Why is chronic kidney disease progressive? Evolutionary adaptations and maladaptations.

Despite significant advances in renal physiology, the global prevalence of chronic kidney disease (CKD) continues to increase. The emergence of multicellular organisms gave rise to increasing complexity of life resulting in trade-offs reflecting ancestral adaptations to changing environments. Three evolutionary traits shape CKD over the lifespan: 1) variation in nephron number at birth, 2) progressive nephron loss with aging, and 3) adaptive kidney growth in response to decreased nephron number. Although providing plasticity in adaptation to changing environments, the cell cycle must function within constraints dictated by available energy. Prioritized allocation of energy available through the placenta can restrict fetal nephrogenesis, a risk factor for CKD. Moreover, nephron loss with aging is a consequence of cell senescence, a pathway accelerated by adaptive nephron hypertrophy that maintains metabolic homeostasis at the expense of increased vulnerability to stressors. Driven by reproductive fitness, natural selection operates in early life but diminishes thereafter, leading to an exponential increase in CKD with aging, a product of antagonistic pleiotropy. A deeper understanding of the evolutionary constraints on the cell cycle may lead to manipulation of the balance between progenitor cell renewal and differentiation, regulation of cell senescence, and modulation of the balance between cell proliferation and hypertrophy. Application of an evolutionary perspective may enhance understanding of adaptation and maladaptation by nephrons in the progression of CKD, leading to new therapeutic advances.