Developmental Origins of Chronic Kidney Disease: Should We Focus on Early Life?

Abstract

Chronic kidney disease (CKD) is becoming a global burden, despite recent advances in management. CKD can begin in early life by so-called "developmental programming" or "developmental origins of health and disease" (DOHaD). Early-life insults cause structural and functional changes in the developing kidney, which is called renal programming. Epidemiological and experimental evidence supports the proposition that early-life adverse events lead to renal programming and make subjects vulnerable to developing CKD and its comorbidities in later life. In addition to low nephron endowment, several mechanisms have been proposed for renal programming. The DOHaD concept opens a new window to offset the programming process in early life to prevent the development of adult kidney disease, namely reprogramming. Here, we review the key themes on the developmental origins of CKD. We have particularly focused on the following areas: evidence from human studies support fetal programming of kidney disease; insight from animal models of renal programming; hypothetical mechanisms of renal programming; alterations of renal transcriptome in response to early-life insults; and the application of reprogramming interventions to prevent the programming of kidney disease.

Keywords: Epigenetic regulation; chronic kidney disease; congenital anomalies of the kidney and urinary tract (CAKUT); developmental origins of health and disease (DOHaD); nephron endowment; oxidative stress; renin-angiotensin system; sex differences; sodium transporter; transcriptome.

Figure 1

Schema outlining the early-life insults that induce renal programming and increase the vulnerability to later superimposed renal injury, leading to chronic kidney disease (CKD) and related comorbidity in later life. CKD can be attributed to multiple hits. A variety of early-life environmental insults (e.g., undernutrition) can cause renal programming, which is associated with low nephron endowment and other molecular mechanisms (e.g., oxidative stress). Renal programming likely constitutes a first-hit to the kidney which makes the kidney more vulnerable to postnatal insults (i.e., 2nd hit) to develop CKD in later life. The blue arrowhead indicates the application of reprogramming strategies in early life may prevent the developmental programming of kidney disease. SNGFR = single nephron glomerular filtration rate. GFR = glomerular filtration rate.