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American Journal of Kidney Diseases

Developmental Origins of CKD: Big Problems From Small Packages

      Related Article, p. 20
      In this issue of AJKD, Eriksson et al
      • Eriksson J.G.
      • Salonen M.K.
      • Kajantie E.
      • et al.
      Prenatal growth and CKD in older adults: longitudinal findings from the Helsinki birth cohort study, 1924-1944.
      analyze data from a Finnish longitudinal birth cohort study of more than 20,000 individuals born from 1924 to 1944 and followed up from birth to death. The study was prompted by the rapidly evolving discipline of the developmental origins of health and disease, established by the seminal observations of Barker and Osmond,
      • Barker D.J.
      • Osmond C.
      Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.
      who discovered a correlation between low birth weight and cardiovascular disease in adults. Barry Brenner et al
      • Brenner B.M.
      • Garcia D.L.
      • Anderson S.
      Glomeruli and blood pressure. Less of one, more the other?.
      subsequently proposed a similar relationship between low nephron number at birth and adult hypertension. Since then, birth weight has been used as a surrogate for nephron number.
      • Hughson M.
      • Farris 3rd, A.B.
      • Douglas-Denton R.
      • Hoy W.E.
      • Bertram J.F.
      Glomerular number and size in autopsy kidneys: the relationship to birth weight.
      During the past 3 decades, advances in counting kidney nephron number have revealed 2 important aspects of human kidney development and life history: (1) there is 10-fold variation in nephron number at birth in the healthy population,
      • Bertram J.F.
      • Douglas-Denton R.N.
      • Diouf B.
      • Hughson M.D.
      • Hoy W.E.
      Human nephron number: implications for health and disease.
      and (2) there is a 50% decrease in nephron number with normal aging.
      • Tan J.C.
      • Workeneh B.
      • Busque S.
      • Blouch K.
      • Derby G.
      • Myers B.D.
      Glomerular function, structure, and number in renal allografts from older deceased donors.
      Attempts have been made to establish low nephron number at birth as a major risk factor for progression of chronic kidney disease (CKD), but studies to date have been limited by small numbers of participants and relatively short follow-up intervals. The report by Eriksson et al,
      • Eriksson J.G.
      • Salonen M.K.
      • Kajantie E.
      • et al.
      Prenatal growth and CKD in older adults: longitudinal findings from the Helsinki birth cohort study, 1924-1944.
      based on a large population sample followed up to the age of 86 years, reveals a significant increase in adult CKD in participants with lower birth weights. This is consistent with the hypothesis that low nephron number is a risk factor for progressive CKD. Although additional parameters measured at birth (ponderal index, body length, and placental weight) were also correlated with adult CKD, these were significant for men only. In the female cohort, prematurity also increased the risk for CKD.
      The primary advantage of the linear follow-up of a cohort of individuals enrolled over a 20-year period and followed up over a subsequent 40-year period is the opportunity to map the natural history of CKD across the life cycle. It is now clear that the incidence and prevalence of CKD vary greatly among populations.
      • Bruck K.
      • Stel V.S.
      • Gambaro G.
      • et al.
      CKD prevalence varies across the European general population.
      • Mills K.T.
      • Xu Y.
      • Zhang W.
      • et al.
      A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010.
      Although the restriction of the Eriksson et al study to a Finnish cohort has the advantage of largely controlling for genetic variation, its extrapolation to the global community must be made with caution. Significant advances in obstetrics since the 1920s include the widespread use of fetal ultrasonography and the evolution of neonatal intensive care units that have markedly improved the outcome for preterm infants, particularly those weighing < 1,000 g. These advances may come at a cost because the increasing survival of very low-birth-weight infants has unmasked additional risk factors for later CKD resulting from incomplete nephrogenesis and acute kidney injury due to nephrotoxicity of antibiotics and other drugs administered routinely to these vulnerable patients.
      • Selewski D.T.
      • Charlton J.R.
      • Jetton J.G.
      • et al.
      Neonatal acute kidney injury.
      The role of neonatal acute kidney injury (particularly recurrent or long-term injury) is increasingly becoming recognized as a major risk factor for CKD.
      • Harer M.W.
      • Pope C.F.
      • Conaway M.R.
      • Charlton J.R.
      Follow-up of acute kidney injury in neonates during childhood years (FANCY): a prospective cohort study.
      • Chaturvedi S.
      • Ng K.H.
      • Mammen C.
      The path to chronic kidney disease following acute kidney injury: a neonatal perspective.
      Much has changed also during the 40-year follow-up period, during which dramatic advances have been made in the diagnosis and treatment of CKD, including imaging of the kidneys and urinary tract, renal replacement therapy, and treatment of hypertension, anemia, and bone disease. The outcomes used in the Eriksson et al study were limited to hospitalization or death from CKD: median age at first diagnosis of CKD was 64 years because measures of early onset of kidney injury or dysfunction were not available. In this regard, unlike the dominant contribution of diabetes and hypertension to CKD in adults, congenital anomalies of the kidneys and urinary tract are the leading cause of CKD in children, and many of these disorders are associated with low nephron number.

