We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

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 (i.e. affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12, and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3, and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

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BACKGROUND Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine–threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.)

Angiotensin II type 1 receptor (AT1R) antibody has been linked to poor allograft outcomes in adult kidney transplantation. However, its clinical consequences in children are unknown. To study this, we examined the relationship of AT1R antibody with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibodies (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for AT1R antibody, HLA DSA, IL-8, TNF-α, IL-1β, IFN-γ, IL-17, and IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first two years post transplantation. AT1R antibody was positive in 38 of the 65 of children but was not associated with HLA DSA. AT1R antibody was associated with renal allograft loss (odds ratio of 13.1 [95% confidence interval 1.48-1728]), the presence of glomerulitis or arteritis, and significantly higher TNF-α, IL-1β, and IL-8 levels, but not rejection or hypertension. AT1R antibody was associated with significantly greater declines in eGFR in patients both with and without rejection. Furthermore, in patients without rejection, AT1R antibody was a significant risk factor for worsening eGFR over the two-year follow-up period. Thus, AT1R antibody is associated with vascular inflammation in the allograft, progressive decline in eGFR, and allograft loss. AT1R antibody and inflammatory cytokines may identify those at risk for renal vascular inflammation and lead to early biopsy and intervention in pediatric kidney transplantation.

Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources.

There are limited data on the impact of COVID‐19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID‐19 in pediatric KT patients. Twenty‐two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS‐CoV‐2 by PCR. Testing indications included symptoms and/or potential exposures to COVID‐19 ( N = 134, 47.7%) and/or testing per hospital policy ( N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID‐19‐positive patients, 16 were managed as outpatients, six received non‐ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID‐19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID‐19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID‐19 disease and excellent short‐term outcomes.

Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence.