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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, and in 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. [ABSTRACT FROM AUTHOR]

Between 15–20% of patients with end stage renal disease (ESRD) do not know the cause of the primary kidney disease and can develop complications after kidney transplantation. We performed a genetic screening in 300 patients with kidney transplantation, or undiagnosed primary renal disease, in order to identify the primary disease cause and discriminate between overlapping phenotypes. We used a custom-made panel for next-generation sequencing (Agilent technology, Santa Clara, CA, USA), including genes associated with Fabry disease, podocytopaties, complement-mediated nephropathies and Alport syndrome-related diseases. We detected candidate diagnostic variants in genes associated with nephrotic syndrome and Focal Segmental Glomerulosclerosis (FSGS) in 29 out of 300 patients, solving about 10% of the probands. We also identified the same genetic cause of the disease (PAX2: c.1266dupC) in three family members with different clinical diagnoses. Interestingly we also found one female patient carrying a novel missense variant, c.1259C>A (p.Thr420Lys), in the GLA gene not previously associated with Fabry disease, which is in silico defined as a likely pathogenic and destabilizing, and associated with a mild alteration in GLA enzymatic activity. The identification of the specific genetic background may provide an opportunity to evaluate the risk of recurrence of the primary disease, especially among patient candidates living with a donor kidney transplant. [ABSTRACT FROM AUTHOR]

Background Percutaneous renal biopsy (PRB) may subject patients to emotional distress and pain before and during the biopsy. The aim of this study was to evaluate the effects of complementary/non-pharmacological interventions such as music therapy (MT) on anxiety, pain and satisfaction in renal patients undergoing PRB. Methods A prospective, single-centre, single-blind, randomized controlled two-arm trial was conducted. Patients ≥18 years of age, hospitalized at the Nephrology, Dialysis and Transplantation Unit (Bari, Italy) and scheduled for PRB were screened. Participants were assigned to standard treatment (CG) or to the music therapy (MT) intervention group. Participants in the MT group received standard care and an MT intervention by a certified music therapist qualified in guided imagery and music. The CG patients received the standard of care. MT and CG patients were subjected to identical measurements (pre/post) of the parameters in the State Trait Anxiety Inventory Y1 (STAI-Y1), visual analogue scale for pain (VAS-P) and satisfaction (VAS-S) and heart rate variability. Results A statistically significant difference in the anxiety scores after PRB between MT and CG patients (STAI-Y1 35.4 ± 6.2 versus 42.9 ± 9.0) was observed. MT also had strong and significant effects on VAS-P compared with CG (5.0 ± 1.4 versus 6.3 ± 1.3, respectively; P  < .001) and VAS-S (7.8 ± 1.0 versus 6.0 ± 0.9, respectively; P  < .001). Decreased activity of the sympathetic nervous system and increased activity of the parasympathetic nervous system was observed after PRB in the MT group. Conclusion Our study supports the use of MT to mitigate the psychological anxiety, pain and sympathetic activation associated with PRB. [ABSTRACT FROM AUTHOR]

Disorders of sex development (DSD) are a group of rare conditions characterized by discrepancy between chromosomal sex, gonads and external genitalia. Congenital abnormalities of the kidney and urinary tract are often associated with DSD, mostly in multiple malformation syndromes. We describe the case of an 11-year-old Caucasian boy, with right kidney hypoplasia and hypospadias. Genome-wide copy number variation (CNV) analysis revealed a unique duplication of about 550 kb on chromosome Xq27, and a 46,XX karyotype, consistent with a sex reversal phenotype. This region includes multiple genes, and, among these, SOX3 emerged as the main phenotypic driver. This is the fifth case reporting a genomic imbalance involving the SOX3 gene in a 46,XX SRY-negative male, and the first with associated renal malformations. Our data provide plausible links between SOX3 gene dosage and kidney malformations. It is noteworthy that the current and reported SOX3 gene duplications are below the detection threshold of standard karyotypes and were found only by analyzing CNVs using DNA microarrays. Therefore, all 46,XX SRY-negative males should be screened for SOX3 gene duplications with DNA microarrays. [ABSTRACT FROM AUTHOR]

The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. [ABSTRACT FROM AUTHOR]

Background: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.Methods: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.Results: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.Conclusions: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.). [ABSTRACT FROM AUTHOR]

Background: Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists.Objective: To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing.Design: Secondary analysis of genetic data.Setting: A tertiary care academic medical center.Patients: A convenience sample of exome sequence data from 7974 self-declared healthy adults.Measurements: Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders.Results: Of all participants, 23.3% carried a candidate pathogenic variant, most of which were attributable to previously reported variants that had implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned.Limitation: Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses.Conclusion: Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties.Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute. [ABSTRACT FROM AUTHOR]

Background: The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown.Objective: To study the diagnostic utility of WES in a selected referral population of adults with CKD.Design: Observational cohort.Setting: A major academic medical center.Patients: 92 adults with CKD of unknown cause or familial nephropathy or hypertension.Measurements: The diagnostic yield of WES and its potential effect on clinical management.Results: Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy.Limitation: The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population.Conclusion: Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted.Primary Funding Source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3 , recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L , a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10 −5 for novel LOF, increased to p = 4.1 × 10 −6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10 −7 ). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD. [ABSTRACT FROM AUTHOR]

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22qll.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22qll.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5xl014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22qll.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. [ABSTRACT FROM AUTHOR]