Evolutionary Nephrology

  • Robert L. Chevalier
    Correspondence
    Correspondence: Robert L. Chevalier, Department of Pediatrics, University of Virginia, PO Box 800386, Charlottesville, Virginia 22908-0386, USA.
    Affiliations
    Department of Pediatrics, The University of Virginia, Charlottesville, Virginia, USA
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Open AccessPublished:January 31, 2017DOI:https://doi.org/10.1016/j.ekir.2017.01.012
      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 from 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 (which 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 the 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

      I conceive that primordially what protoplasm wants is to be left alone, but environment being what it is, it never for long achieves this nirvana of undisturbed quietude.Homer W. Smith
      • Smith H.W.
      Organism or environment: dynamic oppositions.
      An expanding global epidemic of chronic kidney disease (CKD) has prompted new approaches to elucidate the underlying mechanisms: the incidence of end-stage kidney disease (ESKD) in children is <10/million, but in adults, lifetime risk for ESKD rises to over 5%.

      NAPRTCS. North American Pediatric Renal Trials and Collaborative Studies Annual Report. North American Pediatric Renal Trials and Collaborative Studies. Available at: https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf. Accessed February 22, 2017.

      USRDS. United States Renal Data System. 2015 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2015.

      Diabetic nephropathy is now the leading cause of ESKD in adults,

      USRDS. United States Renal Data System. 2015 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2015.

      whereas congenital anomalies of the kidneys and urinary tract (CAKUT) account for the majority of pediatric cases.

      NAPRTCS. North American Pediatric Renal Trials and Collaborative Studies Annual Report. North American Pediatric Renal Trials and Collaborative Studies. Available at: https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf. Accessed February 22, 2017.

      More recently, epidemiologic studies have shown that incomplete recovery from episodes of acute kidney injury (AKI) constitutes a risk factor for progressive CKD, and CKD in turn increases susceptibility to AKI: the proximal tubule therefore becomes a primary target of injury and progression of CKD.
      • Leung K.C.W.
      • Tonelli M.
      • James M.T.
      Chronic kidney disease following acute kidney injury—risk and outcomes.
      • Chevalier R.L.
      The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.

       Physiologic Versus Evolutionary Adaptation (Proximate vs. Ultimate Cause)

      Advances in nephrology have emerged through incremental understanding of kidney structure and function, and of the central role of the nephron in maintenance of homeostasis. Elegant morphologic studies performed by Jean Oliver in the early 20th century revealed the formation of intermixed hypertrophied and atrophied nephrons in the kidneys of patients with CKD (Bright’s disease), an important observation (Figure 1).
      • Oliver J.
      • Lund E.M.
      Plastic studies in abnormal renal architecture. I. The two architectural units in chronic Bright's disease and their possible functional significance.
      Using microdissection techniques, Oliver also described the widespread formation of atubular glomeruli and aglomerular tubules in kidneys of patients with advanced CKD.
      • Oliver J.
      Architecture of the Kidney in Chronic Bright's Disease.
      Subsequent morphometric studies of kidneys from patients with CKD due to vascular, glomerular, tubulointerstitial, or toxic etiologies demonstrated that the formation of atubular glomeruli as a result of proximal tubular destruction is a hallmark of late CKD.
      • Chevalier R.L.
      The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.
      • Chevalier R.L.
      • Forbes M.S.
      Generation and evolution of atubular glomeruli in the progression of renal disorders.
      Micropuncture studies by Barry Brenner and his associates in the 1980s revealed that following experimental renal ablation, the remaining nephrons undergo hyperfiltration that maintains short-term homeostasis but that results in eventual glomerulosclerosis, a response described as “maladaptive”.
      • Brenner B.M.
      Chronic renal failure: a disorder of adaptation.
      In the terminal phases of CKD, widespread deposition of extracellular matrix in the renal interstitium is recognized as a final common pathway for nephron destruction, resulting from maladaptive repair of damaged nephrons.
      • Basile D.P.
      • Bonventre J.V.
      • Mehta R.
      • et al.
      Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments.
      Figure thumbnail gr1
      Figure 1Three-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.
      Reproduced with permission from College of American Pathologists from Oliver J, Lund EM. The two architectural units in chronic Bright’s disease and their possible functional significance. Arch Pathol. 1933;15:755−774.
      • Oliver J.
      • Lund E.M.
      Plastic studies in abnormal renal architecture. I. The two architectural units in chronic Bright's disease and their possible functional significance.
      Copyright © 2010 College of American Pathologists.
      Throughout the 19th century and to the present day, disease has been regarded as a disorder of homeostasis, requiring an understanding of its proximate cause, or stimulus (physiologic adaptation).
      • Mayr E.
      Cause and effect in biology.
      Physiologists expect to find “optimal” homeostatic responses (adaptations) in biological systems; the term “maladaptation” implies deviation from an optimal adaptation to environment, a theoretical ideal that more often reflects the perspective of the physiologist (or physician) than the evolutionist, who recognizes that natural selection leads to traits that are better than the alternatives, but never optimal (Table 1).
      • Crespi B.J.
      The evolution of maladaptation.
      It remains a term that is difficult to identify, because genetic/epigenetic adaptations cannot accurately predict future environmental changes.
      • Nesse R.M.
      Maladaptation and natural selection.
      This approach led to the development of angiotensin inhibitors, which are widely used in slowing hyperfiltration injury but do not arrest progression.
      • Casas J.P.
      • Chua W.
      • Loukogeorgakis S.
      • et al.
      Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis.
      Similarly, inhibitors of mediators of interstitial fibrosis, such as transforming growth factor−β, have also proved to be disappointing.
      • Cho M.E.
      • Kopp J.B.
      Pirfenidone: an anti-fibrotic and cytoprotective agent as therapy for progressive kidney disease.
      A complementary paradigm is needed to understand the behavior of the nephron in CKD: this may lead to the discovery of new biomarkers of progression, and new effective therapies.
      Table 1Chronology of the introduction of evolutionary terms relevant to the progression of chronic kidney disease
      Year, author, titleEvolutionary termDefinition
      1859: Charles Darwin The Origin of Species
      • Darwin C.
      • Costa J.A.
      The Annotated Origin: A Facsimile of the First Edition of On the Origin of Species.
      Darwinian evolutionThe result of natural selection of inherited variations that increase the individual’s reproductive success
      1930: Ronald A. Fisher The Genetical Theory of Natural Selection
      • Fisher R.A.
      The Genetical Theory of Natural Selection.
      Life history theoryEvolution of major features of a life cycle: age distribution of birth and death rates, growth rates, and size of offspring
      • Stearns S.C.
      The Evolution of Life Histories.
      1967: G.C. Williams

      Adaptation and Natural Selection
      • Williams G.C.
      Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought.
      Evolutionary adaptationThe result of reproductive success (fitness) that reflects natural selection
      • Bennett A.F.
      Adaptation and the evolution of physiological character.
      Physiologic adaptationThe result of a homeostatic mechanism (adaptive trait) that responds to an immediate environmental stimulus
      • Bennett A.F.
      Adaptation and the evolution of physiological character.
      1970sEvolutionary physiologyElucidation of evolutionary adaptations through a synthesis of comparative physiology and physiological ecology by comparing physiological, cellular, and molecular characteristics
      • Garland Jr., T.
      • Carter P.A.
      Evolutionary physiology.
      1977: S.J. Gould Ontogeny and Phylogeny
      • Gould S.J.
      Ontogeny and Phylogeny.
      Evolutionary developmental biology (“evo-devo”)Elucidation of the evolution of developmental processes, linking molecular mechanisms (primarily gene regulatory networks) to phenotypic change
      • Gilbert S.F.
      The morphogenesis of evolutionary developmental biology.
      • Sommer R.J.
      The future of evo-devo: model systems and evolutionary theory.
      1988: D.J.P. Barker, C. Osmond

