Cause Of Focal Segmental Glomerulosclerosis Research Articles

Kidney Biopsy in Autosomal Dominant Polycystic Kidney Disease

Proteinuria is an easily quantified biomarker of kidney disease and often a sign of glomerular pathology. Significant proteinuria is uncommon in cystic kidney diseases and should be further evaluated to exclude the presence of another simultaneous kidney disease. While renal biopsy is a valuable part of the diagnostic evaluation of proteinuria, careful consideration of risks and benefits is necessary before proceeding in a patient with bilateral renal cysts. We report the case of a man with Polycystic Kidney Disease (PKD) who was found to have nephrotic-range proteinuria. An ultrasound-guided kidney biopsy revealed evidence of Focal Segmental Glomerulosclerosis (FSGS), which was attributed to hyperfiltration-related injury in the context of extensive kidney cysts. Genetic testing did not reveal a cause of FSGS and showed a variant of uncertain significance in PKD1. We use this case to highlight three important issues that are applicable to patients with PKD: the role of diagnostic evaluation for proteinuria in cystic kidney disease, the feasibility of kidney biopsy despite the presence of bilateral renal cysts, and the roles and limitations of genetic testing in cystic kidney disease and FSGS.

Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, andin which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease.

Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

Clinical, pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study.

Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However, characteristics of those cases had not been intensively studied so far. We retrospectively reviewed clinical, pathological, and genetic characteristics of 37 children (median age, 9.3years) who underwent renal biopsy for persistent isolated proteinuria (urine protein-to-creatinine ratio: UP/C, > 0.2g/g) between 2003 and 2019. Targeted next-generation sequencing (NGS) was utilized for all patients with FSGS, excluding those with secondary FSGS. At biopsy, all patients with FSGS (N = 14) had UP/C ≥ 0.5g/g and the median UP/C was significantly higher in those with FSGS than those with minor glomerular abnormalities (MGA) (N = 23) (1.49 vs. 0.53g/g, P < 0.001). Causative variants were found in seven patients with FSGS (TRPC6, WT1, ACTN4, and INF2 in 3, 2, 1, and 1 patient, respectively): all gene variants were in genes manifesting autosomal dominant inheritance mode. The proportion of the perihilar variant was significantly higher in the genetic FSGS patients than in the non-genetic FSGS patients (4/7 vs. 0/7, P < 0.05). Kaplan-Meier analysis showed that the renal survival rate after ASP diagnosis was significantly lower in the genetic FSGS patients than in the non-genetic FSGS and the MGA patients (P < 0.001). UP/C was a simple and useful predictive parameter for the diagnosis of FSGS. APS without nephrotic syndrome at onset may be associated with autosomal dominant causes of FSGS, especially in those with the perihilar variant.

The role of cationic channels of the potential TRPC receptor in the pathogenesis of idiopathic nephrotic syndrome in children

Idiopathic nephrotic syndrome is the most common glomerulopathy in children, with a prevalence of approximately 16 per 100,000 of child population worldwide. Any chronic glomerular disease has the same type of development mechanism. Regardless of the damaging factor, after the death of a significant part of the nephrons, there occurs a steady decrease in the glomerular filtration rate, while morphologically we most often determine focal segmental glomerulosclerosis. Studying the causes of focal segmental glomerulosclerosis is an urgent problem in pediatric nephrology. Recently, there has been discussed the role of the cation channels of the potential receptor TRPC of podocytes in the development of proteinuria and focal segmental glomerulosclerosis. The article provides data on the role of TRPC receptors in the pathogenesis of focal segmental glomerulosclerosis. The authors present their our own data demonstrating gene expression of the cationic channels family of the potential receptor TRPC1, TRPC3, TRPC4, TRPC5 and TRPC6 in children with idiopathic nephrotic syndrome, depending on the morphological picture of the disease and sensitivity to steroid therapy.

Degree of foot process effacement in patients with genetic focal segmental glomerulosclerosis: a single-center analysis and review of the literature

Determining the cause of focal segmental glomerulosclerosis (FSGS) has crucial implications for evaluating the risk of posttransplant recurrence. The degree of foot process effacement (FPE) on electron micrographs (EM) of native kidney biopsies can reportedly differentiate primary FSGS from secondary FSGS. However, no systematic evaluation of FPE in genetic FSGS has been performed. In this study, percentage of FPE and foot process width (FPW) in native kidney biopsies were analyzed in eight genetic FSGS patients and nine primary FSGS patients. All genetic FSGS patients showed segmental FPE up to 38% and FPW below 2000 nm, while all primary FSGS patients showed diffuse FPE above 88% and FPW above 3000 nm. We reviewed the literature which described the degree of FPE in genetic FSGS patients and identified 38 patients with a description of the degree of FPE. The degree of FPE in patients with mutations in the genes encoding proteins associated with slit diaphragm and cytoskeletal proteins was varied, while almost all patients with mutations in other FSGS genes showed segmental FPE. In conclusion, the present study suggests that the degree of FPE in native kidney biopsies may be useful for differentiating some genetic FSGS patients from primary FSGS patients.

