Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis.Background. Modest maternal protein restriction leads to hypertension and a reduced number of glomeruli in adult male but not female offspring. This study determined whether a more severe protein restriction has equivalent effects on male and female rat offspring, and examined the role of nephrogenesis in this programming.Methods. Sprague-Dawley rats were fed a protein-restricted (5% protein) diet throughout (LLP), or during the first (LLP/NP) or second (NP/LLP) half of pregnancy. Controls ate a normal diet (NP, 19% protein). Adult offspring were chronically instrumented at 22 weeks; glomerular number and volume were estimated using stereologic techniques.Results. Mean arterial pressures in male offspring were significantly higher in LLP (136 ± 2 mm Hg) or NP/LLP (137 ± 2 mm Hg) than in LLP/NP (125 ± 1 mm Hg) or NP (125 ± 2 mm Hg). Moreover, the hypertension was salt-sensitive (increase of 16 ± 4 mm Hg in LLP on a high Na + diet compared to 2 ± 2 mm Hg in NP). Glomerular number (per kidney) was reduced (15,400 ± 2,411 in LLP vs. 27,208 ± 1,534 in NP) but average individual glomerular volume was not different (1.98 ± 0.18 10 6 l 3 in LLP vs. 2.01 ± 0.14 10 6 l 3 in NP). Female offspring showed qualitatively similar results.Conclusion. Severe maternal dietary protein restriction reduces glomerular number and programs for salt-sensitive adult hypertension in both female and male offspring. The window of sensitivity of adult blood pressure to prenatal protein restriction falls within the period of nephrogenesis in the rat. These data are consistent with the hypothesis that maternal protein restriction causes adult hypertension in the offspring through impairment of renal development.Epidemiologic evidence indicates that babies that are born smaller or grow more slowly during the first year of life have an increased risk for adult diseases, including heart disease and hypertension, than do larger babies [1][2][3][4][5][6][7][8]. This indicates that factors in the prenatal and early postnatal environment, that influence growth, can cause permanent changes in the morphology and physiology of specific organ systems, thus "programming" the individual for increased risk of disease later in life. One such factor that is known to cause this programming is maternal undernutrition. In the rat, maternal dietary protein restriction during pregnancy leads to hypertension in adult offspring [9][10][11], but the precise physiologic mechanisms by which this occurs remain controversial. We have previously hypothesized that maternal protein restriction causes suppression of the fetal/newborn intrarenal renin-angiotensin system (RAS), and thus impaired renal development, leading to permanent alterations in kidney structure and function, including a reduced number of nephrons, resulting in hypertension. In support of this postulate, we found that renal renin gene expression, renin protein, and angiotensin II levels are suppressed in newborn male o...

Anaplasia, defined by the presence of extreme nuclear and mitotic atypia, is a potent marker of adverse prognosis in Wilms tumor (WT). Anaplastic WT cells apparently have increased resistance to therapy rather than increased aggressiveness. The distribution of anaplasia should therefore have critical prognostic relevance. The original definitions for focal anaplasia (FA) and diffuse anaplasia (DA) were based on quantitative rather than topographical criteria and lacked prognostic significance. A new definition was developed based on the distribution of anaplastic changes within the tumor: FA applies only to tumors with anaplasia confined to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere. This revised definition was evaluated in 165 cases with anaplastic WT entered on the third and fourth National Wilms Tumor Study. Only three relapses and one death occurred among 39 cases with FA, regardless of tumor stage, a result comparable to that for nonanaplastic WT. Eight children with metastases at diagnosis and FA in the primary tumor were alive and free of relapse; 22 of 23 children with stage IV DA WT died of tumor. This new definition reinforces the importance of carefully documenting the exact site from which each tumor section is obtained.