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ABSTRACT: Hypertension and its cardiovascular complications affect African Americans more severely than whites, a disparity variously ascribed to low birth weight, low glomerular number, an exaggerated arteriolonephrosclerotic blood pressure response, and inflammation-induced oxidative stress.
Case series.
Autopsy kidneys of 107 African Americans and 87 whites aged 18 to 65 years at a single medical center between 1998 and 2005. Excluded were persons with known premorbid kidney disease; pathological findings of severe arterioarteriolonephrosclerosis, nodular and diffuse diabetic glomerulosclerosis, or nonischemic cardiomyopathy.
Associations of: (1) race, age, sex, birth weight, obesity, and glomerular number (predictors) with hypertension and death from coronary artery (CAD) and cerebrovascular disease (CVD; outcomes); and (2) age, blood pressure, and race (predictors) with arteriolonephrosclerotic changes, including chronic tubulointerstitial inflammation (outcomes).
Hypertension ascertained from chart review and heart weight. Cause of death determined from chart review and autopsy findings. Birth weight obtained from birth records (115 persons). Total glomerular number (N(glom)) estimated by using the dissector/fractionator technique. Arteriolosclerosis, glomerulosclerosis, cortical fibrosis, and chronic inflammation by using CD68 density were measured morphometrically.
59 African Americans (55%) and 32 whites (37%) were classified as hypertensive. CAD and CVD were the cause of death in 64 (33%) and 18 persons (9%), respectively. By using multiple linear regression, birth weight (P < 0.001) and sex (P < 0.01), but not race (P = 0.3) or age (P = 0.2), predicted N(glom) (P < 0.001; adjusted r(2) = 0.176). Hypertension was associated with African American race (P = 0.04), older age (P < 0.001), and male sex (P = 0.01), but not with N(glom) (P = 0.9), body mass index (P = 0.9), or birth weight (P = 0.4). Hypertension was the only significant factor associated with CAD and CVD (P < 0.001 for both). Interactions of age and blood pressure with race showed that although African Americans had more severe hypertension (P < 0.001) and arteriolosclerosis (P = 0.01) at a younger age than whites, there were no significant racial differences in degrees of arteriolosclerosis, glomerulosclerosis, cortical fibrosis, or CD68 density for any level of increased blood pressure.
The study is observational and descriptive.
The more severe hypertension found in African Americans could not be attributed to racial differences in N(glom) or birth weight. CAD and CVD death and increased arteriolonephrosclerosis, including CD68 density, were determined by using blood pressure without a significant interacting contribution from race.
American Journal of Kidney Diseases 07/2008; 52(1):18-28. · 5.43 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: To discuss studies evaluating associations of glomerular number (Nglom) and glomerular volume with hypertension and kidney disease. IMPORTANT FINDINGS: The association of low Nglom with hypertension and renal insufficiency was described in the 1930s. Many investigators have noted loss of glomeruli with age, with most disappearing entirely, and have proposed that hypertension follows. In a recent German study, hypertensive patients had fewer glomeruli and larger mean glomerular volumes than nonhypertensive people. Among the 10-fold range of Nglom in our multiracial autopsy series, the lowest were in Australian Aborigines, who have the highest rates of renal failure. Nglom fell with age. There was a five-fold range in mean glomerular volume and considerable heterogeneity in individual glomerular volumes within a patient. Larger mean glomerular volume and greater individual glomerular volume heterogeneity correlated with lower Nglom, larger body size, hypertension, and black race. Hypertension increased with age and was marked by glomerular enlargement, intimal thickening and higher rates of glomerulosclerosis. In whites and Aborigines, but not in US blacks, lower Nglom was associated with hypertension, while robust numbers were highly protective. SUMMARY: Higher mean glomerular volume and individual glomerular volume heterogeneity mark glomerular stress. Low Nglom is an important determinant of hypertension and renal disease. Many 'missing' nephrons have probably been lost during life, leaving little trace. Additional factors contribute to high rates of hypertension in blacks.