      Infant Mortality, Childhood Mortality and Ischaemic Heart Disease
      • Barker D.J.P.
      • Osmond C.
      Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.
      Developmental origins of health and disease (developmental programming)Elucidation of environmental factors during early animal and human development, and interactions between environmental and genetic factors, that influence health in later life and risk of disease
      • Barker D.J.P.
      The origins of the developmental origins theory.
      1991: G.C. Williams, R.M. Nesse

      The Dawn of Darwinian Medicine
      • Williams G.C.
      • Nesse R.M.
      The dawn of Darwinian medicine.
      Evolutionary medicine (Darwinian medicine)The study of disease mechanisms through the application of evolutionary theory, leading to the elucidation of factors underlying disease susceptibility
      • Nesse R.M.
      • Williams G.C.
      Evolution and Healing: The New Science of Darwinian Medicine.
      2005: R.M. Nesse Maladaptation and Natural Selection
      • Nesse R.M.
      Maladaptation and natural selection.
      MaladaptationDeviation from an optimal adaptation to environment, which can never be perfect—very difficult to identify because of asynchronous changes in genetic systems and environments over time
      • Crespi B.J.
      The evolution of maladaptation.
      • Nesse R.M.
      Maladaptation and natural selection.
      In contrast to its proximate cause, the ultimate cause of a biologic response can be revealed by an understanding of its evolutionary origins through the process of natural selection.
      • Mayr E.
      Cause and effect in biology.
      Evolutionists look for ancestral environments and selective pressures that determine disease vulnerability; traits that increase reproductive success at the cost of disease vulnerability (Table 1).
      • Nesse R.M.
      Maladaptation and natural selection.
      In his book, From Fish to Philosopher, Homer Smith argued that the complex structure of the kidney can be explained by a series of evolutionary adaptations in our vertebrate ancestors, who transitioned from marine to fresh water environments and ultimately to survival on land (Figure 2).
      • Smith H.W.
      From Fish to Philosopher.
      Written by the leading American renal physiologist of the mid-20th century, this book reveals how an evolutionary perspective explains the dependence of renal excretory function on filtration of 180 L of plasma per day and reclamation of 99% of the filtrate. Many of the early advances in renal physiology were based on animal studies that required an understanding of evolution to apply the results to human beings.
      • Gottschalk C.W.
      • Berliner R.W.
      • Giebisch G.H.
      Renal Physiology: People and Ideas.
      The context of the word “adaptation” has major consequences: physiologic adaptation (adaptive trait) is a homeostatic mechanism that responds to an immediate environmental stimulus, whereas evolutionary adaptation is the result of reproductive success that reflects natural selection (Table 1).
      • Bennett A.F.
      Adaptation and the evolution of physiological character.
      Quantitative analysis of the relationship between physiologic and evolutionary adaptation in hemoglobin oxygen saturation across 25 mammals under varying physiologic conditions demonstrates that the 2 forms of adaptation operate on different parameters so that the adaptive ranges can be maintained in new environments.
      • Milo R.
      • Hou J.H.
      • Springer M.
      • et al.
      The relationship between evolutionary and physiological variation in hemoglobin.
      This remarkable study reveals the relationship between homeostatic and evolutionary adaptation.
      Figure thumbnail gr2
      Figure 2The 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.
      Reproduced with permission from University Extension Division, University of Kansas from Smith HW. The evolution of the kidney. In: Studies in the Physiology of the Kidney. Lawrence, KS: University of Kansas; 1939 (subsequently reproduced as endpapers in Smith HW. From Fish to Philosopher. Boston, MA: Little, Brown and Company; 1953
      • Smith H.W.
      From Fish to Philosopher.
      ).

       Evolutionary Medicine

      Although evolutionary theory has traditionally been applied to studies of comparative anatomy and physiology, an evolutionary approach to disease continued to be largely neglected until a new discipline was developed in the 1990s by G.C. Williams and Randolph Nesse, now recognized as “evolutionary medicine” (Table 1).
      • Williams G.C.
      • Nesse R.M.
      The dawn of Darwinian medicine.
      • Nesse R.M.
      • Williams G.C.
      Evolution and Healing: The New Science of Darwinian Medicine.
      In 1957, Williams argued that natural selection of deleterious effects must be ascribed to other effects of the same genes.
      • Williams G.C.
      Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought.
      He reasoned that senescence can be explained by antagonistic pleiotropy, whereby a gene has a beneficial effect through reproductive age, but has detrimental effects afterward.
      • Williams G.C.
      Pleiotropy, natural selection, and the evolution of senescence.
      Antagonistic pleiotropy remains the basis for the evolutionary origin of senescence in all animals.
      • Gluckman P.
      • Beedle A.
      • Buklijas T.
      • Low F.
      • Hanson M.
      Principles of Evolutionary Medicine.
      However, additional factors may play a role in species with prolonged life after reproduction (only human beings and some whales have evolved menopause), but these remain to be elucidated.
      • Croft D.P.
      • Brent L.J.N.
      • Franks D.W.
      • et al.
      The evolution of prolonged life after reproduction.
      The core concept of Darwinian evolution, as proposed in The Origin of Species, first published in 1859, is the process of natural selection of inherited variations that increase an individual’s reproductive success.
      • Darwin C.
      • Costa J.A.
      The Annotated Origin: A Facsimile of the First Edition of On the Origin of Species.
      The primary challenge to the adoption of an evolutionary approach to disease rests on the practice of medicine itself: physicians are charged with the responsibility for diagnosing and treating a particular disorder in an individual patient, a process that appears far removed from evolutionary concerns. However, the history (present illness, past history, and family history) is the key component in diagnosis. Seeking concordance with established medical sciences (genetics, anatomy, physiology, biochemistry), evolutionary medicine relies on evolutionary biology to create a “deep” history of human populations. The rationale for the evolutionary perspective is that rather than causing disease, our evolutionary history determines our risk of disease in a given environment, a context that overlaps with public health, global health, and health care disparities. Thus, in addition to the current investigation of cellular and physiologic processes resulting from nephron injury, a complementary approach would include the study in defined populations of variation in genotype and phenotype, as well as its interaction with environmental factors from early nephrogenesis through senescence (life history). Coupled with advances in genomics, epigenetics, and developmental biology, the evolutionary perspective has already contributed significantly to understanding human health and disease (Table 2).
      • Gluckman P.D.
      • Low F.M.
      • Buklijas T.
      • et al.
      How evolutionary principles improve the understanding of human health and disease.
      Overuse of antibiotics in human beings and domestic animals has led to a global epidemic of microbial resistance resulting from rapid evolution of antibiotic resistance in bacteria through horizontal as well as vertical gene transfer.
      • Gluckman P.D.
      • Low F.M.
      • Buklijas T.
      • et al.
      How evolutionary principles improve the understanding of human health and disease.
      The recognition of lymphocyte clonal selection by Macfarlane Burnet was based on the application of evolutionary principles, leading more recently to the design of individualized chemotherapy to suppress the emergence of mutant clones of malignant cells.
      • Alvarado A.S.
      Cellular hyperproliferation and cancer as evolutionary variables.
      Table 2Evolutionary explanations for medical questions: application to nephrology
      QuestionEvolutionary explanation
      Examples of successful application of evolutionary medicineWhat drives antibiotic resistance in microorganisms?Rapid evolution with exchange of genetic information stimulated by the host environment
      What explains the diversity of antibodies in the immune response?Adaptive immunity results from clonal selection of lymphocytes by a process analogous to natural selection
      What accounts for the development of resistance to cancer chemotherapy?As for antibiotic resistance and adaptive immunity, selection of malignant mutant clones can be prevented by application of evolutionary principles to the design of chemotherapy
      Application of evolutionary medicine to nephrologyWhat accounts for vulnerability of the kidney to injury in AKI?Kidney evolution through transition from marine to freshwater environment to land necessitated high GFR with energy-consuming tubular sodium reclamation in a hypoxic, hyperosmolar microenvironment subject to ischemia
      What accounts for maladaptation in CKD (nephron loss through cell death with interstitial fibrosis)?Nephron loss→ hypertrophy of remaining nephrons→ increased energy consumption that cannot be maintained→ tubular cell death and formation of atubular glomeruli, a response shared with certain marine fish as they mature
      AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate.
      In the 2 decades since Nesse and Williams published their landmark book, Evolution and Healing: The New Science of Darwinian Medicine,
      • Nesse R.M.
      • Williams G.C.
      Evolution and Healing: The New Science of Darwinian Medicine.
      a number of additional texts have been published, greatly expanding the scope of evolutionary medicine, but none of which includes more than cursory references to kidney disease.
      • Gluckman P.
      • Beedle A.
      • Buklijas T.
      • Low F.
      • Hanson M.
      Principles of Evolutionary Medicine.
      • Stearns S.C.
      Evolution in Health and Disease.
      • Trevathan W.R.
      • Smith E.O.
      • McKenna J.J.
      Evolutionary Medicine and Health. New Perspectives.
      • Perlman R.L.
      Evolution and Medicine.
      • Lieberman D.E.
      The Story of the Human Body. Evolution, Health and Disease.
      • Taylor J.
      Body by Darwin. How Evolution Shapes Our Health and Transforms Medicine.
      • Alvergne A.
      • Jenkinson C.
      • Faurie C.
      Evolutionary Thinking in Medicine. From Research to Policy and Practice.
      • Stearns S.C.
      • Medzhitov R.
      Evolutionary Medicine.
      An Arthur M. Sackler Colloquium of the National Academy of Sciences, “Evolution in Health and Medicine,” was held in Washington in 2009,