MO294COMPARISON OF TIP AND CELLULAR VARIANT OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims After membranous nephropathy, focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in European population. According to Columbia classification, there are five histological variants of FSGS defined on light microscopy (tip, cellular, perihilar, collapsing and not otherwise specified - NOS) and this classification has a prognostic significance. The aim is to compare features and outcomes of tip and cellular variant of primary FSGS. Method All patients with FSGS were identified by a retrospective review of the Registry of kidney biopsies at the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb, from 2003 until 2020. Each kidney specimen was analyzed by light, immunofluorescent and electron microscopy and Columbia classification was applied by experienced nephropathologist. Patients with primary FSGS met following criteria: full nephrotic syndrome and diffuse podocyte foot process effacement in absence of secondary causes of FSGS. Laboratory findings were obtained for every patient at the time of biopsy and following outpatient visits. Complete remission was defined as proteinuria &amp;lt; 0.3 g/day with normal kidney function and partial remission as proteinuria 0.3 - 3.5 g/day. Variables are expressed as median ± IQR (interquartile range) and frequencies. Statistical comparison between groups of patients with tip and cellular variant of primary FSGS and disease outcome analysis were done. Results Out of 200 patients with FSGS, 59 (29.5 %) had primary form of disease. Tip variant was the most common form of primary FSGS (22 patients, 37 %) followed by NOS (20, 34 %), cellular (13, 22 %), perihilar (2, 3.5 %) and collapsing (2, 3.5 %) variant. Demographic and clinical features with initial laboratory findings are shown in Table 1. There were no significant differences between two groups in all analyzed variables in Figure 1. All patients were treated by anti-RAAS agents and steroids. Median follow-up was 55 months (range 1 – 196 months), and followup data were unavailable for three patients. Figure 2 shows treatment regimens in both patient grouos with treatment outcomes. Remission rate was significantly higher in tip variant (90 % vs. 41 %, p = 0.002). There was no difference in relapse rate between the two groups (p = 0.717). Conclusion There were no significant differences in clinical features and laboratory findings at the time of clinical presentation between tip and cellular variant of primary FSGS. Patients with tip variant had significantly higher remission rate than patients with cellular variant.

Next-generation sequencing in patients with familial FSGS: first report of collagen gene mutations in Tunisian patients.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at presentation. FSGS is considered as a podocyte disease due to the fact that in the majority of patients with FSGS, the lesion results from defects in the podocyte structure. However, FSGS does not result exclusively from podocyte-associated genes. In this study, we used a genetic approach based on targeted next-generation sequencing (NGS) of 242 genes to identify the genetic cause of FSGS in seven Tunisian families. The sequencing results revealed the presence of eight distinct mutations including seven newly discovered ones: the c.538G>A (p.V180M) in NPHS2, c.5186G>A (p.R1729Q) in PLCE1 and c.232A>C (p.I78L) in PAX2 and five novel mutations in COL4A3 and COL4A4 genes. Four mutations (c.209G>A (p.G70D), c.725G>A (p.G242E), c.2225G>A (p.G742E), and c. 1681_1698del) were detected in COL4A3 gene and one mutation (c.1424G>A (p.G475D)) was found in COL4A4. In summary, NGS of a targeted gene panel is an ideal approach for the genetic testing of FSGS with multiple possible underlying etiologies. We have demonstrated that not only podocyte genes but also COL4A3/4 mutations should be considered in patients with FSGS.

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28× 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p=2.21× 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association.

Focal segmental glomerulosclerosis (FSGS) is a histological term that describes a pathologic renal entity affecting both adults and children, with a wide array of possible underlying etiologies. Podocyte damage with scarring, the hallmark of this condition, leads to altered permeability of the glomerular barrier, which may result in massive proteinuria and relentless renal function deterioration. A definite cause of focal segmental glomerulosclerosis can be confirmed in a minority of cases, while most forms have been traditionally labeled as primary or idiopathic. Despite this definition, increasing evidence indicates that primary forms are a heterogenous group rather than a single disease entity: several circulating factors that may affect glomerular permeability have been proposed as potential culprits, and both humoral and cellular immunity have been implicated in the pathogenesis of the disease. Consistently, immunosuppressive drugs are considered as the cornerstone of treatment for primary focal segmental glomerulosclerosis, but response to these agents and long-term outcomes are highly variable. In this review we provide a summary of historical and recent advances on the pathogenesis of primary focal segmental glomerulosclerosis, focusing on implications for its differential diagnosis and treatment.

