Abstract
BackgroundPosterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. ObjectiveTo identify genetic variants associated with kidney injury in patients with obstructive uropathy. Design, setting, and participantsWe included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. Outcome measurements and statistical analysisSigns of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. Results and limitationsDespite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10–7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. ConclusionsThis study identified CDH12 as a candidate gene for kidney injury in PUV. Patient summaryWe found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.
Highlights
Posterior urethral valves (PUV) and ureteropelvic junction obstruction (UPJO) are congenital anomalies of the urinary tract that impair urinary flow
Knowledge about the molecular pathways involved in the pathophysiology of kidney injury in congenital obstructive uropathy has mainly been derived from neonatal rats and mice with induced complete unilateral ureteral obstruction (UUO)
For single-nucleotide polymorphisms (SNPs) passing the threshold of p = 1 Â 10–5, we examined the associations separately for PUV and UPJO patients to verify the assumption of similar genetic variants associated with kidney function decline in these phenotypes, performed Kaplan-Meier and Cox regression analyses to include 130 patients with
Summary
Posterior urethral valves (PUV) and ureteropelvic junction obstruction (UPJO) are congenital anomalies of the urinary tract that impair urinary flow. Kidney response to experimental UUO involves oxidative stress, monocyte infiltration, uncontrolled apoptosis of tubular cells, fibroblast accumulation, and increased deposition of extracellular matrix [3] This is similar to the response in human obstructed kidneys, where the extent of monocyte infiltration correlates with the intensity of tubulointerstitial damage, and inflammatory molecules, such as MCP1, are upregulated [5]. In addition to elements from proinflammatory pathways, several other molecules have been suggested to play a pathological role in kidney injury in obstructive uropathy in animal models (such as angiotensin II and Tgf-b) [3,6,7] Several of these were confirmed in human expression studies
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