Bioenergetics: the evolutionary basis of progressive kidney disease

Chronic kidney disease (CKD) affects >10% of the world population, with increasing prevalence in middle age. The risk for CKD is dependent on the number of functioning nephrons through the life cycle, and 50% of nephrons are lost through normal aging, revealing their vulnerability to internal and external stressors. Factors responsible for CKD remain poorly understood, with limited availability of biomarkers or effective therapy to slow progression. This review draws on the disciplines of evolutionary medicine and bioenergetics to account for the heterogeneous nephron injury that characterizes progressive CKD following episodes of acute kidney injury with incomplete recovery. The evolution of symbiosis in eukaryotes led to the efficiencies of oxidative phosphorylation and the rise of metazoa. Adaptations to ancestral environments are the products of natural selection that have shaped the mammalian nephron with its vulnerabilities to ischemic, hypoxic, and toxic injury. Reproductive fitness rather than longevity has served as the driver of evolution, constrained by available energy and its allocation to homeostatic responses through the life cycle. Metabolic plasticity has evolved in parallel with robustness necessary to preserve complex developmental programs, and adaptations that optimize survival through reproductive years can become maladaptive with aging, reflecting antagonistic pleiotropy. Consequently, environmental stresses promote trade-offs and mismatches that result in cell fate decisions that ultimately lead to nephron loss. Elucidation of the bioenergetic adaptations by the nephron to ancestral and contemporary environments may lead to the development of new biomarkers of kidney disease and new therapies to reduce the global burden of progressive CKD.

Automated summary

Chronic kidney disease (CKD) affects a significant portion of the world population, particularly middle-aged individuals. The risk for CKD is related to the loss of functioning nephrons, which are vulnerable to both internal and external stressors. The factors responsible for CKD are not well understood, and there is a lack of effective biomarkers or therapies to slow its progression. This review explores the role of evolutionary medicine and bioenergetics in understanding the heterogeneous nephron injury in progressive CKD after episodes of acute kidney injury. It suggests that the adaptations of the mammalian nephron to ancestral environments can become maladaptive with aging, leading to nephron loss. The elucidation of bioenergetic adaptations may provide valuable insights for developing new biomarkers and therapies for CKD.