External Validation of a Urinary Biomarker Risk Score for the Prediction of Steroid Responsiveness in Adults With Nephrotic Syndrome.

Introduction: In idiopathic nephrotic syndrome, response to corticosteroids remains the best indicator of prognosis. Noninvasive markers to predict a patient's response to steroids would allow improved prognostication and a more personalized approach to management. We have previously derived a urinary biomarker risk score which can differentiate steroid sensitive nephrotic syndrome (SSNS) from steroid resistant nephrotic syndrome (SRNS) in children. The goal of this study was to validate this previously derived biomarker risk score in a cohort of steroid-naïve adult patients, to determine whether the panel could be used to predict steroid responsiveness at the time of initial diagnosis. Methods: In this external validation study, clinical data, and urinary specimens (obtained before initiation of steroid treatment) from adult patients were used in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. A panel of 5 previously identified and validated urinary biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), vitamin D binding protein (VDBP), Fetuin-A (FetA), Transthyretin (TTR), and alpha-1 acid glycoprotein 2 (AGP2) was measured. A summary risk score for steroid resistance was calculated based on biomarker concentrations. Receiver operating characteristic curves were created for each log-transformed biomarker concentration and for the individual and combined biomarker risk score. Results: The urine biomarker risk score predicted development of steroid resistance, with optimal sensitivity and specificity of 0.74, and area under the receiver operating characteristic curve (AUC) of 0.79 using both absolute and creatinine-corrected concentrations. Conclusion: This study validates the previously derived urinary biomarker risk score to predict steroid resistance in adult patients with nephrotic syndrome at initial diagnosis.

Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.

Clinical course and management of children with IgA vasculitis with nephritis.

BACKGROUND: IgA vasculitis is the most common vasculitis in children and is often complicated by acute nephritis (IgAVN). Risk of chronic kidney disease (CKD) among children with IgAVN remains unknown. This study aimed to describe the clinical management and kidney outcomes in a large cohort of children with IgAVN. METHODS: This observational cohort study used the PEDSnet database to identify children diagnosed with IgAV between January 1, 2009, and February 29, 2020. Demographic and clinical characteristics were compared among children with and without kidney involvement. For children followed by nephrology, clinical course, and management patterns were described. Patients were divided into four categories based on treatment: observation, renin-angiotensin-aldosterone system (RAAS) blockade, corticosteroids, and other immunosuppression, and outcomes were compared among these groups. RESULTS: A total of 6802 children had a diagnosis of IgAV, of whom 1139 (16.7%) were followed by nephrology for at least 2 visits over a median follow-up period of 1.7 years [0.4,4.2]. Conservative management was the most predominant practice pattern, consisting of observation in 57% and RAAS blockade in 6%. Steroid monotherapy was used in 29% and other immunosuppression regimens in 8%. Children receiving immunosuppression had higher rates of proteinuria and hypertension compared to those managed with observation (p < 0.001). At the end of follow-up, 2.6 and 0.5% developed CKD and kidney failure, respectively. CONCLUSIONS: Kidney outcomes over a limited follow-up period were favorable in a large cohort of children with IgAV. Immunosuppressive medications were used in those with more severe presentations and may have contributed to improved outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Frontotemporal degeneration genetic risk loci and transcription regulation as a possible mechanistic link to disease risk.

The etiology of Frontotemporal Degeneration (FTD) is not well understood. Genetic studies have established common genetic variants (GVs) that are associated with increased FTD risk. We review previous genome wide association studies (GWAS) of FTD and nominate specific transcriptional regulators as potential key players in the etiology of this disease. A list of GVs associated with FTD was compiled from published GWAS. The regulatory element locus intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk GVs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation (ChIP-seq) experiments. After linkage disequilibrium expansion of the previously reported tag associated GVs, we identified 914 GV at 47 independent risk loci. Using the RELI algorithm, we identified several transcriptional regulators with enriched binding at FTD risk loci (0.05 < corrected P value <1.18 × 10-27), including Tripartite motif-containing 28 (TRIM28) and Chromodomain-Helicase DNA-binding 1 (CHD1) which have previously observed roles in FTD. FTD is a complex disease, and immune dysregulation has been previously implicated as a potential underlying cause. This assessment of established FTD risk loci and analysis of possible function implicates transcriptional dysregulation, and specifically particular transcriptional regulators with known roles in the immune response as important in the genetic etiology of FTD.

Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss.

Primary hyperoxaluria type 1 is a rare inherited disorder caused by abnormal liver glyoxalate metabolism leading to overproduction of oxalate, progressive kidney disease, and systemic oxalosis. While the disorder typically presents with nephrocalcinosis, recurrent nephrolithiasis, and/or early chronic kidney disease, the diagnosis is occasionally missed until it recurs after kidney transplant. Allograft outcomes in these cases are typically very poor, often with early graft loss. Here we present the case of a child diagnosed with primary hyperoxaluria type 1 after kidney transplant who was able to maintain kidney function, thanks to aggressive renal replacement therapy as well as initiation of a new targeted therapy for this disease. This case highlights the importance of having a high index of suspicion for primary hyperoxaluria in patients with chronic kidney disease and nephrocalcinosis/nephrolithiasis or with end stage kidney disease of uncertain etiology, as initiating therapies early on may prevent poor outcomes.

Comprehensive Review of Steroid-Sensitive Nephrotic Syndrome Genetic Risk Loci and Transcriptional Regulation as a Possible Mechanistic Link to Disease Risk.

