Evolutionary Nephrology

Abstract

Progressive kidney disease follows nephron loss, hyperfiltration, and incomplete repair, a process described as "maladaptive." In the past 20 years, a new discipline has emerged that expands research horizons: evolutionary medicine. In contrast to physiologic (homeostatic) adaptation, evolutionary adaptation is the result of reproductive success that reflects natural selection. Evolutionary explanations for physiologically maladaptive responses can emerge from mismatch of the phenotype with environment or evolutionary tradeoffs. Evolutionary adaptation to a terrestrial environment resulted in a vulnerable energy-consuming renal tubule and a hypoxic, hyperosmolar microenvironment. Natural selection favors successful energy investment strategy: energy is allocated to maintenance of nephron integrity through reproductive years, but this declines with increasing senescence after ~40 years of age. Risk factors for chronic kidney disease include restricted fetal growth or preterm birth (life history tradeoff resulting in fewer nephrons), evolutionary selection for APOL1 mutations (that provide resistance to trypanosome infection, a tradeoff), and modern life experience (Western diet mismatch leading to diabetes and hypertension). Current advances in genomics, epigenetics, and developmental biology have revealed proximate causes of kidney disease, but attempts to slow kidney disease remain elusive. Evolutionary medicine provides a complementary approach by addressing ultimate causes of kidney disease. Marked variation in nephron number at birth, nephron heterogeneity, and changing susceptibility to kidney injury throughout life history are the result of evolutionary processes. Combined application of molecular genetics, evolutionary developmental biology (evo-devo), developmental programming and life history theory may yield new strategies for prevention and treatment of chronic kidney disease.

Keywords: adaptation; chronic kidney disease; energy; evolution; life history; progression.

Figure 1

Three-dimensional reconstructions of individual nephrons from serial sections of human kidneys, depicting the fate (atrophy or hypertrophy) of the nephron population in chronic Bright’s disease. (a) Glomerulotubular unit from a normal kidney, redrawn from Peter K. Untersuchungen uber Bau und Entwickelung der Niere. Jena, Germany: Gustav Fischer; 1909. (b) Hypertrophic unit and (c) atrophic unit from an adult with hemorrhagic Bright’s disease following streptococcal tonsillitis. AKI, acute kidney injury; CKD, chronic kidney disease.

Figure 2

The more important steps in the evolution of the vertebrate kidney in relation to saltwater (darkly shaded) and freshwater (lightly shaded) environments. Schematic nephrons are depicted, beginning with glomerular nephrons in freshwater chordates. The evolutionary tree is followed through primitive fish, amphibians, reptiles, birds, and mammals with adaptation to a terrestrial environment (differentiation of proximal and distal tubules, and loop of Henle). In the Devonian period, major changes in the earth’s crust forced fish to adapt to saltwater: high-filtering glomeruli became a liability in this hyperosmolar environment, and were lost in some fish (sculpin and deep sea fishes [lower right]). The timeline at the bottom shows the geologic periods and eras, with the final Pleistocene being compressed.

Figure 3

Relationship of maturation and aging to overall mortality and the progression of chronic kidney disease. (a) Age- and sex-specific mortality (all causes) over the life span in a modern developed country (Canada, 1971). A decline in mortality from ∼2000 per 100,000 in fetal life to a nadir of 50 per 100,000 at 12 years of age reflects the dramatic contribution of lethal mutations to mortality in prereproductive life, followed by a logarithmic rise in mortality in the postreproductive period of senescence. Reproduced with permission from John Wiley and Sons from Costa T, Scriver CR, Childs B. The effect of Mendelian disease on health: a measurement. Am J Med Genet. 1985;21:231−242. Copyright © John Wiley & Sons. (b) Relative contribution to chronic kidney disease of natural selection, genetic/epigenetic factors, and experience (environment) according to age at onset. Fetal/neonatal disorders (e.g., congenital anomalies of the kidneys and urinary tract [CAKUT]) are primarily attributable to genetic/epigenetic factors largely influenced by natural selection, whereas later mortality is primarily governed by environmental factors (e.g., diabetes, hypertension). Adapted with permission from Nature Publishing Group from Childs B. Acceptance of the Howland Award. Pediatr Res. 1989;26:390−393. Copyright © Nature Publishing Group. (c) Lifetime risk for diagnosis of end-stage kidney disease (ESKD) over the life span. Risk of ESKD remains <1% until after peak reproductive age (30 years), after which risk accelerates more rapidly in black than in white cohorts and in males than in females.

Figure 4

The kidney over the life span: the nephron number is highly variable at birth and decreases with increasing fraction of glomerulosclerosis following the reproductive years. (a) Relationship between birth weight and glomerular number among infants, children, and adults. Solid line, regression; dashed line, 95% regression confidence interval; r = 0.423, P = 0.0012, N = 56. Reprinted with permission from Elsevier from Hughson MD, Farris AB, Douglas-Denton R, et al. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63:2113−2122. Copyright © International Society of Nephrology. (b) Number of functioning (nonsclerosed) glomeruli per kidney in renal allograft cadaveric donors younger than 40 years (N = 12) and older than 55 years (N = 13). Reproduced with permission from the American Society of Nephrology from Tan JC, Workeneh B, Busque S, et al. Glomerular function, structure, and number in renal allografts from older deceased donors. J Am Soc Nephrol. 2009;20:181−188. Copyright © American Society of Nephrology. (c) Percentage of sclerotic glomeruli from 122 autopsied patients plotted against age.

Figure 5

Relationship of homeostasis to natural selection in determining nephron responses to environmental stress in acute kidney injury (AKI) and chronic kidney disease (CKD). Primary phenotypic characteristics of the proximal tubule (biochemistry, physiology, and morphology) are determined by the interaction of the genotype and environment on the developing nephrons. Epigenetic factors also influence the performance capacity of the nephron, which in turn limits the behavior of tubular cells in response to environmental stressors. Natural selection acts on the reproductive success (fitness) of the organism as affected by maintenance of proximal tubular homeostasis in the face of AKI and CKD.

Figure 6

The aging kidney: 2 interrelated pathways in early chronic kidney disease (CKD): relationship of risk factors and kidney function to nephron hypertrophy and glomerulosclerosis among 1395 healthy living kidney donors. Nephron hypertrophy and lower nonsclerotic glomerular density were correlated with aging, male sex, family history of end-stage renal disease (ESRD), obesity, hyperuricemia, hyperfiltration, and albuminuria. Glomerulosclerosis was associated with aging, lower glomerular filtration rate, and hypertension. Adaptive hypertrophy of functional nephrons with aging may create a positive feedback loop with glomerulosclerosis, a process that is accelerated in CKD. GFR, glomerular filtration rate.