      Omenn GS. Evolution in health and medicine. Available at: www.nasonline.org/Sackler_Evolution_Health_Medicine/. Accessed February 22, 2017.

      and a major policy paper was published in the journal Proceedings of the National Academy of Sciences, emphasizing the importance of including evolutionary biology in the basic science curriculum of medical schools.
      • Nesse R.M.
      • Bergstrom C.T.
      • Ellison P.T.
      • et al.
      Making evolutionary biology a basic science for medicine.
      Subsequently, in collaboration with the Biological Sciences Curriculum Studies (BSCS), the National Institutes of Health published a comprehensive curriculum for American high school teachers entitled Evolution and Medicine.
      • Pennisi E.
      Darwinian medicine's drawn-out dawn.
      • Fuchs B.A.
      The authors propose that “evolution’s greatest benefits will be to provide a theoretical framework for understanding the following: (i) why organisms are vulnerable to disease; (ii) how infectious agents evolve; and (iii) how common ancestry helps scientists use the results from animal models to understand issues related to human health.”
      • Fuchs B.A.
      As is the case for the published textbooks, the medical disciplines included in the NIH curriculum do not include kidney disease.
      • Fuchs B.A.
      To fill this gap, the present review seeks to present the case for an evolutionary perspective to enhance our understanding of progressive kidney disease, by explaining why the kidney is vulnerable to maladaptive nephron loss. The noted philosopher of science Karl Popper was initially critical of evolutionary theory, because he believed that it could not be tested.
      • Popper K.
      Unended Quest: an Intellectual Autobiography.
      However, he subsequently concluded, “I have changed my mind about the testability and the logical status of the theory of natural selection; and I am glad to have an opportunity to make a recantation. … What is important is to realize the explanatory task of natural selection.”
      • Popper K.
      Natural selection and the emergence of mind.

       Life History, Tradeoff, and Mismatch

      On one hand, species have evolved different life histories as a consequence of living in different environments. On the other hand, individual species have evolved flexible life histories and so are able to respond physiologically to life in different environments (Tables 1 and 3).
      • Fisher R.A.
      The Genetical Theory of Natural Selection.
      • Stearns S.C.
      The Evolution of Life Histories.
      This explains the remarkable diversity of body plans, number and size of offspring, rates of growth and maturation, life span, and senescence. The life history for human beings entails the production of few offspring, with a prolonged period of maturation to sexual maturity, followed by a long period of senescence. Mortality rate follows a “V” curve, explained by high fetal/infant mortality, with a nadir at 12 years, and a steady increase after peak reproductive years (Figure 3a).
      • Costa T.
      • Scriver C.R.
      • Childs B.
      The effect of Mendelian disease on human health: a measurement.
      The majority of early fetal death (spontaneous abortion) is shaped by natural selection of lethal chromosomal abnormalities (Table 3). Higher mortality for males than for females (Figure 3a) has been regarded as a maladaptation, but may result from sex-specific optimization of a tradeoff between reproduction and survival.
      • Maklakov A.A.
      • Lummaa V.
      Evolution of sex differences in lifespan and aging: causes and controversies.
      Regarding risk factors for CKD, the V-curve can be separated into 2 overlapping curves, the first reflecting a predominance of genetic/epigenetic risk factors associated with CAKUT and determined largely by natural selection, and the second reflecting primarily environmental factors, leading to diabetes and hypertension (Figure 3b).
      • Childs B.
      Acceptance of the Howland Award.
      Notably, for most children with CAKUT progressing to ESKD, renal replacement therapy is delayed until adulthood.
      • Wuhl E.
      • van Stralen K.J.
      • Verrina E.
      • et al.
      Timing and outcome of renal replacement therapy in patients with congenital malformations of the kidney and urinary tract.
      New genomic analysis reveals an expanding number of mutations that account for CAKUT,
      • Vivante A.
      • Kohl D.
      • Hwang D.Y.
      • et al.
      Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans.

      Vivante A, Hwang DY, Kohl S, et al. Exome sequencing discerns syndromes in patient from consanguineous families with congenital anomalies of the kidneys and urinary tract. J Am Soc Nephrol., In press.

      and epigenetic mechanisms may be of even greater importance.
      • Hilliard S.A.
      • El-Dahr S.S.
      Epigenetic mechanisms in renal development.
      The lifetime risk for developing ESKD remains below 1% throughout the reproductive years, then increases markedly, with greater rates in males than in females and in black than in white race/ethnicity (Figure 3c).

      USRDS. United States Renal Data System. 2015 USRDS annual data report: Epidemiology of kidney disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2015.

