Bioenergetics: the evolutionary basis of progressive kidney disease

Abstract

Chronic kidney disease (CKD) affects over 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 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 tradeoffs 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.

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…It is particularly important to pay attention to the regulation of renal cells [ 113 ]. The main risk factors of kidney disease include age [ 114 ], smoking, obesity [ 115 ], hypertension [ 116 ], diabetes [ 117 ], cardiovascular disease [ 118 ], hyperuricemia [ 119 ], and environmental factors [ 120 ]. Notably, sirtuins modulate most of these risk factors [ 23 ], and slow the progression of renal nephropathy by regulating metabolic homeostasis, autophagy, apoptosis, mitochondrial biogenesis, and oxidative stress; improving serum creatinine and blood urea nitrogen levels and reducing proteinuria [ 121 – 124 ].…”

Urine Epidermal Growth Factor and Kidney Function Decline in Middle-Aged Adults

“…1 , 2 Although more than half of the kidney’s mass consists of proximal tubules, and the vast majority of the kidney’s energy consumption occurs within the tubules, it is noteworthy that current CKD measures predominantly center on glomerular filtration (estimated glomerular filtration rate [eGFR]) and injury (albuminuria). 3 This glomerulocentric approach incompletely captures the potential role of kidney tubule damage in CKD development and progression. 4 , 5 , 6 …”