Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

BACKGROUND: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. METHODS: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. RESULTS: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. CONCLUSIONS: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

Urea-induced ROS accelerate senescence in endothelial progenitor cells.

BACKGROUND AND AIMS: The pathogenic events responsible for the reduction of endothelial progenitor cell (EPC) number and function seen in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that increased concentrations of urea associated with CRF increase ROS production directly in EPCs, causing abnormalities associated with coronary artery disease risk. METHODS: Human EPCs were isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of 20 mmol/L urea. RESULTS: Urea at concentrations seen in CRF induced ROS production in cultured EPCs. Urea-induced ROS reduced the number of endothelial cell colony forming units, uptake and binding of Dil-Ac-LDL and lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2-positive cells. Moreover, urea-induced ROS generation accelerated the onset of EPC senescence, leading to a senescence-associated secretory phenotype (SASP). Normalization of mitochondrial ROS production prevented each of these effects of urea. CONCLUSIONS: These data suggest that urea itself causes both reduced EPC number and increased EPC dysfunction, thereby contributing to the pathogenesis of cardiovascular disease in CRF patients.