      This can be explained by the dominance of natural selection through reproductive years, and its decrease in the postreproductive period, characterized by senescence and cumulative environmental insults (Fig. 3B). A greater increase in males than in females may be explained in part by estrogen receptor modulation of mitochondrial oxidative status and ovulatory cycle−dependent metabolic responses by proximal tubular cells.
      • Nishi Y.
      • Satoh M.
      • Nagasu H.
      • et al.
      Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative stress.
      • Seppi T.
      • Prajczer S.
      • Dorler M.M.
      • et al.
      Sex differences in renal proximal tubular cell homeostasis.
      The relevance of evolutionary principles to understanding the racial disparity in CKD has been recently underscored by the discovery of increased risk for CKD in populations of West African ancestry with APOL1 mutations (Table 4).
      • Genovese G.
      • Friedman D.J.
      • Ross M.D.
      • et al.
      Association of tyrpanolotic ApoL1 variants with kidney disease in African Americans.
      This is the result of adaptive selection of the heterozygous state that confers protection from infection with Trypanosoma brucei rhodesiense, but homozygosity markedly increases susceptibility to glomerular injury and progressive CKD, a classic tradeoff.
      • Kruzel-Davila E.
      • Wasser W.G.
      • Aviram S.
      • et al.
      APOL1 nephropathy: from gene to mechanisms of kidney injury.
      Similar tradeoffs have been established for malaria (hemoglobinopathies and G6PD deficiency) and tuberculosis (cystic fibrosis).
      • Gluckman P.
      • Beedle A.
      • Buklijas T.
      • Low F.
      • Hanson M.
      Principles of Evolutionary Medicine.
      The discovery of the association of APOL1 mutation with risk of CKD resulted from combining genome analysis with the geographic distribution of mutations, revealing its protective role in trypanosome infection and its prevalence to the present. This suggests a model for future studies of polymorphisms that increase risk of CKD driven by ancestors’ exposure to microbes or parasites.
      Table 3Life history in epidemiology and pathogenesis of chronic kidney disease (CKD)
      QuestionEvolutionary explanation
      EpidemiologyWhy are congenital anomalies of the kidney and urinary tract the leading cause of CKD, but CKD is rare in childhood?Mutations and intrauterine environmental stress alter normal renal development. Natural selection reduces the incidence of severe malformations (lethal mutations)
      How does variability in nephron number at birth contribute to adult CKD (developmental programming)?Intrauterine stress impairs fetal and neonatal renal growth, an adaptation to restricted energy supplies, favoring early infant survival, but the tradeoff is reduced nephron number; additional nephrons can be formed in utero, but not after birth
      Why are diabetes and cardiovascular disease the leading causes of adult CKD?The Western diet (developed only 10,000 years ago), high in fat and sodium, is mismatched to the Pleistocene diet of 100,000 years ago
      Nephron heterogeneity and selectionHow does mammalian nephron heterogeneity account for selective nephron vulnerability in progression of CKD?Nephron heterogeneity evolved in adapting to life on land (enhanced urine concentration and sodium conservation); the tradeoff: short-loop nephrons are more susceptible to hypoxia and ischemia
      Why is there a 50% reduction in nephron number during adulthood?Accumulated stresses and insults combined with senescence (decreased energy available for repair) lead to continued nephron selection through cycles of hypertrophy →atrophy unresponsive to natural selection in postreproductive period; this is accompanied by an interstitial inflammatory response and leads to interstitial fibrosis
      Figure thumbnail gr3
      Figure 3Relationship 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.
      • Costa T.
      • Scriver C.R.
      • Childs B.
      The effect of Mendelian disease on human health: a measurement.
      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.
      • Childs B.
      Acceptance of the Howland Award.
      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.
      Reprinted with permission of Elsevier from Grams ME, Chow EKH, Segev DL, et al. Lifetime incidence of CKD Stages 3−5 in the United States. Am J Kidney Dis. 2013;62:245−252.
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • et al.
      Lifetime incidence of CKD stages 3–5 in the United States.
      Copyright © National Kidney Foundation, Inc. Colored box indicates peak reproductive years.
      Table 4Evolutionary explanations for physiologic maladapatation in kidney disease
      CKD, chronic kidney disease; FSGS, focal segmental glomerulosclerosis.
      ,
      • Nesse R.M.
      Maladaptation and natural selection.
      Evolutionary explanationNatural selectionFactors that increase susceptibility to CKD
      TradeoffSelection is determined by reproductive fitness, not by long-term healthAPOL1 mutation increases resistance to trypanosome infection but→FSGS
      • Genovese G.
      • Friedman D.J.
      • Ross M.D.
      • et al.
      Association of tyrpanolotic ApoL1 variants with kidney disease in African Americans.


      CKD bears similarities to senescence, and accelerates after reproductive peak
      • Whitfield J.
      In the Beat of a Heart. Life, Energy, and the Unity of Nature.
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • et al.
      Lifetime incidence of CKD stages 3–5 in the United States.
      • Zurbig P.
      • Decramer S.
      • Dakna M.
      • et al.
      The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease.
      • Kiberd B.
      The chronic kidney disease epidemic: Stepping back and looking forward.
      Selection cannot solve some problems irrespective of timeAdaptation to land required energy-consuming proximal tubule susceptible to injury
      • Smith H.W.
      From Fish to Philosopher.
      • Cohen J.J.
      Relationship between energy requirements for Na+ reabsorption and other renal functions.


      Glomerulotubular disconnection→energy conservation in fish and CKD
      • Chevalier R.L.
      • Forbes M.S.
      Generation and evolution of atubular glomeruli in the progression of renal disorders.
      • Grafflin A.L.
      Glomerular degeneration in the kidney of the daddy sculpin (Myoxocephalus scorpius).


      Homeothermic physiology imposes regenerative constraints on nephrons
      • Reichman O.J.
      Evolution of regeneration capabilities.
      • Romagnani P.
      • Remuzzi G.
      Renal progenitors: an evolutionary conserved strategy for kidney regeneration.
      Mismatch of phenotype to environmentSelection cannot keep pace with rapid environmental changeLow nephron number in growth-restricted fetus
      • Luyckx V.A.
      • Bertram J.F.
      • Brenner B.M.
      • et al.
      Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease.
      and preterm infant
      • Rodriguez M.M.
      • Gomez A.H.
      • Abitbol C.L.
      • et al.
      Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants.


      Hyperfiltration response to Western diet
      • Odermatt A.
      The western-style diet: a major risk factor for impaired kidney function and chronic kidney disease.
      a CKD, chronic kidney disease; FSGS, focal segmental glomerulosclerosis.
      The development of agriculture about 10,000 years ago led to a decline in potassium intake and a marked increase in sodium intake, major risk factors for the development of hypertension.
      • Ungar P.S.
      Evolution of the Human Diet: The Known, the Unknown, and the Unknowable.
      This has been compounded by a modern western diet that leads to excessive formation of uric acid that contributes to metabolic syndrome
      • Johnson R.J.
      • Sautin Y.Y.
      • Oliver W.J.
      • et al.
      Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?.
      and that yields a daily net acid load of 50 mEq, leading to low-grade metabolic acidosis that worsens as a consequence of age-related nephron loss: a case of environmental mismatch (Tables 3 and 4).
      • Ungar P.S.
      Evolution of the Human Diet: The Known, the Unknown, and the Unknowable.
      • Sebastian A.
      • Frassetto L.A.
      • Sellmeyer D.E.
      • et al.
      Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors.
      • Odermatt A.
      The western-style diet: a major risk factor for impaired kidney function and chronic kidney disease.

