Exome analysis links kidney malformations to developmental disorders and reveals causal genes.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.

Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

Key Points: We conducted a clinical, genetic, and pathological analysis on 64 cases from 39 families with TRPC6-associated podocytopathy (TRPC6-AP). Analysis of 37,542 individuals excluded a major contribution of loss-of-function variants to TRPC6-AP, legitimating current drug discovery approaches. This study identifies key features of disease that can help intervention studies design and suggests similarities between TRPC6-AP and primary FSGS.

C3 Hypocomplementemia Predicts the Progression of CKD towards End-Stage Kidney Disease in IgA Nephropathy, Irrespective of Histological Evidence of Thrombotic Microangiopathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30-40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role.

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers.

Strong protective effect of the p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers.

Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

Significance Statement: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.

Evidence for charge-based mimicry in anti dsDNA antibody generation.

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9.

The Role of Rituximab in Primary Focal Segmental Glomerular Sclerosis of the Adult.

Introduction: Primary focal segmental glomerular sclerosis (FSGS) is a rare, likely immune-mediated disease. Rituximab (RTX) may play a role in management, although data in adults are scanty.

Methods: We collected cases of RTX-treated primary FSGS within the Italian Society of Nephrology Immunopathology Working Group and explored response rate (24-hour proteinuria <3.

Second Wave Antibodies in Autoimmune Renal Diseases: The Case of Lupus Nephritis.

Clinical Trial registry name and registration number: Zeus study, NCT02403115.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.

Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR.

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.

Serum IgG2 antibody multicomposition in systemic lupus erythematosus and lupus nephritis (Part 1): cross-sectional analysis.

Objectives: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis.

Methods: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study.

Serum IgG2 antibody multi-composition in systemic lupus erythematosus and in lupus nephritis (Part 2): prospective study.

Objectives: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes.

Methods: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99).

Ultrasound to address medullary sponge kidney: a retrospective study.

Background: Medullary sponge kidney (MSK) is a rare disease characterized by cystic dilatation of papillary collecting ducts. Intravenous urography is still considered the gold standard for diagnosis. We identified a cohort of patients from our outpatient clinic with established diagnosis of MSK to outline some ultrasonographic characteristics that may help establish a diagnosis.

Rituximab for very low dose steroid-dependent nephrotic syndrome in children: a randomized controlled study.

Background: Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26).

Methods: We enrolled 30 children 4-15 years who had developed SDNS 6-12 months before and were maintained in remission with low prednisone doses (0.

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.

Low-dose ofatumumab for multidrug-resistant nephrotic syndrome in children: a randomized placebo-controlled trial.

Background: Children with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m) and partial remission at standard dose (1000 mg/1.

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD).