Developmental Origins of Renal Disease

Abstract

That an adverse environment early in life— in utero or in the early postnatal period—can create vulnerability to chronic disease in later life is no longer a surprise. Following the lead of Barker and colleagues beginning in the late 1980s, a burgeoning literature now documents the increased risk of later-life hypertension (1), diabetes (2), coronary disease (3), and obesity (4) conferred by low birth weight, a surrogate for poor intrauterine growth. However, solid data documenting clinical relevance of the “developmental origins of disease” concept to the kidney have been slower to emerge. We know that the critical window of kidney development spans 9 to 35 wk gestational age (GA) (5), although the point of completion can vary from 32 to 35 wk (6,7). Nephrogenesis involves successive branching of the ingrowing ureteral bud, with new nephron units forming at branch tips via co-inductive crosstalk between the ureteral bud epithelium and surrounding undifferentiated mesenchyme. Of note, this process proceeds in concentric layers, such that newly forming nephrons are located in the outer layer, with the more mature nephron units occupying successively deeper layers. Fortunately, when growth rate is impaired during this fixed developmental window, the fetal kidney forms—not incomplete nephrons—but fewer layers of normal nephrons. Nonetheless, because no new nephrons form after 35 wk GA, nephron endowment is at that point fixed for life. Thus poor intrauterine growth during nephrogenesis may yield a nephron deficit as a permanent structural legacy. As in postnatal life, the developing fetal kidney is exquisitely sensitive to body size such that fetal kidney weight reflects body weight and—on the basis of careful studies in humans (8,9) and nonhuman primates (10)—grows by adding new nephrons. Recent stereologic studies of autopsied kidneys have shown that, in humans born at term, nephron number is in fact …