       Evolutionary Physiology: Mismatch Explained

      The number of nephrons in man is fixed at birth, with completion of nephrogenesis by the 36th week of gestation, and nephron number ranging more than 10-fold, from 200,000 to 2,700,000 (Figure 4a).
      • Bertram J.F.
      • Douglas-Denton R.N.
      • Diouf B.
      • et al.
      Human nephron number: implications for health and disease.
      • Chevalier R.L.
      • Charlton J.R.
      The human kidney at birth: structure and function in transition.
      • Hughson M.D.
      • Farris A.B.
      • Douglas-Denton R.
      • et al.
      Glomerular number and size in autopsy kidneys: the relationship to birth weight.
      This should not be surprising, as our species is characterized by wide variation in our metabolic and anatomic parameters (phenotypic plasticity). The hyperfiltration theory would predict that nephron number below the median represents a risk factor for CKD.
      • Brenner B.M.
      • Garcia D.L.
      • Anderson S.
      Glomeruli and blood pressure. Less of one, more of the other?.
      This appears to be the case. In the 1980s, David Barker, an epidemiologist, reported that adults dying of cardiovascular disease have significantly lower birth weight than the median, and follow-up studies revealed an increased incidence of hypertension and cardiovascular disease in individuals with lower nephron numbers.
      • Barker D.J.P.
      • Osmond C.
      Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.
      • Barker D.J.P.
      The origins of the developmental origins theory.
      Barker’s insight into the significance of fetal and perinatal impact on the entire life cycle spawned an entire new discipline: developmental programming of health and disease (Tables 13, and 4).
      • Luyckx V.A.
      • Bertram J.F.
      • Brenner B.M.
      • et al.
      Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease.
      • Gluckman P.D.
      • Hanson M.A.
      Developmental origins of disease paradigm: a mechanistic and evolutionary perspective.
      Formation of a reduced number of nephrons by fetuses in an unfavorable maternal environment can be explained by investing in fewer energy-consuming nephrons, favoring early reproductive success over a predicted short life span.
      • Whitfield J.
      In the Beat of a Heart. Life, Energy, and the Unity of Nature.
      If, on the other hand, the infant is born into a rich nutritional environment, there will be a mismatch between a low nephron number and the resultant hyperfiltration, leading to CKD, physiologic maladaptation (Tables 1, 3, and 4).
      • Odermatt A.
      The western-style diet: a major risk factor for impaired kidney function and chronic kidney disease.
      • Gluckman P.D.
      • Hanson M.A.
      • Cooper C.
      • et al.
      Effect of in utero and early-life conditions on adult health and disease.
      Figure thumbnail gr4
      Figure 4The 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.
      • Hughson M.D.
      • Farris A.B.
      • Douglas-Denton R.
      • et al.
      Glomerular number and size in autopsy kidneys: the relationship to birth weight.
      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.
      • Tan J.C.
      • Workeneh B.
      • Busque S.
      • et al.
      Glomerular function, structure, and number in renal allografts from older deceased donors.
      Copyright © American Society of Nephrology. (c) Percentage of sclerotic glomeruli from 122 autopsied patients plotted against age.
      Reprinted with permission from Elsevier from Kaplan C, Pasternack B, Shah H, et al. Age-related incidence of sclerotic glomeruli in human kidneys. Am J Pathol. 1975;80:227−234.
      • Kaplan C.
      • Pasternack B.
      • Shah H.
      • Gallo G.
      Age-related incidence of sclerotic glomeruli in human kidneys.
      Copyright © American Society for Investigative Pathology.
      Garland and Carter have proposed a discipline entitled “evolutionary physiology” (Table 1).
      • Garland Jr., T.
      • Carter P.A.
      Evolutionary physiology.
      Applying these principles to the nephron, gene polymorphisms, and environmental stimuli/stressors during development determine its phenotypic characteristics, including nephron number (Figure 5). Modulated by epigenetics, homeostatic function of the nephron is determined by its performance capacity and limited by its defenses against cell death and capacity for hypertrophy, proliferation, and repair (Figure 5). Maximal tubular size is limited by luminal diameter and tubular length that optimize reabsorption while minimizing resistance to tubular fluid flow. Thus, physical factors constrain adaptation by hypertrophy alone. In the whale, the kidney is multi-renculated, effectively packaging 30,000 nephrons in each of 7,000 discrete capsules joined to a common collecting system (approximately 200 million nephrons on either side).
      • Oliver J.
      Nephrons and Kidneys: a Quantitative Study of Developmental and Evolutionary Mammalian Renal Architectonics.
      In addition to effects on early development, environmental factors can have an impact on homeostatic responses to injury that are activated by AKI and CKD. The accelerating change in global climate with increasing water shortage is testing the limits of the performance capacity of renal sodium and water conservation, leading to new epidemics of CKD attributable to this mismatch.
      • Johnson R.J.
      • Stenvinkel P.
      • Jensen T.
      • et al.
      Metabolic and kidney diseases in the setting of climate change, water shortage, and survival factors.
      Figure thumbnail gr5
      Figure 5Relationship 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.
      Adapted with permission from the American Physiological Society, Annual Reviews, Inc., from Garland T Jr, Carter PA. Evolutionary physiology. Annu Rev Physiol. 1994;56:579−621.
      • Garland Jr., T.
      • Carter P.A.
      Evolutionary physiology.
      Copyright © Annual Reviews Inc.

       Plasticity Versus Robustness: A Necessary Tradeoff

      The relatively new discipline of evolutionary developmental biology (“evo-devo”) fosters comparison of embryonic development to the response to injury across phylogeny (Table 1).
      • Gould S.J.
      Ontogeny and Phylogeny.
      • Gilbert S.F.
      The morphogenesis of evolutionary developmental biology.
      • Sommer R.J.
      The future of evo-devo: model systems and evolutionary theory.
      This involves the study of phenotypic variation resulting from mutations of regulatory genes, thereby establishing the evolutionary history of developmental programs.
      • Gilbert S.F.
      The morphogenesis of evolutionary developmental biology.
      Patrick Bateson and Peter Gluckman have summarized a useful concept to elucidate the maladaptation paradox: the tension between plasticity and robustness (Table 5).
      • Bateson P.
      • Gluckman P.
      Plasticity, Robustness, Development and Evolution.
      Drawing on evo-devo, the case is made for the importance of robustness of developmental regulatory mechanisms, to buffer this critical early phase of life from environmental or genetic perturbation.
      • Bateson P.
      • Gluckman P.
      Plasticity, Robustness, Development and Evolution.
      Homeostatic feedback loops and mechanisms of repair and regeneration are regarded as robust, with responses that are determined by evolutionary history. Thus, injury can result either in the formation of blastema (limb or tail regeneration in reptiles and amphibians) or fibrosis (in mammals). The robustness bestowed by homeothermy in mammals reduced liability to kidney injury below the threshold needed to preserve energy-consuming regrowth, a tradeoff (Table 4).
      • Goss R.J.
      The evolution of regeneration: adaptive or inherent?.
      In the course of evolution, mammals have developed sophisticated pathways of wound healing that, by blocking formation of blastema, can actually inhibit energy-consuming regeneration (Table 5).
      • Reichman O.J.
      Evolution of regeneration capabilities.
      • Romagnani P.
      • Remuzzi G.
      Renal progenitors: an evolutionary conserved strategy for kidney regeneration.
      Mammalian physiologic adaptation to acute tissue injury reduces hemorrhage and infection by activating inflammatory and fibrotic responses—these are shared by AKI. However, the response to persistent nephron injury (tubular atrophy and interstitial fibrosis) leads to CKD.
      Table 5Evolutionary tension: tradeoff between plasticity and robustness
      • Bennett A.F.
      Adaptation and the evolution of physiological character.
      • Bateson P.
      • Gluckman P.
      Plasticity, Robustness, Development and Evolution.
      PlasticityRobustness
      Adaptive: accommodates to disruptions of development, often in response to environmental cuesBuffers plasticity: maintains phenotypic consistency despite environmental perturbations
      Late development—adultEarly development—embryo
      Must outweigh cost of disadvantageous phenotypeMaintained by repair/regeneration
      Must deal with responses to ambiguous cuesPromotes increased fitness but may result in physiologic maladaptation
      The complementary process, plasticity, accommodates disruptions of normal development caused by mutation, toxins, or accident, and are regulated by epigenetic processes, such as reduced nephron number in the growth-restricted fetus (Tables 3, 4, and 5). Although mammals cannot form additional nephrons after the completion of nephrogenesis, unilateral nephrectomy in fetal lambs or pigs results in a 45% to 50% increase in nephron number of the remaining kidney, a testament to the importance of the stage of life history in the regenerative response to renal injury.
      • Douglas-Denton R.
      • Moritz K.M.
      • Bertram J.F.
      • et al.
      Compensatory renal growth after unilateral nephrectomy in the ovine fetus.
      • van Vuuren S.H.
      • Sol C.M.
      • Borekhuizen R.
      • et al.
      Compensatory growth of congenital solitary kidneys in pigs reflects increased nephron numbers rather than hypertrophy.
      Protection from infection and injury provided by the intrauterine environment is likely to play a role in this adaptive response: preterm birth in human infants results in impaired nephrogenesis in the very−low-birth-weight neonate.
      • Rodriguez M.M.
      • Gomez A.H.
      • Abitbol C.L.
      • et al.
      Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants.
      • Gubhaju L.
      • Sutherland M.R.
      • Yoder B.A.
      • et al.
      Is nephrogenesis affected by preterm birth? Studies in a non-human primate model.
      Urine of preterm neonates born before the completion of nephrogenesis is rich in progenitor cells, which apparently fail to differentiate in the extrauterine environment.
      • Arcolino F.O.
      • Zia S.
      • Held K.
      • et al.
      Urine of preterm neonates as a novel source of kidney progenitor cells.
      There is a tradeoff between the number of progenitor cells in maturing tissues required for maintenance and repair: their persistence beyond reproductive years increases the risk of malignancy.
      • Alvarado A.S.
      Cellular hyperproliferation and cancer as evolutionary variables.
      Notably, reduced nephron number in preterm infants increases lifetime risk for the development of CKD.
      • Carmody J.B.
      • Charlton J.R.
      Short-term gestation, long-term risk: prematurity and chronic kidney disease.