      NAPRTCS. 2014 North American Pediatric Renal Trials and Collaborative Studies Annual Report [online]. https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf. Accessed July 1, 2017.

      Moreover, most kidney failure resulting from congenital anomalies develops in young adulthood, and this category of disease was not included in the analysis of the Finnish report.
      In the 1980s, Brenner
      • Brenner B.M.
      Chronic renal failure: a disorder of adaptation.
      and associates argued that injury or disease-induced nephron loss resulted in adaptive glomerular hypertrophy, hyperfiltration, and subsequent glomerulosclerosis, leading to further nephron loss aggravated by interstitial collagen accumulation. This paradigm has driven research in CKD for more than 30 years. More recently, attention has focused on the renal tubule, which contributes to the bulk of growing kidney in childhood, as well as to the compensatory growth of the kidney following nephron loss.
      • Chevalier R.L.
      The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.
      The kidneys constitute <1% of body mass, but consume 10% of oxygen, largely due to mitochondrial metabolism required for tubular reabsorption of sodium.
      • Cohen J.J.
      Relationship between energy requirements for Na+ reabsorption and other renal functions.
      As a consequence of evolutionary constraints, energy is allocated to growth in early development through the reproductive years, then switches to repair or regeneration in later adulthood.
      • Whitfield J.
      In the Beat of a Heart. Life, Energy, and the Unity of Nature.
      Tubular oxygen consumption is initially increased following compensatory growth of the remaining nephrons, but sustained accelerated mitochondrial adenosine triphosphate (ATP) production cannot match demand and respiratory complexes become highly reduced, leading to cell death and tubular atrophy.
      • Chevalier R.
      Evolutionary nephrology.
      This process presumably contributes to nephron loss in the senescent kidney, as well as to the progression of CKD.
      The importance of nephron number in lifetime kidney health is now coming into focus. The 10-fold variation in nephron number at birth reflects phenotypic plasticity, such that the fetus can respond to a restricted maternal nutritional environment by diverting precious energy supply to the developing brain rather than the kidney, for which the role is supplied by the placenta. Notably, in the study of Eriksson et al,
      • Eriksson J.G.
      • Salonen M.K.
      • Kajantie E.
      • et al.
      Prenatal growth and CKD in older adults: longitudinal findings from the Helsinki birth cohort study, 1924-1944.
      there was no association of neonatal head circumference (a measure of brain growth) with risk for CKD. A generous “renal reserve” supports the growing child and adult through the reproductive years, but the tradeoff is hypertrophy of the reduced nephron population, which because of increased energy demands increases the risk for tubular atrophy and progressive CKD. The Eriksson et al study also highlights the importance of sex as a potential biological determinant in the development of CKD. Previous work on sex differences in nephron number have had conflicting results, but in a large study using an unbiased stereologic approach performed by Hughson et al,
      • Hughson M.D.
      • Douglas-Denton R.
      • Bertram J.F.
      • Hoy W.E.
      Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States.
      glomerular number was significantly lower in females (794,493 ± 248,725) as compared with males (941,023 ± 337,705). Although the Eriksson et al article did not report the pregnancy history of their female cohort, attention should be paid to the “resilience” of the female sex against CKD, particularly because most females incur the additional renal stress of pregnancy and may have a lower nephron number.
      Fetal programming, presumably through epigenetic mechanisms, can be viewed as a finely tuned evolutionarily conserved response to the intrauterine and perinatal environment. The findings of the Eriksson et al article provide further evidence of the association between low birth weight and kidney disease in adulthood. However, whether low birth weight is truly a surrogate for nephron number and whether it is the causal mechanism for kidney disease in adulthood cannot be gleaned from this report. Furthermore, the interaction with sex requires further exploration. Because measures of total kidney function (such as serum creatinine concentration) obscure compensatory adaptation by a reduced nephron number, to assess the contribution of low nephron number to adverse kidney outcomes, an accurate noninvasive method of counting nephrons is needed. Significant progress is being made in the development of magnetic resonance imaging of the kidneys following injection of cationic ferritin, which allows resolution of functional glomeruli.
      • Baldelomar 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.
      • Beeman S.C.
      • Cullen-McEwen L.A.
      • Puelles V.G.
      • et al.
      MRI-based glomerular morphology and pathology in whole human kidneys.
      • Bennett K.M.
      • Zhou H.
      • Sumner J.P.
      • et al.
      MRI of the basement membrane using charged nanoparticles as contrast agents.
      Serial measurements could then be performed in patients identified by obstetricians, neonatologists, and pediatric nephrologists, with follow-up through transition to adult health care providers. Such information could identify those at highest risk for progressive CKD and could provide critical guidance for the care of patients at risk for progressive CKD.

