Role of the kidney in the fetal programming of adult cardiovascular disease: an update
Introduction
Once it was thought a fetus was conceived with a ‘template’ for development based on their parents’ genes. As long as the growing fetus received the right nutrients and avoided harmful substances, this template would develop into a healthy baby. This view has been completely overturned. At each stage of development, the organism uses cues from its environment to decide how best to construct itself within the framework of its genes.
Indeed, in the last two decades it has become widely acknowledged that exposure to a poor intra-uterine environment increases the risk of cardiovascular, metabolic and renal disease in adulthood [1, 2, 3]. This has evolved into the ‘developmental programming’ hypothesis that states if a fetus is exposed to a suboptimal environment it makes adaptive responses to ensure short-term survival, which alters fetal growth or development of particular organs leading in later life to increased risk of adult disease [4••]. More recently this hypothesis has evolved to also encompass perturbations that occur during the early postnatal period [5, 6].
Epidemiological [7, 8, 9••], clinical [10•] and animal studies [1, 2, 3, 11•] have demonstrated convincingly that, hypertension can be programmed by an adverse maternal or postnatal environment. These animal models offer the opportunity to explore the mechanisms involved in the initiation of hypertension of developmental origin and to investigate potential therapeutic interventions.
Section snippets
Nephron complement
Suboptimal renal development, leading to reduced renal mass and a low nephron number is a common pattern observed in the fetal programming of hypertension and cardiovascular disease in animal models (i.e. maternal glucocorticoids, protein restriction or hypoxia); though this is not a universal finding [1, 3, 12, 13, 14]. Similarly, in humans, low birth weight (a surrogate marker of a poor in utero environment), has been shown to correlate strongly with a reduced nephron endowment [15]. In
A reduction in glomerular podocyte number
A theory, that has gained increasing acceptance, is that reduced nephron endowment contributes to the development of hypertension. In 1988, Brenner and colleagues first postulated that reduced filtration surface area associated with a low nephron number would lead to sodium retention and ultimately the development of systemic hypertension as a compensatory response to maintain sodium homeostasis [18, 19]. They further suggested that the elevation in systemic pressure would lead to glomerular
Renal adaptations to life ex utero
In the newborn, the kidney avidly retains sodium such that a state of positive sodium balance exists. This is essential for normal growth to occur. Thus, the developing kidney can conserve sodium efficiently. However, the young compared to the adult kidney has a reduced ability to excrete a sodium load (see [11•]). At birth, each nephron must rapidly adapt to takeover the role of maintaining extracellular fluid homeostasis from the placenta. In a kidney with fewer nephrons, the glomerulus and
Impaired renal sodium handling
Sodium excretion by the kidney is tightly regulated, with urinary sodium output precisely matched to dietary intake. Powerful renal mechanisms ensure that changes in sodium intake are matched by equivalent increases or decreases in renal sodium excretion [35]. Thus the kidney plays a major role in the maintenance of an optimal internal fluid environment and the regulation of arterial pressure. It is widely accepted that sustained hypertension is not possible without an alteration in kidney
Interventions to ameliorate a poor beginning to life
Whilst prevention of the initial programming events, would be by far the best option, this is not always possible. Ways of preventing or limiting the in-exorable progression of the deficit in renal function are needed. To date a few studies have made progress in this area and have shown that targeting oxidative stress and increasing nitric oxide bio-availability may be viable options, as oxidative stress and inflammation are key mechanistic pathways involved in endothelial dysfunction. In a
Clinical assessment of glomerular number
In addition, to developing intervention strategies to prevent the deleterious sequelae of being born with a reduced nephron complement it is necessary to develop tools to be able to identify those at risk. Currently, there are no techniques that allow the determination of nephron number in vivo, but these are being developed [63••]. It is difficult to identify those children at risk due to a poor nephron endowment since nephron number can be reduced without concomitant changes in birth weight [2
Conclusion
The clinical implications of these studies are far reaching and include the recommendation for the continued surveillance of children born of low birth weight for the early identification of disease and prevention of end-organ damage. The identification of mechanistic pathways in the renal programming of hypertension has opened up the possibility for preventive treatments. Finally, the need for counseling with respect to controlling salt intake, especially in young children with suspected renal
Conflicts of interest statement
The authors have no conflicts of interest to declare.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
Dr Reetu Singh (APP#1046594) and Prof Kate Denton (APP#1011844) are support by National Health and Medical Research Council of Australia funding.