       Conservation of Energy: Tradeoff Explained

      The kidney constitutes 1% of body weight but uses 10% of total body oxygen consumption, primarily devoted to proximal tubular sodium reabsorption.
      • Cohen J.J.
      Relationship between energy requirements for Na+ reabsorption and other renal functions.
      As pointed out by Homer Smith, the necessity for reabsorption of 180 L of glomerular filtrate per day is the result of our evolutionary heritage.
      • Smith H.W.
      From Fish to Philosopher.
      Transition from a marine to freshwater environment gave rise to a high filtering glomerulus that was necessary to counteract the osmotic gradient, but adaptation to land and homeothermy necessitated reclamation of 99% of the filtrate, leading to a large energy requirement (Fig. 2).
      • Smith H.W.
      From Fish to Philosopher.
      • Cohen J.J.
      Relationship between energy requirements for Na+ reabsorption and other renal functions.
      A diet rich in meat such as that consumed by our Pleistocene ancestors would have provided the selection pressure to maintain a high glomerular filtration rate, necessary to excrete urea produced by protein metabolism.
      • Brenner B.M.
      • Meyer T.W.
      • Hostetter T.H.
      Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease.
      There is growing evidence that energy is the unifying principle of life (comprising evolution, ecology, allometry, and metabolism).
      • Whitfield J.
      In the Beat of a Heart. Life, Energy, and the Unity of Nature.
      Life history strategies are driven by the balance between acquisition and allocation of energy.
      • Perlman R.L.
      Evolution and Medicine.
      Natural selection favors a species’ successful investment strategy, exchanging energy for offspring: a fundamental tradeoff (Table 4).
      • Whitfield J.
      In the Beat of a Heart. Life, Energy, and the Unity of Nature.
      Growth slows with attainment of reproductive age, because energy resources are increasingly spent on maintenance, rather than expansion (Table 4). Throughout the reproductive years, energy is allocated to maintenance of nephron integrity in the face of constant threats of hypoxia and oxidative stress, but this selection pressure is reduced after 20 years (Figure 3b), reflected by the sharp rise in ESKD in later adulthood (Tables 3 and 4, Figure 3c).
      • Grams M.E.
      • Chow E.K.H.
      • Segev D.L.
      • et al.
      Lifetime incidence of CKD stages 3–5 in the United States.
      Life expectancy for our Paleolithic ancestors who survived infancy was approximately 35 to 40 years, and this changed little until the industrial revolution in the past 200 years, during which life expectancy doubled.
      • Gluckman P.
      • Beedle A.
      • Buklijas T.
      • Low F.
      • Hanson M.
      Principles of Evolutionary Medicine.
      A mathematical model has been developed to describe the relationship among growth, maintenance, and reproduction in the determination of fitness, the Euler−Lotka formula.
      • Stearns S.C.
      • Medzhitov R.
      Evolutionary Medicine.
      This reveals that the influence of natural selection begins to decline in women by approximately 20 years of age.
      • Gluckman P.
      • Beedle A.
      • Buklijas T.
      • Low F.
      • Hanson M.
      Principles of Evolutionary Medicine.
      The comorbidities associated with senescence of other organs (dementia, cardiovascular disease, diabetes, cancer) compound the management of CKD, and share common mechanisms involving oxidative injury and inflammation.
      • Finch C.E.
      The Biology of Human Longevity. Inflammation, Nutrition, and Aging in the Evolution of Lifespans.
      Following renal ablation, oxygen consumption by the remaining hypertrophied nephrons initially doubles.
      • Nath K.A.
      • Croatt A.J.
      • Hostetter T.H.
      Oxygen consumption and oxidant stress in surviving nephrons.
      However, consistent with evolutionary conservation of energy, persistent upregulation of oxygen consumption by hypertrophied proximal tubules is not sustainable, thereby contributing to aging or the progression of CKD (Tables 2 and 3). Prolonged renal artery stenosis in the rat treated with an angiotensin-converting enzyme inhibitor results in atrophic tubules and 90% reduction in Na-K-ATPase activity, which is reversible within 3 weeks following removal of the clip and discontinuation of angiotensin inhibition.
      • Grone H.-J.
      • Helmchen U.
      Impairment and recovery of the clipped kidney in two kidney, one clip hypertensive rats during and after antihypertensive therapy.
      • Grone H.-J.
      • Warnecke E.
      • Olbricht C.J.
      Characteristics of renal tubular atrophy in experimental renovascular hypertension: a model of kidney hibernation.
      However, patients with severe chronic renal artery stenosis undergo widespread irreversible tubular atrophy and formation of atubular glomeruli.
      • Marcussen N.
      Atubular glomeruli in renal artery stenosis.
      These observations indicate that short-term tubular energy consumption increases in parallel with hyperfiltration and increased tubular reabsorption (physiologic adaptation), but that prolonged renal ischemia reduces energy consumption, a response that can be reversed in mild but not severe injury (evolutionary adaptation).
      The model of complete unilateral ureteral obstruction (UUO), currently the most widely used animal model of CKD,
      • Chevalier R.L.
      The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.
      • Chevalier R.L.
      • Forbes M.S.
      • Thornhill B.A.
      Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy.
      results in profound reduction in tubular energy consumption, followed within 2 weeks by proximal tubule cell death and widespread formation of atubular glomeruli.
      • MacLellan D.L.
      • Mataija D.
      • Doucette A.
      • et al.
      Alterations in urinary metabolites due to unilateral ureteral obstruction in a rodent model.
      • Forbes M.S.
      • Thornhill B.A.
      • Chevalier R.L.
      Proximal tubular injury and rapid formation of atubular glomeruli in mice with unilateral ureteral obstruction: a new look at an old model.
      Formation of atubular glomeruli in CKD may represent an atavism that harks back to a common ancestor with fish that were faced with adaptation from freshwater back to saltwater. The daddy sculpin (a marine fish) belongs to 1 of these groups, and, with increasing age, nephrons undergo progressive degeneration of the glomerulotubular junction, resulting in atubular glomeruli and aglomerular tubules (Table 2).
      • Grafflin A.L.
      Glomerular degeneration in the kidney of the daddy sculpin (Myoxocephalus scorpius).
      When viewed from an evolutionary perspective, the physiologically maladaptive response to hypoxic and oxidative stress resulting from complete UUO emerges as a tradeoff to suppress a major source of energy loss in a nonfunctioning organ that no longer enhances fitness. Studies of gene activation responsible for glomerulotubular disconnection in the sculpin may reveal similar gene regulatory networks leading to proximal tubular cell death and formation of atubular glomeruli in CKD (Table 6).
      Table 6Future research guided by evolutionary nephrology
      1By combining physiologic and genomic techniques across large sample sizes of many species’ life histories, application of systems biology could provide new evolutionary insight into maladaptation in CKD
      2The study in defined human populations from early nephrogenesis through senescence of variation in genotype and phenotype, coupled with its interaction with environmental factors, is likely to reveal age-specific mechanisms of renal injury and repair
      3The search for factors responsible for selection (survival or death) of individual cells or nephrons in the microenvironment of the injured kidney may lead to new biomarkers or therapies for progressive CKD
      4Studies of gene activation responsible for glomerulotubular disconnection in the sculpin (a marine fish) may reveal similar gene regulatory networks leading to proximal tubular cell death and formation of atubular glomeruli in CKD
      5Because additional nephrons are generated in fetal mammals subjected to renal ablation, experimental manipulation of the critical period of late nephrogenesis may lead to new approaches to increase nephron number in the developing kidney
      CKD, chronic kidney disease.
      The pattern of short-term successful adaptation to renal injury but long-term maladaptation with progression to CKD shares many characteristics with those of chronic inflammatory systemic diseases, such as rheumatoid arthritis and diabetes.
      • Straub R.H.
      • Schradin C.
      Chronic inflammatory systemic diseases—an evolutionary trade-off between acutely beneficial but chronically harmful programs.
      The common evolutionary basis for these disorders resides in an adaptive commitment of energy (inflammatory response) to suppress infection or to repair acute injury, but which can only be sustained through the reproductive period of the life cycle, after which progression accelerates and fitness is reduced.
      • Straub R.H.
      • Schradin C.
      Chronic inflammatory systemic diseases—an evolutionary trade-off between acutely beneficial but chronically harmful programs.
      Derived from the ancestral innate immune response, the gene regulatory networks that are activated in the acute phase of chronic inflammatory systemic diseases were likely selected in response to prevalent infectious diseases.
      • Straub R.H.
      • Schradin C.
      Chronic inflammatory systemic diseases—an evolutionary trade-off between acutely beneficial but chronically harmful programs.
      Genome-wide association studies were used to test the hypothesis that selection simultaneously increased fitness and susceptibility to complex disease. Results showed a predominance of alleles increasing susceptibility to type 1 diabetes and rheumatoid arthritis, consistent with the hypothesis.
      • Corona E.
      • Dudley J.T.
      • Butte A.J.
      Extreme evolutionary disparities seen in positive selection across seven complex diseases.

