Pregnancy support- Fetal Programming

Hypertension - updated: 03 November 2008

Adult hypertension and kidney disease: the role of fetal programming

Hypertension. 2006 Mar;47(3):502-8. Epub 2006 Jan 16

Zandi-Nejad K, Luyckx VA, Brenner BM.

Hypertension (HTN) and chronic kidney disease are highly prevalent diseases that tend to occur more frequently among disadvantaged populations, in whom prenatal care also tends to be poor. More and more evidence is emerging highlighting the important role of fetal programming in the development of adult disease, suggesting a possible common pathophysiologic denominator in the development of these disorders. Epidemiologic evidence accumulated over the past 2 decades has demonstrated an association between low birth weight and subsequent adult HTN, diabetes, and cardiovascular disease. More recently, a similar association has been found with chronic kidney disease. Animal studies and indirect evidence from human studies support the hypothesis that low birth weight, as a marker of adverse intrauterine circumstances, is associated with a congenital deficit in nephron number. The precise mechanism of the reduction in nephron number has not been established, but several hypotheses have been put forward, including changes in DNA methylation, increased apoptosis in the developing kidney, alterations in renal renin-angiotensin system activity, and increased fetal glucocorticoid exposure. A reduction in nephron number is associated with compensatory glomerular hypertrophy and an increased susceptibility to renal disease progression. HTN in low birth weight individuals also appears to be mediated in part through a reduction in nephron number. Increased awareness of the implications of low birth weight and inadequate prenatal care should lead to public health policies that may have long-term benefits in curbing the epidemics of HTN, diabetes, and kidney disease in generations to come.

Publication Types:

• Review

Low birth weight, nephron number, and kidney disease

Kidney Int Suppl. 2005 Aug;(97):S68-77

Luyckx VA, Brenner BM.

More and more evidence is emerging that highlights the far-reaching consequences of prenatal (intrauterine) programming on organ function and adult disease. In humans, low birth weight (LBW) occurs more frequently in disadvantaged communities among whom there is often a disproportionately high incidence of adult cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Indeed, many epidemiologic studies have found an inverse association between LBW and higher blood pressures in infancy and childhood, and overt hypertension in adulthood. Multiple animal models have demonstrated the association of LBW with later hypertension, mediated, at least in part, by an associated congenital nephron deficit. Although no direct correlation has been shown between nephron number and birth weight in humans with hypertension, nephron numbers were found to be lower in adults with essential hypertension, and glomeruli tend to be larger in humans of lower birth weight. An increase in glomerular size is consistent with hyperfiltration necessitated by a reduction in total filtration surface area, which suggests a congenital nephron deficit. Hyperfiltration manifests clinically as microalbuminuria and accelerated loss of renal function, the prevalence of which are higher among adults who had been of LBW. A kidney with a reduced nephron number has less renal reserve to adapt to dietary excesses or to compensate for renal injury, as is highlighted in the setting of renal transplantation, where smaller kidney to recipient body-weight ratios are associated with poorer outcomes, independent of immunologic factors. Both hypertension and diabetes are leading causes of end-stage renal disease worldwide, and their incidences are increasing, especially in underdeveloped communities. Perinatal programming of these 2 diseases, as well as of nephron number, may therefore have a synergistic impact on the development of hypertension and kidney disease in later life. Existing evidence suggests that birth weight should be used as a surrogate marker for future risk of adult disease. Although the ideal solution to minimize morbidity would be to eradicate LBW, until this panacea is realized, it is imperative to raise awareness of its prognostic implications and to focus special attention toward early modification of risk factors for cardiovascular and renal disease in individuals of LBW.

Publication Types:

• Review

Maternal nutrition, low nephron number, and hypertension in later life: pathways of nutritional programming

J Nutr. 2007 Apr;137(4):1066-72

Bagby SP.

A large body of epidemiologic literature supports an inverse relation between birth weight and both systolic blood pressure and prevalence of hypertension, but mechanisms through which lower birth weight increases risk for hypertension are not established. This article advances the view that 1) permanently reduced nephron number is essential but not alone sufficient to mediate nutritionally induced hypertension; and 2) fetally programmed propensity for increased appetite and accelerated postnatal growth, thus generating inappropriately increased body mass, is a necessary "second hit" to actualize hypertension vulnerability. Based on decades of nephrologic research, this increased ratio of body mass (excretory load) to nephron number (excretory capacity) induces intrarenal compensations (tubular and glomerular hypertrophy with single-nephron hyperfiltration and intrarenal renin-angiotensin II activation), which maintain normal glomerular filtration rate at the expense of systemic and glomerular hypertension and at the risk of progressive renal disease. The vigor of the intrarenal compensatory responses is markedly greater in the immature than in the mature kidney, potentially explaining the greater risk of nephron deficits being present early in life as compared with the minimal risk in adult kidney donors. Effective interventions have not yet been defined. Suboptimal maternal nutrition, pervasive in both developed and developing countries, offers a window of opportunity to enhance the cardiovascular and renal health of future generations.

Publication Types:

• Review

Influence of fetal environment on kidney development

Int J Dev Biol. 1999;43(5):453-6

Merlet-Bénichou C.

Several lines of evidence, mostly derived from animal studies, indicate that changes in fetal environment may affect renal development. Besides maternal hyperglycemia or drug exposure, that were recently found to alter nephrogenesis, changes in vitamin A supply to the fetus may prove to be responsible for most of the variations in nephron number found in the population. A low vitamin A status in the fetus may be a major cause of inborn nephron deficit, either as a feature of intrauterine growth retardation or independently of growth retardation. The possibility that vitamin A status may also influence renal vascular development is raised. We suggest that low vitamin A supply to the fetus plays a role in the intrauterine programming of chronic renal disease and hypertension.

Publication Types:

• Review

Publication Types:

• Review