      References

        • Eriksson J.G.
        • Salonen M.K.
        • Kajantie E.
        • et al.
        Prenatal growth and CKD in older adults: longitudinal findings from the Helsinki birth cohort study, 1924-1944.
        Am J Kidney Dis. 2018; 71: 20-26
        • Barker D.J.
        • Osmond C.
        Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.
        Lancet. 1986; 1: 1077-1081
        • Brenner B.M.
        • Garcia D.L.
        • Anderson S.
        Glomeruli and blood pressure. Less of one, more the other?.
        Am J Hypertens. 1988; 1: 335-347
        • Hughson M.
        • Farris 3rd, A.B.
        • Douglas-Denton R.
        • Hoy W.E.
        • Bertram J.F.
        Glomerular number and size in autopsy kidneys: the relationship to birth weight.
        Kidney Int. 2003; 63: 2113-2122
        • Bertram J.F.
        • Douglas-Denton R.N.
        • Diouf B.
        • Hughson M.D.
        • Hoy W.E.
        Human nephron number: implications for health and disease.
        Pediatr Nephrol. 2011; 26: 1529-1533
        • Tan J.C.
        • Workeneh B.
        • Busque S.
        • Blouch K.
        • Derby G.
        • Myers B.D.
        Glomerular function, structure, and number in renal allografts from older deceased donors.
        J Am Soc Nephrol. 2009; 20: 181-188
        • Bruck K.
        • Stel V.S.
        • Gambaro G.
        • et al.
        CKD prevalence varies across the European general population.
        J Am Soc Nephrol. 2016; 27: 2135-2147
        • Mills K.T.
        • Xu Y.
        • Zhang W.
        • et al.
        A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010.
        Kidney Int. 2015; 88: 950-957
        • Selewski D.T.
        • Charlton J.R.
        • Jetton J.G.
        • et al.
        Neonatal acute kidney injury.
        Pediatrics. 2015; 136: e463-e473
        • Harer M.W.
        • Pope C.F.
        • Conaway M.R.
        • Charlton J.R.
        Follow-up of acute kidney injury in neonates during childhood years (FANCY): a prospective cohort study.
        Pediatr Nephrol. 2017; 32: 1067-1076
        • Chaturvedi S.
        • Ng K.H.
        • Mammen C.
        The path to chronic kidney disease following acute kidney injury: a neonatal perspective.
        Pediatr Nephrol. 2017; 32: 227-241
      1. NAPRTCS. 2014 North American Pediatric Renal Trials and Collaborative Studies Annual Report [online]. https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf. Accessed July 1, 2017.

        • Brenner B.M.
        Chronic renal failure: a disorder of adaptation.
        Perspect Biol Med. 1989; 32: 434-444
        • Chevalier R.L.
        The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.
        Am J Physiol Renal Physiol. 2016; 311: F145-F161
        • Cohen J.J.
        Relationship between energy requirements for Na+ reabsorption and other renal functions.
        Kidney Int. 1986; 29: 32-40
        • Whitfield J.
        In the Beat of a Heart. Life, Energy, and the Unity of Nature.
        Joseph Henry Press, Washington, DC2006
        • Chevalier R.
        Evolutionary nephrology.
        Kidney Int Rep. 2017; 2: 302-317
        • Hughson M.D.
        • Douglas-Denton R.
        • Bertram J.F.
        • Hoy W.E.
        Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States.
        Kidney Int. 2006; 69: 671-678
        • Baldelomar 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.
        Kidney Int. 2015; 89: 498-505
        • Beeman S.C.
        • Cullen-McEwen L.A.
        • Puelles V.G.
        • et al.
        MRI-based glomerular morphology and pathology in whole human kidneys.
        Am J Physiol Renal Physiol. 2014; 306: F1381-F1390
        • Bennett K.M.
        • Zhou H.
        • Sumner J.P.
        • et al.
        MRI of the basement membrane using charged nanoparticles as contrast agents.
        Magn Reson Med. 2008; 60: 564-574

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