INTRODUCTION: The etiology of steroid-sensitive nephrotic syndrome (SSNS) is not well understood. Genetic studies have established common single nucleotide polymorphisms (SNPs) that are associated with increased SSNS disease risk. We review previous genetic association studies of SSNS and nominate particular transcriptional regulators and immune cells as potential key players in the etiology of this disease. METHODS: A list of SNPs associated with SSNS was compiled from published genome wide association and candidate gene studies. The Regulatory Element Locus Intersection (RELI) tool was used to calculate the enrichment of the overlap between disease risk SNPs and the genomic coordinates of data from a collection of >10,000 chromatin immunoprecipitation sequencing experiments. RESULTS: After linkage disequilibrium expansion of the previously reported tag associated SNPs, we identified 192 genetic variants at 8 independent risk loci. Using the Regulatory Element Locus Intersection algorithm, we identified transcriptional regulators with enriched binding at SSNS risk loci (10-05 < P corrected < 10-124), including ZNF530, CIITA, CD74, RFX5, and ZNF425. Many of these regulators have well-described roles in the immune response. RNA polymerase II binding in B cells also demonstrated enriched binding at SSNS risk loci (10-37

Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination - A Case Report.

We present the case of an infant referred to our NICU born at 39 weeks' gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the PMM2gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

The Search for Biomarkers to Aid in Diagnosis, Differentiation, and Prognosis of Childhood Idiopathic Nephrotic Syndrome.

Identification of genes associated with childhood-onset nephrotic syndrome has significantly advanced our understanding of the pathogenesis of this complex disease over the past two decades, however the precise etiology in many cases remains unclear. At this time, we still rely on invasive kidney biopsy to determine the underlying cause of nephrotic syndrome in adults. In children, response to steroid therapy has been shown to be the best indicator of prognosis, and therefore all children are treated initially with corticosteroids. Because this strategy exposes a large number of children to the toxicities of steroids without providing any benefit, many researchers have sought to find a marker that could predict a patient's response to steroids at the time of diagnosis. Additionally, the identification of such a marker could provide prognostic information about a patient's response to medications, progression to end stage renal disease, and risk of disease recurrence following transplantation. Major advances have been made in understanding how genetic biomarkers can be used to predict a patient's response to therapies and disease course, especially after transplantation. Research attempting to identify urine- and serum-based biomarkers which could be used for the diagnosis, differentiation, and prognosis of nephrotic syndrome has become an area of emphasis. In this review, we explore the most exciting biomarkers and their potential clinical applications.

Kidney biopsy findings in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Renal damage is a progressive complication of sickle cell disease (SCD). Microalbuminuria is common in children with SCD, while a smaller number of children have more severe renal manifestations necessitating kidney biopsy. There is limited information on renal biopsy findings in children with SCD and subsequent management and outcome. METHODS: This is a multicenter retrospective analysis of renal biopsy findings and clinical outcomes in children and adolescents with SCD. We included children and adolescents (age ≤ 20 years) with SCD who had a kidney biopsy performed at a pediatric nephrology unit. The clinical indication for biopsy, biopsy findings, subsequent treatments, and outcomes were analyzed. RESULTS: Thirty-six SCD patients (ages 4-19 years) were identified from 14 centers with a median follow-up of 2.6 years (0.4-10.4 years). The indications for biopsy were proteinuria (92%) and elevated creatinine (30%). All biopsies had abnormal findings, including mesangial hypercellularity (75%), focal segmental glomerulosclerosis (30%), membranoproliferative glomerulonephritis (16%), and thrombotic microangiopathy (2%). There was increased use of hydroxyurea, angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers following renal biopsy. At last follow-up, 3 patients were deceased, 2 developed insulin-dependent diabetes mellitus, 6 initiated chronic hemodialysis, 1 received a bone marrow transplant, and 1 received a kidney transplant. CONCLUSIONS: Renal biopsies, while not commonly performed in children with SCD, were universally abnormal. Outcomes were poor in this cohort of patients despite a variety of post-biopsy interventions. Effective early intervention to prevent chronic kidney disease (CKD) is needed to reduce morbidity and mortality in children with SCD.

Bleeding Complications after Pediatric Kidney Biopsy: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Kidney biopsy is an essential tool for the diagnosis and treatment of patients with kidney disease; however, because of its invasive nature, bleeding complications may arise. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a meta-analysis of prospective or retrospective observational studies and randomized, controlled trials in pediatric patients undergoing native or transplant kidney biopsy in an inpatient or outpatient setting in MEDLINE-indexed studies from January 1998 to November 1, 2017 to determine the proportion of patients who develop hematoma, need blood transfusion, or need an additional intervention due to a complication after kidney biopsy. RESULTS: Twenty-three studies of 5504 biopsies met inclusion criteria. The proportion of patients developing hematoma after biopsy was between 11% (95% confidence interval, 7% to 17%) and 18% (95% confidence interval, 9% to 35%) using two analyses that included different time periods. The proportion needing blood transfusion was 0.9% (95% confidence interval, 0.5% to 1.4%). The proportion needing an additional intervention due to postbiopsy complication was 0.7% (95% confidence interval, 0.4% to 1.1%). Secondary analysis was not possible due to lack of data in the original manuscripts on laboratory values, needle gauges, number of needle passes, age of patient, or performer (attending versus trainee). Analysis with metaregression found that use of real-time ultrasound during biopsy did not modify the risk for hematoma, requirement of a blood products transfusion, or requirement of an additional procedure after biopsy. Analysis with metaregression comparing native biopsies with transplant biopsies did not reveal that biopsy type (native kidney biopsy versus transplant kidney biopsy) was associated with the need for a blood transfusion or requirement of an additional intervention after biopsy. CONCLUSIONS: The development of perinephric hematoma after kidney biopsy is not an infrequent finding. The proportion of patients requiring blood transfusion or needing an additional intervention as a result of kidney biopsy in pediatric patients is significantly smaller.