Phenotypic analysis of mice carrying human-type MAFB p.Leu239Pro mutation

The transcription factor, MafB, plays important role in the differentiation and functional maintenance of various cells and tissues, such as the inner ear, kidney podocyte, parathyroid gland, pancreatic islet, and macrophages. The rare heterozygous substitution (p.Leu239Pro) of the DNA binding domain in MAFB is the cause of Focal Segmental Glomerulosclerosis associated with Duane Retraction Syndrome, which is characterized by impaired horizontal eye movement due to cranial nerve maldevelopment in humans. In this research, we generated mice carrying MafB p.Leu239Pro (Mafbmt/mt) and retrieved their tissues for analysis. As a result, we found that the phenotype of Mafbmt/mt mouse was similar to that of the conventional Mafb deficient mouse. This finding suggests that the Leucine residue at 239 in the DNA binding domain plays a key role in MafB function and could contribute to the diagnosis or development of treatment for patients carrying the MafB p.Leu239Pro missense variant.

Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1 Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child

IntroductionMonogenetic renal diseases, including recessively inherited nephrotic syndromes, represent a significant health burden despite being rare conditions. Precise diagnosis, including identification of the underlying molecular cause, is especially difficult in low-income countries and/or if affected individuals are unavailable for biochemical testing. Whole-exome sequencing (WES) has opened up novel diagnostic perspectives for these settings. However, sometimes the DNA of affected individuals is not suitable for WES due to low amounts or degradation.MethodsWe report on the use of parental WES with implementation of specific stepwise variant filtering to identify the underlying molecular cause of the childhood-onset nephrotic syndrome as nephrosialidosis resulting from a mutation in NEU1.ResultsSequencing both parents enabled a nephrosialidosis diagnosis in the deceased child. To date, only 16 other cases of nephrosialidosis have been reported in the literature, with only 1 genetically confirmed case. After we reviewed the clinical information of all reported cases, we found that most patients presented with proteinuria, which started at between 2 and 3 years of age. Renal pathology showed mainly focal segmental glomerulosclerosis (FSGS)with vacuolated cells, and steroid treatment was always unsuccessful. Hepatomegaly was present in nearly all cases, whereas corneal clouding and a cherry red spot on the macula was observed in only approximately 50% of cases. Fourteen of 16 previously reported cases were no longer alive at the time of reporting.ConclusionsOur findings demonstrate the power of parental WES to diagnose rare genetic diseases, such as childhood-onset nephrotic syndrome. We further provide a comprehensive overview of the clinical course of nephrosialidosis and raise awareness of this ultra-rare condition as an underlying cause of FSGS.

Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a histologically defined form of kidney injury typically mediated by podocyte dysfunction. Podocytes rely on their intricate actin-based cytoskeleton to maintain the glomerular filtration barrier in the face of mechanical challenges resulting from pulsatile blood flow and filtration of this blood flow. This review summarizes the mechanical challenges faced by podocytes in the form of stretch and shear stress, both of which may play a role in the progression of podocyte dysfunction and detachment. It also reviews how podocytes respond to these mechanical challenges in dynamic fashion through rearranging their cytoskeleton, triggering various biochemical pathways, and, in some disease states, altering their morphology in the form of foot process effacement. Furthermore, this review highlights the growing body of evidence identifying several mutations of important cytoskeleton proteins as causes of FSGS. Lastly, it synthesizes the above evidence to show that a better understanding of how these mutations leave podocytes vulnerable to the mechanical challenges they face is essential to better understanding the mechanisms by which they lead to disease. The review concludes with future research directions to fill this gap and some novel techniques with which to pursue these directions.

Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) is a histologic lesion resulting from a variety of pathogenic processes that cause injury to the podocytes. Recently, mutations in more than 50 genes expressed in podocyte or glomerular basement membrane were identified as causing genetic forms of FSGS, the majority of which are characterized by onset in childhood. The prevalence of adult-onset genetic FSGS is likely to be underestimated and its clinical and histological features have not been clearly described. A small number of studies of adult-onset genetic FSGS showed that there is heterogeneity in clinical and histological findings, with a presentation ranging from sub-nephrotic proteinuria to full nephrotic syndrome. A careful evaluation of adult-onset FSGS that do not have typical features of primary or secondary FSGS (familial cases, resistance to immunosuppression and absence of evident cause of secondary FSGS) should include a genetic evaluation. Indeed, recognizing genetic forms of adult-onset FSGS is of the utmost importance, given that this diagnosis will have major implications on treatment strategies, selecting of living-related kidney donor and renal transplantation success.

Focal Segmental Glomerulosclerosis in Related Miniature Schnauzer Dogs.

