Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD

Abstract

There is greater than tenfold variation in nephron number of the human kidney at birth. Although low nephron number is a recognized risk factor for CKD, its determinants are poorly understood. Evolutionary medicine represents a new discipline that seeks evolutionary explanations for disease, broadening perspectives on research and public health initiatives. Evolution of the kidney, an organ rich in mitochondria, has been driven by natural selection for reproductive fitness constrained by energy availability. Over the past 2 million years, rapid growth of an energy-demanding brain in Homo sapiens enabled hominid adaptation to environmental extremes through selection for mutations in mitochondrial and nuclear DNA epigenetically regulated by allocation of energy to developing organs. Maternal undernutrition or hypoxia results in intrauterine growth restriction or preterm birth, resulting in low birth weight and low nephron number. Regulated through placental transfer, environmental oxygen and nutrients signal nephron progenitor cells to reprogram metabolism from glycolysis to oxidative phosphorylation. These processes are modulated by counterbalancing anabolic and catabolic metabolic pathways that evolved from prokaryote homologs and by hypoxia-driven and autophagy pathways that evolved in eukaryotes. Regulation of nephron differentiation by histone modifications and DNA methyltransferases provide epigenetic control of nephron number in response to energy available to the fetus. Developmental plasticity of nephrogenesis represents an evolved life history strategy that prioritizes energy to early brain growth with adequate kidney function through reproductive years, the trade-off being increasing prevalence of CKD delayed until later adulthood. The research implications of this evolutionary analysis are to identify regulatory pathways of energy allocation directing nephrogenesis while accounting for the different life history strategies of animal models such as the mouse. The clinical implications are to optimize nutrition and minimize hypoxic/toxic stressors in childbearing women and children in early postnatal development.

CAKUT: A Pediatric and Evolutionary Perspective on the Leading Cause of CKD in Childhood

“…Thus, every patient should undergo a thorough review of family history for the presence of CAKUT, and be referred to genetic counseling when indicated [ 13 , 14 ]. Recent studies reveal that epigenetic regulation of nephron differentiation by histone modifications and DNA methyltransferases regulate nephron number in response to energy provided to the fetus through the placenta [ 15 ]. By increasing susceptibility to glomerular injury, APOL1 mutations, present in some populations of African ancestry, accelerate the rate of CKD progression in adulthood ( Figure 2 ) [ 16 ].…”

“…Evolution is the product of adaptation to the external environment through natural selection driven not by longevity, but by reproductive fitness constrained by available energy. Because reproductive success in Homo sapiens was favored by prioritization of fetal brain over kidney development, reduced nephron number represents an adaptation to maternal stress that is balanced by compensatory nephron hypertrophy that can begin in fetal life [ 15 ]. If the nephron deficit is not severe, and compensatory hypertrophy by remaining nephrons can preserve homeostasis, this evolutionary strategy can maintain homeostasis through peak reproductive years, after which natural selection plays a diminishing role ( Figure 2 ).…”

Impact of early life development on later onset chronic kidney disease and hypertension and the role of evolutionary trade‐offs

“…Human and animal studies therefore support a direct impact of environmental exposures during gestation on kidney development, supported further by recent evidence that the number of nephrons can be ‘reprogrammed’ through various interventions applied during pregnancies at risk (Nusken et al., 2018 ). The developmental programing has therefore long been regarded as an individual‐level maladaptation to fetal stress; however, a complementary explanation might lie in the evolutionary history of the human kidney (Chevalier, 2020 ).…”

“…Modulating this balance, epigenetic responses to environmental exposures are operative in three generations during fetal life: the mother (reflecting her prior fetal exposure), the fetus and its germ cells (Barker et al., 2012 ). These considerations would favour selection for diversion of energy from nephrogenesis to fetal brain growth and a reduced number of nephrons in the undernourished fetus (Chevalier, 2020 ).…”

“…This is a process regulated by epigenetic signalling. Environmental metabolic constraints signalled to the fetus via the placenta promote fetal DNA hypomethylation of nephron progenitor cells, thereby limiting the number of nephrons to preserve brain development but also meeting the metabolic demand of the fetus through postnatal maturation (Chevalier, 2020 ; Wanner et al., 2019 ).…”