Unraveling the natural history of presymptomatic cystinuria.

PURPOSE OF REVIEW: Servais et al. recently published clinical practice recommendations for the care of cystinuria patients. However, these guidelines were largely based on retrospective data from adults and children presenting with stones. Significant questions remain about the natural history of cystinuria in presymptomatic children. RECENT FINDINGS: We review the natural history of cystinuria in presymptomatic children followed from birth. In total, 130 pediatric patients were assigned putative genotypes based on parental urinary phenotype: type A/A (N = 23), B/B (N = 6), and B/N (N = 101). Stones were identified in 12/130 (4% of A/A, 17% of B/B, and 1% of B/N patients). Type B/B patients had lower cystine excretion than type A/A patients. Although urine cystine/creatinine fell with age, urine cystine/l rose progressively in parallel with the risk of nephrolithiasis. Each new stone was preceded by 6-12 months of urine specific gravity of more than 1.020. However, average urine specific gravity and pH were not different in stone formers vs. nonstone formers, suggesting that intrinsic stone inhibitors or other unknown factors may be the strongest determinants of individual risk. SUMMARY: The current study reviews the clinical evolution of cystinuria in a cohort of children identified by newborn screening, who were categorized by urinary phenotype and followed from birth.

A no-nonsense approach to hereditary kidney disease.

The advent of a new class of aminoglycosides with increased translational readthrough of nonsense mutations and reduced toxicity offers a new therapeutic strategy for a subset of patients with hereditary kidney disease. The renal uptake and retention of aminoglycosides at a high intracellular concentration makes the kidney an ideal target for this approach. In this review, we explore the potential of aminoglycoside readthrough therapy in a number of hereditary kidney diseases and discuss the therapeutic window of opportunity for subclasses of each disease, when caused by nonsense mutations.

Heterozygous loss-of-function mutation in Odd-skipped related 1 (Osr1) is associated with vesicoureteric reflux, duplex systems, and hydronephrosis.

Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse. OSR1 was sequenced in 186 children with primary vesicoureteric reflux, and 17 have single nucleotide polymorphisms. Fifteen children have a common synonymous variant, rs12329305, one child has a rare nonsynonymous variant, rs3440471, and one child has a rare 5'-UTR variant, rs45535040 The impact of these SNPs is not clear; therefore, the role of OSR1 in human disease remains to be elucidated. Osr1 is a candidate gene implicated in the pathogenesis of vesicoureteric reflux and congenital abnormalities of the kidney and urinary tract in mice.

Vesicoureteral reflux and the extracellular matrix connection.

Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes.

Children with vesicoureteric reflux have joint hypermobility and occasional tenascin XB sequence variants.

INTRODUCTION: To consider alternative mechanisms that give rise to a refluxing ureterovesical junction (UVJ), we hypothesized that children with a common heritable urinary tract defect, vesicoureteric reflux (VUR), may have a defect in the extracellular matrix composition of the UVJ and other tissues that would be revealed by assessment of the peripheral joints. Hypermobile joints can arise from defects in the extracellular matrix within the joint capsule that affect proteins, including tenascin XB (TNXB). METHODS: We performed an observational study of children with familial and non-familial VUR to determine the prevalence of joint hypermobility, renal scarring, and DNA sequence variants in TNXB. RESULTS: Most children (27/44) exhibited joint hypermobility using the Beighton scoring system. This included 15/26 girls (57.7%) and 12/18 boys (66.7%), which is a significantly higher prevalence for both sexes when compared to population controls (p<0.005). We found no association between joint hypermobility and renal scarring. Seven of 49 children harbored rare pathogenic sequence variants in TNXB, and two also exhibited joint hypermobility. No sequence variants in TNXB were identified in 25/27 children with VUR and joint hypermobility. Due to the observational design of the study, there was missing data for joint hypermobility scores in six children and for dimercaptosuccinic acid (DMSA) scans in 17 children. CONCLUSIONS: We observed a high prevalence of VUR and joint hypermobility in children followed within a tertiary care pediatric urology clinic. While mutations in TNXB have been reported in families with VUR and joint hypermobility, we identified only two children with these phenotypes and pathogenic variants in TNXB. We, therefore, speculate that VUR and joint hypermobility may be due to mutations in other extracellular matrix genes.