A Common RET Variant Is Associated with Reduced Newborn Kidney Size and Function

Abstract

Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.

Serum Creatinine Levels Are Significantly Influenced by Renal Size in the Normal Pediatric Population

“…This population has been shown to have kidneys with fewer nephrons and to more frequently develop hypertension, proteinuria, and chronic renal failure (18,19). Similarly, Zhang et al (10) have shown that a common variant of the RET gene is associated with reduced KS in newborns and in the number of glomeruli, as measured in autopsy specimens of children that died before the age of 3 months.…”

“…Autopsy data, however, suggest that subjects with fewer nephrons tend to have smaller kidneys that contain hypertrophic glomeruli (9). A direct correlation between kidney weight and nephron number has been also reported in infants (10). In this study, we hypothesized that, in the normal pediatric population, part of the physiologic variance in BP and in GFR, as assessed by the serum creatinine, is related to differences in renal size.…”

Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease

“…Nephrogenesis in humans ends at around 36 weeks of gestation, after which no new nephrons can form 16 . In the Monash series, nephron number in 15 infants who died before the age of 3 months ranged 4.5-fold, from 246,181 to 1,106,062, suggesting that much of the variation in adult human nephron number is determined before birth 18 .…”

“…Search for common polymorphisms in several genes known to participate in kidney development have shown correlations between altered gene transcription and newborn kidney size, which is proportional to nephron number (Table 1) 18 . These studies have been conducted in primarily Caucasian populations, therefore implications in other populations need to be investigated 18,46,47 . The molecular mechanisms regulating nephrogenesis are expertly reviewed elsewhere 48 .…”

“…Consistent with this, increased glomerular size is a predictor of poorer renal outcomes among African Americans, Pima Indians and Aboriginal Australians, and in the absence of other causes, should be considered a surrogate for low nephron number 9 . Given the heterogeneity and hypertrophy occurring in glomeruli, kidney size has not been consistently found to correlate with nephron number in adults, but the relationship appears linear in infants under 3 months of age 18,52 Clinical impact of nephron mass…”