Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

Abstract

Some studies have reported up to 40% of patients born with a single kidney develop hypertension, proteinuria, and in some cases renal failure. The increased susceptibility to renal injury may be due, in part, to reduced nephron numbers. Notably, children who undergo nephrectomy or adults who serve as kidney donors exhibit little difference in renal function compared with persons who have two kidneys. However, the difference in risk between being born with a single kidney versus being born with two kidneys and then undergoing nephrectomy are unclear. Animal models used previously to investigate this question are not ideal because they require invasive methods to model congenital solitary kidney. In this study, we describe a new genetic animal model, the heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, which demonstrates 50%-75% spontaneous incidence of a single kidney. The HSRA model is characterized by reduced nephron number (more than would be expected by loss of one kidney), early kidney/glomerular hypertrophy, and progressive renal injury, which culminates in reduced renal function. Long-term studies of temporal relationships among BP, renal hemodynamics, and renal function demonstrate that spontaneous single-kidney HSRA rats are more likely than uninephrectomized normal littermates to exhibit renal impairment because of the combination of reduced nephron numbers and prolonged exposure to renal compensatory mechanisms (i.e., hyperfiltration). Future studies with this novel animal model may provide additional insight into the genetic contributions to kidney development and agenesis and the factors influencing susceptibility to renal injury in individuals with congenital solitary kidney.

Single-Nephron Glomerular Filtration Rate in Healthy Adults

“…Previous studies have linked larger nephrons to a higher single-nephron GFR in an animal model, 26 and the present study extends this finding to humans. In studies in animals, surgical renal ablation leads to a higher glomerular pressure and blood flow, which drives increases in both glomerular size and single-nephron GFR.…”

Single-Nephron Glomerular Filtration Rate in Healthy Adults

“…The apparent failure of the single-nephron GFR to increase with the expected age-related nephron loss, whereas it increased with nephro-sclerosis beyond the level expected for age, may support an age-based approach to the identification of chronic kidney disease. 25 Previous studies have linked larger nephrons to a higher single-nephron GFR in an animal model, 26 and the present study extends this finding to humans. In studies in animals, surgical renal ablation leads to a higher glomerular pressure and blood flow, which drives increases in both glomerular size and single-nephron GFR.…”

Temporal Expression and Cellular Localization of PAPPA2 in the Developing Kidney of Rat

“…The link between low nephron number and the risk of hypertension and kidney disease has been shown in humans and experimental animals. 34–36 Brenner et al 43 first identified an inverse association between nephron number and human hypertension. There has been great interest in the hypothesis proposed by this group that reductions in nephron numbers lead to glomerular hyperfiltration, enlargement, and injury.…”

“…Azar et al 19 reported that kidneys of SS rats have 15% fewer nephron than age-matched salt-resistant rats. The loss of nephron has an inverse relationship with renal hemodynamics, BP, and renal function in human and rodent animal models, 34–36 which is discussed later.…”