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.

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease

“…Fetal programming has been implicated in the development of conditions such as cardiovascular disease, hypertension, T2D, obesity, and CKD (22). In kidney disease, it is suggested that insults occurring during critical periods in utero can impair nephrogenesis and normal renal physiology (23,24). Much of the evidence for fetal programming in renal disease is derived from epidemiologic studies demonstrating that malnutrition during gestation is associated with low birth weight and reduced nephron number (23).…”

“…In kidney disease, it is suggested that insults occurring during critical periods in utero can impair nephrogenesis and normal renal physiology (23,24). Much of the evidence for fetal programming in renal disease is derived from epidemiologic studies demonstrating that malnutrition during gestation is associated with low birth weight and reduced nephron number (23). Lower nephron endowment increases the workload of the remaining nephrons, leading to microalbuminuria, glomerular and tubular hypertrophy, glomerulosclerosis, and hypertension, which exacerbate nephron loss in later life (6,7,23).…”

“…Much of the evidence for fetal programming in renal disease is derived from epidemiologic studies demonstrating that malnutrition during gestation is associated with low birth weight and reduced nephron number (23). Lower nephron endowment increases the workload of the remaining nephrons, leading to microalbuminuria, glomerular and tubular hypertrophy, glomerulosclerosis, and hypertension, which exacerbate nephron loss in later life (6,7,23). Consequently, individuals with low birth weight have a 70% increased risk of developing CKD later in life (22).…”

“…We and others have proposed several possible mechanisms by which maternal obesity programs metabolic syndrome and CKD in offspring. These include upregulation of inflammatory, oxidative stress and lipid pathways, mitochondrial stress and alterations in the renin-angiotensin system, renal sympathetic nervous activity, and increased sodium reabsorption (20,21,23,27,29,31,32). In rodent models, we have previously identified increased levels of renal oxidative stress in the offspring of obese mothers.…”

High Fat Diets Sex-Specifically Affect the Renal Transcriptome and Program Obesity, Kidney Injury, and Hypertension in the Offspring

“…A number of mechanisms have been proposed to interpret renal programming, including oxidative stress, inappropriate activation of the renin-angiotensin system (RAS), and impaired tubular sodium handling [8,9,10,11]. Additionally, renal circadian clocks are involved in the sodium balance and BP control [12].…”