References (63)
- et al.
Maternal and social origins of hypertension
Hypertension
(2007) - et al.
Early life influences on cardio-metabolic disease risk in aboriginal populations — what is the evidence? A systematic review of longitudinal and case–control studies
Int J Epidemiol
(2012) - et al.
Nephron number in patients with primary hypertension
N Engl J Med
(2003) - et al.
Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease
Lancet
(2013) - et al.
Adult rabbit offspring of mothers with secondary hypertension have increased blood pressure
Hypertension
(2003) - et al.
A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products
Diabetologia
(2006) Effect of age on compensatory renal growth
Kidney Int
(1983)- et al.
Physiological regulation of prostaglandins in the kidney
Annu Rev Physiol
(2008) - et al.
Ontogeny of NO synthase and renin in juxtaglomerular apparatus of rat kidneys
Am J Physiol Renal Physiol
(1995) - et al.
Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms
Am J Physiol Heart Circ Physiol
(2011)
Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction
Pediatr Nephrol
Renal programming: cause for concern?
Am J Physiol Regul Integr Comp Physiol
Developmental programming of a reduced nephron endowment: more than just a baby's birth weight
Am J Physiol Renal Physiol
Short- and long-term effects of exposure to natural and synthetic glucocorticoids during development
Clin Exp Pharmacol Physiol
The origins of the developmental origins theory
J Intern Med
Uninephrectomy in young age or chronic salt loading causes salt-sensitive hypertension in adult rats
Hypertension
Impaired kidney growth in low-birth-weight children: distinct effects of maturity and weight for gestational age
Kidney Int
Does in utero exposure to illness matter? The 1918 influenza epidemic in Taiwan as a natural experiment
J Health Econ
Placental vascular dysfunction, fetal and childhood growth, and cardiovascular development: the generation R study
Circulation
Compensatory responses to nephron deficiency: adaptive or maladaptive?
Nephrology (Carlton)
Maternal nutrition, low nephron number and arterial hypertension in later life
Biochim Biophys Acta
Human nephron number: implications for health and disease
Pediatr Nephrol
Systemic arterial pressure at maturity in rats following chronic hypoxia in early life
Am J Hypertens
Glomerular number and size in autopsy kidneys: the relationship to birth weight
Kidney Int
High nephron endowment protects against salt-induced hypertension
Am J Physiol Renal Physiol
Glomeruli and blood pressure less of one, more the other?
Am J Hypertens
How many ways can a podocyte die?
Semin Nephrol
Glomerular hypertrophy in subjects with low nephron number: contributions of sex, body size and race
Nephrol Dial Transplant
Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race
Nephrol Dial Transplant
Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats
PLoS One
Angiotensin peptides modulate bradykinin levels in the interstitium of the dog heart in vivo
J Pharmacol Exp Ther
Cited by (11)
Life course pathways from parental education to age-related decrements in kidney function among Black and white American adults
2021, PsychoneuroendocrinologyCitation Excerpt :It should also be acknowledged that there may have been an additional influence of prenatal factors, including delivery-related outcomes, that were not assessed in the MIDUS project. A number of studies have shown that prematurity and low birth weight can have a pervasive influence on the early life programming of the kidney, with effects on the nephron endowment (Brophy et al., 2018; Kett and Denton, 2010; Singh and Denton, 2015; Tiniakos et al., 2004; Wintour et al., 2003). Unfortunately, the occurrence of premature birth is still significantly more common among Black women, and provides another example of the early etiology of health disparities.
Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ<sup>12,14</sup>-prostagandin J<inf>2</inf> prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring
2016, Prostaglandins and Other Lipid MediatorsCitation Excerpt :Even though prenatal glucocorticoid is recommended to accelerate fetal lung maturation, emerging evidence indicates that glucocorticoid excess in early life links programming to a variety of diseases in adulthood, including hypertension [2,3]. The kidney controls blood pressure (BP) and plays a crucial role on the development of hypertension [4,5], thus renal programming is considered a key mechanism for programmed hypertension [4–7]. We recently observed that early dexamethasone (DEX) exposure induced hypertension in adult male offspring [8–10].
Fetal Programming
2023, The Placenta: Basics and Clinical SignificanceCan Fetal Alcohol Exposure Increase the Risk of Hypertension? A New Study in Children and Adolescents Diagnosed With Fetal Alcohol Spectrum Disorder Suggests It Can
2019, Alcoholism: Clinical and Experimental Research