Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3 UTR (963 T3 G; 1003 T3 C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a wholegenome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.

SummaryBackground and objectives Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease. The hypothesis was that nutritional vitamin D (ergocalciferol) supplementation in children with CKD stages 2-4 delays the onset of secondary hyperparathyroidism.Design, setting, participants, & measurements A randomized, double-blinded, placebo-controlled study in children with CKD2-4 who had 25-hydroxyvitamin D [25(OH)D] deficiency was conducted. Ergocalciferol (or a matched placebo) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines. The primary endpoint was the time to development of hyperparathyroidism.Results Seventy-two children were screened. Forty-seven children were 25(OH)D-deficient and randomly assigned to receive ergocalciferol or placebo. Twenty children in each arm completed the study; median followup was 12 months. Groups were well matched for age, race, estimated GFR, and season when recruited. Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95% confidence interval, 1.02-21.00). The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95% confidence interval, 0.09-0.93, P=0.05). With ergocalciferol treatment, normal 25(OH)D levels were achieved in all 8 children with CKD2, 8 of 11 children with CKD3, but not in the single patient with CKD4. There were no ergocalciferol-related adverse events. 25(OH)D levels .100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D.Conclusions Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2-3.

Vitamin D deficiency is common in adult renal transplant recipients, but data in children are scarce. Vitamin D is shown to have multiple effects on the cardiovascular system, renal function, and maintenance of bone health. We hypothesized that 25(OH)D deficiency is common in pediatric renal transplant recipients, and may be associated with hyperparathyroidism, short stature, renal function, and blood pressure control. We recruited 106 children during the winter/spring season who had a functioning renal transplant for at least 3 months. Twenty-five hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured and correlated with clinical and biochemical parameters. Of the renal transplant patients, 38% were 25(OH)D deficient, 54% had insufficient levels, and only 8% had adequate 25(OH)D levels. Despite alfacalcidol supplementation in 59 (56%) patients, parathyroid hormone was increased in 58 (55%) and showed an inverse correlation with 25(OH)D (p = 0.0003, r = 0.61) but not with 1,25(OH)(2)D levels. Height standard deviation score (SDS) correlated with 25(OH)D (p = 0.007, r = 0.42) and time post transplantation (p = 0.02, r = 0.23); both were significant and independent predictors of height SDS. 25(OH)D inversely correlated with systolic BP SDS (p = 0.02, r =-0.26); this association was lost on multiple regression analysis, but 25(OH)D was the only modifiable risk factor for hypertension. There was no correlation with estimated GFR or proteinuria. In conclusion, 25(OH)D deficiency is common in pediatric renal transplant recipients and correlates with hyperparathyroidism and short stature. 25(OH)D deficiency may be a modifiable risk factor for hypertension in transplant recipients. Further studies are required to test if routine supplementation with ergo or cholecalciferol is safe and effective in children after renal transplantation.

Our survey demonstrates very encouraging results for long-term HRQoL of infants with severe CKD and highlights the negative impact of comorbidities. These data will help clinicians to counsel and inform families.