall GLB, Khan K, Pediaditakis I, Xiao J, Wu G, Wang L, Kovalik ME, Chryst-Stangl M, Davis EE, Spurney RF, Gbadegesin RA (2018) The human FSGS-causing ANLN R431C mutation induces dysregulated PI3K/AKT/mTOR/Rac1 signaling in podocytes. J Am Soc Nephrol 29:2011–2122Google Scholar
  123. 123.
    Bagga A, Mudigoudar BD, Hari P, Vasudev V (2004) Enalapril dosage in steroid-resistant nephrotic syndrome. Pediatr Nephrol 19:45–50CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Li Z, Duan C, He J, Wu T, Xun M, Zhang Y, Yin Y (2010) Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 25:883–888CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Wada T, Nangaku M (2015) A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. Clin Kidney J 8:708–715CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Konigshausen E, Sellin L (2016) Circulating permeability factors in primary focal segmental glomerulosclerosis: a review of proposed candidates. Biomed Res Int 2016:3765608CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Pelletier JHKK, Engen R, Bensimhon A, Varner J, Rheault M, Srivastava T, Straatmann C, Silva C, Davis TK, Wenderfer S, Gibson K, Selewski D, Barcia J, Weng P, Licht C, Jawa N, Kallash M, Foreman JW, Wigfall DR, Chua AN, Chambers E, Hornik CP, Brewer ED, Nagaraj SK, Greenbaum LA, Gbadegesin RA (2018) Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings. Pediatr Nephrol 33:1773–1780CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Winn MP, Alkhunaizi AM, Bennett WM, Garber RL, Howell DN, Butterly DW, Conlon PJ (1999) Focal segmental glomerulosclerosis: a need for caution in live-related renal transplantation. Am J Kidney Dis 33:970–974CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of NephrologyDuke University Medical CenterDurhamUSA
  2. 2.Department of Medicine, Division of NephrologyDuke University Medical CenterDurhamUSA
  3. 3.Duke Molecular Physiology InstituteDurhamUSA

Personalised recommendations