       Nephron Heterogeneity From Birth Through Senescence

      There is marked internephron heterogeneity in the developing kidney, with over 50% of nephrons forming after ureteral epithelial branching has ceased.
      • Short K.M.
      • Combes A.N.
      • Lefevre J.
      • et al.
      Global quantification of tissue dynamics in the developing mouse kidney.
      Nephron heterogeneity contributes to a number of vital functions of the mature mammalian kidney, including the regulation of sodium, water, phosphate, and osmolar balance, and is linked to variations in vascular and neural connections as well as to variations in nephron size and length.
      • Walker L.A.
      • Valtin H.
      Biological importance of nephron heterogeneity.
      • Bankir L.
      • Bouby N.
      • Trinh-Trang-Tan M.-M.
      Heterogeneity of nephron anatomy.
      In mammals, long-loop thin descending limbs of nephrons are highly permeable to sodium, whereas short loops are highly permeable to urea,
      • Imai M.
      • Hayashi M.
      • Araki M.
      Functional heterogeneity of the descending limbs of Henle's loop. 1. Internephron heterogeneity in the hamster kidney.
      thereby enhancing urine concentration.
      • Bankir L.
      • Bouby N.
      • Trinh-Trang-Tan M.-M.
      Heterogeneity of nephron anatomy.
      The tradeoff: short-loop nephrons are more susceptible to hypoxia and ischemia than long-loop nephrons because the latter have a more robust vascular supply (Table 3).
      • Bankir L.
      • Bouby N.
      • Trinh-Trang-Tan M.-M.
      Heterogeneity of nephron anatomy.
      There is a 50% reduction in nephron number in cadaveric renal transplant donors older than 55 years compared to those younger than 40 years (Figure 4b),
      • Tan J.C.
      • Workeneh B.
      • Busque S.
      • et al.
      Glomerular function, structure, and number in renal allografts from older deceased donors.
      and this is correlated with a marked increase in the fraction of sclerotic glomeruli in the normal population beyond reproductive age (Figure 4c).
      • Kaplan C.
      • Pasternack B.
      • Shah H.
      • Gallo G.
      Age-related incidence of sclerotic glomeruli in human kidneys.
      In healthy kidney transplant donors, hyperfiltration and mild albuminuria are associated with hypertrophied nephrons, whereas hypertension and older age are associated with glomerulosclerosis (Figure 6).
      • Elsherbiny H.E.
      • Alexander M.P.
      • Kremers W.K.
      • et al.
      Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors.
      Nephron loss with aging appears to result from atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons.
      • Denic A.
      • Lieske J.C.
      • Chakkera H.A.
      • et al.
      The substantial loss of nephrons in healthy human kidneys with aging.
      Nephron hypertrophy may result from either lower congenital nephron endowment or from metabolic risk factors later in life, highlighting the importance of both developmental plasticity and lifestyle environmental factors superimposed on senescence (Table 3) (Figure 6).
      • Elsherbiny H.E.
      • Alexander M.P.
      • Kremers W.K.
      • et al.
      Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors.
      Of note, albuminuria is associated with increasing parenchymal volume in apparently healthy adults, suggesting hypertrophy in hyperfiltering nephrons.
      • Wang X.
      • Vrtiska T.J.
      • Avula R.T.
      • et al.
      Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney.
      Figure thumbnail gr6
      Figure 6The 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.
      Reproduced with permission from the American Society of Nephrology from Elsherbiny HE, Alexander MP, Kremers WK, et al. Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors. Clin J Am Soc Nephrol. 2014;9:1892−1902.
      • Elsherbiny H.E.
      • Alexander M.P.
      • Kremers W.K.
      • et al.
      Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors.
      Copyright © American Society of Nephrology.

       AKI and CKD as Accelerated Senescence: Nephron Selection

      These considerations provide strong support for better understanding the biology of senescence
      • Baudisch A.
      • Vaupel J.W.
      Getting at the root of aging.
      • Rodwell G.E.
      • Sonu R.
      • Zahn J.M.
      • et al.
      A transcriptional profile of aging in the human kidney.
      : a high concordance between the human urinary proteome for the normal aging population and patients with CKD suggests common mechanisms.
      • Zurbig P.
      • Decramer S.
      • Dakna M.
      • et al.
      The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease.
      Aging as a risk factor for disease reflects evolutionarily conserved pathways selected for early in life, but decreasing selection pressure later in life (Figure 3b).
      • Niccoli T.
      • Partridge L.
      Ageing as a risk factor for disease.
      Following AKI, injured proximal tubular cells can either undergo proliferation or G2/M cell cycle arrest—a fate that can lead to senescence in the case of multiple episodes of AKI progressing to CKD.
      • Bonventre J.V.
      Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis.
      This raises a key unanswered question: what are the factors determining the survival or death of individual nephrons (the fate depicted in Figure 1)? Similar to animal or human populations, the population of nephrons in the patient with CKD may behave as an ecosystem within an environmental landscape contained in the renal capsule. The selection process (for survival or death of nephrons) then becomes a function of the microenvironment and epigenetic variation among nephrons (Table 3). Of particular relevance to the role of microenvironment in CKD, tumor necrosis factor−related weak inducer of apoptosis (TWEAK, a cytokine) induces tubular cell proliferation following unilateral nephrectomy (a noninflammatory microenvironment), but stimulates apoptosis in folic acid−induced AKI (an inflammatory microenvironment).
      • Sanz A.B.
      • Sanchez-Nino M.D.
      • Izquierdo M.C.
      • et al.
      Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia.
      With this paradigm in mind, the search for factors responsible for selection of individual nephrons for survival or death may lead to new biomarkers of progressive CKD.

       Nephron or Cellular Selection?

