Role of the kidney in the fetal programming of adult cardiovascular disease: an update

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Highlights

  • Suboptimal kidney development increases the risk of cardiovascular disease.

  • Postnatal compensatory adaptations in renal function drive this phenomenon.

  • New methods to determine nephron number in vivo are being developed.

  • Interventions during the postnatal period ameliorate programmed hypertension.

It is well established that an adverse in utero environment can impinge upon fetal development and place the offspring on a track leading to future cardiovascular disease. Significantly, this may occur in the absence of any outward manifestations at birth. In this brief review, we focus on potential renal mechanisms that lead to adaptations in glomerular and tubular function that initiate hypertension of developmental origin and examine potential therapeutic interventions. This report updates recent data in this field.

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.

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