Focal segmental glomerulosclerosis (FSGS) recently has been recognized as a common cause of proteinuria in dogs in general, and in Miniature Schnauzer dogs in particular. This study describes the morphologic features present in the kidneys of 8 related proteinuric Miniature Schnauzer dogs. The FSGS, characterized by solidification of portions of the capillary tuft, affected 32% to 49% of examined glomeruli in these dogs. Synechiae, often accompanied by hyalinosis, were present in 13% to 54% of glomeruli and were more prevalent in older dogs. Seven of 8 dogs had arteriolar hyalinosis. Ultrastructurally, all dogs had evidence of a podocytopathy in the absence of electron-dense deposits, glomerular basement membrane splitting, or fibrils. All dogs had multifocal to extensive podocyte foot process effacement. Other podocyte changes included microvillous transformation, the presence of vacuoles or protein resorption droplets, cytoplasmic electron-dense aggregates, and occasional binucleation. Variable amounts of intraglomerular lipid were present in all dogs. All dogs were proteinuric, with measured values for the urine protein-to-creatinine ratio ranging from 1.2 to 6.5. Azotemia was mild to absent and dogs were euthanatized at 5.1 to 14 years of age, in all cases due to nonrenal diseases. The underlying cause of FSGS in these Miniature Schnauzer dogs has yet to be determined, but contributors likely include genetic podocytopathy, lipid abnormalities, and glomerular hypertension.

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

BackgroundSchimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila.ResultsWe found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways.ConclusionsWe conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0519-7) contains supplementary material, which is available to authorized users.

Mitochondrial dysfunction in inherited renal disease and acute kidney injury.

Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.

Decreased glomerular filtration as the primary factor of elevated circulating suPAR levels in focal segmental glomerulosclerosis

Circulating factor(s) has been thought to be the underlying cause of focal segmental glomerulosclerosis (FSGS), and recent studies foster this idea by demonstrating increased soluble urokinase receptor (suPAR) levels in the serum of FSGS patients. To explore the possible contribution of suPAR in FSGS pathogenesis, we analyzed serum suPAR levels in 17 patients with FSGS and compared them with those in patients with steroid-sensitive nephrotic syndrome, chronic glomerulonephritis, or non-glomerular kidney diseases. Serum suPAR levels in patients with FSGS were higher than those in patients with steroid-sensitive nephrotic syndrome or chronic glomerulonephritis, but not higher than those in patients with non-glomerular kidney diseases. suPAR levels negatively correlate with estimated glomerular filtration rate and were decreased after renal transplantation in patients with FSGS as well as in those with non-glomerular kidney diseases. Furthermore, 6 FSGS patients with post-transplant recurrence demonstrated that suPAR levels were not high during the recurrence. Based on our results, elevated suPAR levels in FSGS patients were attributed mainly to decreased glomerular filtration. These data warrant further analysis for involvement of possible circulating factor(s) in FSGS pathogenesis.

Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients

Several genes have been identified to be causative for the disease in a subset of patients with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS). Mutations in genes with autosomal dominant inheritance mostly affect adolescent or adult patients. In rare cases recessive mutations in NPHS2 are associated with late-onset FSGS. Hereditary FSGS is associated with poor renal survival and low rates of disease recurrence after renal transplantation. Aim of the study was to evaluate the incidence of gene mutations within a cohort of adult patients with primary FSGS and/or NS and progression to end-stage renal disease (ESRD). Genotyping for TRPC6, ACTN4, CD2AP, WT1, INF2, NPHS2 and NPHS1 was performed in all patients with primary FSGS and ESRD registered on the waiting list for kidney transplantation of a large German transplant center (n = 26 out of 478 registered patients). Mean age at onset was 31.7 years; a positive family history for renal disease was documented in 11 (42%) patients, of these one with familiar history of FSGS. A missense mutation (p.R360H) was identified in TRPC6, 2 missense mutations in compound heterozygous state in NPHS1 (p.P368L; p.G412C), a sequence variation of unknown significance (p.R310Q) in ACTN4 and the non-neutral NPHS2 polymorphism p.R229Q in two additional patients. No mutations were detected in INF2, CD2AP and WT1. The observed mutation rate was 8% in this single-center cohort of adult patients with primary FSGS. Mutations in podocyte genes seem to be a rare cause of FSGS and renal failure in adult patients. However, they should be considered as the underlying cause in a subset of patient as the impact on family counseling and patients' life perspectives are significant.

Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice

Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome in children and adults. Although FSGS is considered a podocyte disease, the aetiology is diverse. In recent years, many inheritable genetic forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. In the present commentary, we review these genetic causes of FSGS and describe their prevalence in familial and sporadic FSGS. In routine clinical practice, the decision to perform the costly DNA analysis should be based on the assessment if the results affect the care of the individual patient with respect to the evaluation of extra-renal manifestations, treatment decisions, transplantation and genetic counselling.