      In describing an organism’s response to threat or injury, Walter Cannon coined the phrase “fight or flight” that could result either in restoration of homeostasis, or in a deleterious response.
      • Cannon W.B.
      Bodily Changes in Pain, Hunger, Fear and Rage.
      Michael Goligorsky has extended this formulation to the cellular level, demonstrating how fight reactions are directed to attenuate the stressor (e.g., production of antioxidant enzymes), or flight reactions using cell motility or exfoliation: the switch between responses is dictated by the intensity of the insult and the threshold for response by the cell.
      • Goligorsky M.S.
      The concept of cellular “fight-or-flight” reaction to stress.
      Stressors leading to DNA damage activate 1 of the following programs: DNA repair, cell cycle arrest, or programmed cell death. A key question is the nature of the metabolic checkpoint that tilts the balance between cell death and survival.
      • Green D.R.
      • Galluzzi L.
      • Kroemer G.
      Metabolic control of cell death.
      Death and survival use the same mechanisms conserved by evolution: as is the case for development and differentiation, death mechanisms are robust to avoid being hijacked by opportunistic parasitic organisms.
      • Nicotera P.
      • Petersen O.H.
      • Melino G.
      • et al.
      Janus a god with two faces: death and survival utilise same mechanisms conserved by evolution.
      John Torday has developed a novel concept of the process of evolution based on cell−cell communication directed by gene regulatory networks.
      • Torday J.S.
      Evolutionary biology redux.
      Citing Cannon’s original use of the term “homeostasis,” Torday proposes a central role for homeostasis in driving “internal” selection, or adaptation due to modification of visceral organs.
      • Torday J.S.
      Evolutionary biology redux.
      Rather than focusing on the level of the nephron or tubule, attention is focused on individual cells, the behavior of which is dictated by homeostatic constraints within microenvironments. Close examination of proximal tubules in a rat model of AKI reveals injured individual cells adjacent to normal cells with normal basement membrane and interstitium.
      • Suzuki T.
      • Kimura M.
      • Asano M.
      • et al.
      Role of atrophic tubules in development of interstitial fibrosis in microembolism-induced renal failure in rat.
      It appears that even on a single-cell basis, selection shapes regulatory mechanisms according to the costs and benefits of responding versus not responding to ambiguous cues (Table 5). As noted above for variation and selection at the nephron level, investigation of factors determining the selection of individual cells in the microenvironment of the injured kidney may lead to new insights into the progression of CKD (Table 6).

       Evolutionary Nephrology: A Complementary Paradigm for Future Research

      Through the circuitous evolutionary process that brought our ancestors from marine and freshwater environments to homeothermic life on land, mammals inherited energetically expensive nephrons that are susceptible to ischemic and hypoxic injury. Physiologic maladaptation may be explained by underlying evolutionary adaptation: the concepts of life history, mismatch, and tradeoffs provide insight into the expanding epidemic of CKD that should lead to the identification of new risk factors.
      • Kiberd B.
      The chronic kidney disease epidemic: Stepping back and looking forward.
      The recent combination of the retrospective view provided by evo-devo and the prospective power of population genetics reveals rapid change in allele frequencies in cancer.
      • Alvarado A.S.
      Cellular hyperproliferation and cancer as evolutionary variables.
      Techniques used in the investigation of “tissue ecosystems” in these studies can be applied to the kidney in models of AKI and CKD. Current models of acute severe injury in rodents, such as temporary complete renal ischemia (a model of AKI) or ureteral ligation (a model of CKD) should be complemented by animal models with divergent life histories to seek evolutionary explanations for physiologic maladaptation.
      • Agarwal A.
      • Dong Z.
      • Harris R.
      • et al.
      Cellular and molecular mechanisms of AKI.
      Vampire bats are azotemic secondary to high dietary protein intake, but do not develop hyperfiltration or CKD; the hibernating bear can reuse urea nitrogen for protein synthesis.
      • Singer M.A.
      Vampire bat, shrew, and bear: comparative physiology and chronic renal failure.
      Comparison of metabolic responses and gene activation in models of kidney injury across species may yield new insights through the evo-devo paradigm. Not only mammals but yeast, flies, and fish should be included,
      • Kolb A.R.
      • Buck T.M.
      • Brodsky J.L.
      Saccharomyces cervisiae as a model system for kidney disease: what can yeast tell us about renal function?.
      • Singh S.R.
      • Hou S.X.
      Lessons learned about adult kidney stem cells from the Malpighian tubules of Drosophila.
      • Dow J.A.T.
      • Romero M.F.
      Drosophila provides rapid modeling of renal development, function, and disease.
      • Hildebrandt F.
      • Benzing T.
      • Katsanis N.
      Ciliopathies.
      • Uhl E.W.
      • Warner N.J.
      Mouse models as predictors of human responses: evolutionary medicine.
      and studied in the context of evolved differences between species, not just their genetic homologies.
      • Perlman R.L.
      Mouse models of human disease: an evolutionary perspective.
      Because additional nephrons are generated in fetal mammals subjected to renal ablation,
      • Douglas-Denton R.
      • Moritz K.M.
      • Bertram J.F.
      • et al.
      Compensatory renal growth after unilateral nephrectomy in the ovine fetus.
      • van Vuuren S.H.
      • Sol C.M.
      • Borekhuizen R.
      • et al.
      Compensatory growth of congenital solitary kidneys in pigs reflects increased nephron numbers rather than hypertrophy.
      the critical period of late nephrogenesis may provide an optimal opportunity to manipulate the fate of progenitor cells and to enhance nephron number.
      • Short K.M.
      • Combes A.N.
      • Lefevre J.
      • et al.
      Global quantification of tissue dynamics in the developing mouse kidney.
      Refined magnetic resonance imaging techniques permit accurate measurement of glomerular number and volume in intact rodent and human kidneys, potentially valuable biomarkers of progression.
      • Beeman S.C.
      • Cullen-McEwen L.A.
      • Puelles V.G.
      • et al.
      MRI-based glomerular morphology and pathology in whole human kidneys.
      • Bandelomar E.J.
      • Charlton J.R.
      • Beeman S.C.
      • et al.
      Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction.
      Renal metabolism provides the key to understanding the link between AKI and CKD
      • Chevalier R.L.
      The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.
      : novel targets in epithelial cells include mitochondrial biogenesis and function, cellular senescence/cell cycle, and microRNAs.
      • Agarwal A.
      • Dong Z.
      • Harris R.
      • et al.
      Cellular and molecular mechanisms of AKI.
      • Humphreys B.D.
      • Cantaluppi V.
      • Portilla D.
      • et al.
      Targeting endogenous repair pathways after AKI.
      Consideration of the evolutionary context may be of particular relevance in developing novel renal regenerative therapies, with the identification of progenitor cell microenvironments, and signaling pathways to enhance plasticity.
      • Romagnani P.
      • Remuzzi G.
      Renal progenitors: an evolutionary conserved strategy for kidney regeneration.
      Rapid advances in molecular genetics have revealed that mutations are not the sole drivers of evolution: heritable variation can be generated by proteins (prions or chaperones) or by errors in mRNA synthesis.
      • Rosenberg S.M.
      • Queitsch C.
      Combating evolution to fight disease.
      By combining physiologic and genomic techniques across large sample sizes of many species’ life histories, the application of systems biology could provide new evolutionary insights into maladaptation in CKD.
      • Milo R.
      • Hou J.H.
      • Springer M.
      • et al.
      The relationship between evolutionary and physiological variation in hemoglobin.
      New therapies could be developed to target the processes that drive selection of the population of cells in diseased or injured tissue. By framing kidney research in the context of life history theory, the clues to renal senescence may be found in the epigenetic mechanisms of fetal programming, accounting for the transition from pediatric to adult CKD.

      Disclosure

      The author declared no competing interests.

      Acknowledgments

      This work was published in abstract form and presented at the Second Annual Meeting of the International Society for Evolution, Medicine and Public Health, Durham, NC, June 22−25, 2016. The author is indebted to Dr. Robert L. Perlman for his critical review of the manuscript and most helpful suggestions. Portions of the author’s work were supported by National Institutes of Health (NIH) Center of Excellence in Pediatric Nephrology DK096373.

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