Current Opinion in Nephrology and Hypertension 06/2008; 17(3):258-65. · 4.33 Impact Factor
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Current Opinion in Nephrology and Hypertension 06/2008; · 4.33 Impact Factor
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Current Opinion in Nephrology and Hypertension 06/2008; · 4.33 Impact Factor
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ABSTRACT: Changes in glomerular volume (V(glom)) play an important role in the initiation and progression of various glomerulopathies. Estimation of V(glom) in the normal kidney provides baseline values for studies of glomerular hypertrophy in disease. The traditional model-based method of Weibel and Gomez is widely applied to estimate V(glom) in clinical biopsy specimens. Assumptions of glomerular size distribution and shape required by this method are potential sources of bias that have not been verified. We evaluated the applicability of the glomerular size distribution coefficient in estimating V(glom) in human kidneys. V(glom) of 720 non-sclerotic glomeruli in histologically normal kidneys of 24 males (20-69 years) was estimated by the unbiased disector/Cavalieri approach. Accurate glomerular diameters were calculated from Cavalieri estimates of V(glom) assuming glomerular sphericity. The coefficients of variation (CV) of glomerular diameters were compared with the corresponding values of the size distribution coefficient predicted by the Weibel and Gomez method. Mean (SD) glomerular diameter was 201 (28) mm (range 110-276 mm). The CV of glomerular diameter within each kidney ranged from 4.9 to 14.6%. Corresponding glomerular size distribution coefficients predicted by the formula of Weibel and Gomez ranged from 1.00 to just 1.03. The value of the size distribution coefficient required by the Weibel and Gomez technique when estimating V(glom) in normal human kidneys is remarkably constant. This is despite large variations in V(glom). Future studies should examine the extent of bias introduced by the glomerular shape assumptions of this method.
Journal of Anatomy 06/2007; 210(5):578-82. · 2.37 Impact Factor
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ABSTRACT: We and others have shown previously that fetuses at midgestation can survive 30 min of complete umbilical cord occlusion, although hydrops fetalis (or gross fetal edema) results. To investigate whether this hydrops resolves by late gestation and if there are any long-term consequences of the asphyxial insult on the heart and kidneys, eight fetuses were subjected to 30 min of complete umbilical cord occlusion at 0.6 gestation (90 days; term 150 days) and were compared to a sham group (n = 10). During the occlusion period, fetuses became severely hypoxemic, hypercapnemic, and acidotic, with both blood pressure and heart rate decreasing. Most variables had returned to normal by 2-hr recovery. At 129 +/- 1 days of gestation, approximately 40 days post occlusion, some fetuses were still slightly hydropic as skin fold measurements were increased (P < 0.01), although fetal body weight was not different from the sham group. The two groups had similar heart and kidney weights, ventricular cardiac myocyte nucleation, and glomerular number. By contrast, brain weight was reduced by 37% (P < 0.001) and the cerebral lateral ventricles were grossly dilated. Lungs were 50% smaller than in sham fetuses (P < 0.001). Thus, the hydrops that develops at midgestation as a result of a severe asphyxial episode can, but does not always, fully resolve by late gestation. Also, while fetuses at midgestation can survive this asphyxial episode with no long-term impact in renal or cardiac size, nephron number, or cardiomyocyte nucleation, the brain and lungs are severely affected.
The Anatomical Record Part A Discoveries in Molecular Cellular and Evolutionary Biology 10/2006; 288(10):1112-20.
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ABSTRACT: Enlarged glomerular size is a feature of focal segmental glomerulosclerosis, obesity-related glomerulopathy, diabetic nephropathy, and hypertension. The distribution of glomerular volumes within different cortical zones and glomerular volume alterations with age and obesity may contribute to understanding the evolution of these diseases. We analyzed the distributions of volumes of individual glomeruli in the superficial, middle, and juxtamedullary cortex of normal human kidneys using the disector/Cavalieri method. Volumes (V(glom)) of 720 nonsclerotic glomeruli (30 per kidney, 10 per zone) were estimated in autopsy kidneys of 24 American men, 12 aged 20 to 30 yr and 12 aged 51 to 69 yr. Black and white individuals were represented equally. The range of individual V(glom) within subjects varied from two- to eight-fold. There were no significant zonal differences in V(glom) in the young or those with body surface area (BSA) < or = 2.11 m(2). In contrast, superficial glomeruli in the older age group, in those with BSA > 2.11 m(2), and in white subjects were significantly larger than juxtamedullary glomeruli. Black subjects tended toward larger V(glom) than white subjects, and this difference was significant and most marked in the juxtamedullary zone and independent of age, BSA, and glomerular number. There is a wide range in individual V(glom) in adults. BSA, race, and age independently influence V(glom) in different zones of the renal cortex. These findings might reflect processes of aging and susceptibility factors to renal disease.
Journal of the American Society of Nephrology 10/2005; 16(10):3102-9. · 9.66 Impact Factor
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Journal of the American Society of Nephrology 10/2005; 16(9):2557-64. · 9.66 Impact Factor
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ABSTRACT: The arginine vasopressin (AVP) type 1a receptor (V1a) is well known to mediate vasoconstriction. In pregnancy, blood flow in the placenta is crucial for sustaining normal growth and development of the fetus. This is the first AVP receptor study in the placenta and fetal membranes. The aim was to compare, quantitatively, the level of V1a gene expression with that of a known marker for vascularization, aquaporin 1 (AQP1). V1a and AQP1 gene expression did not correlate; placental V1a mRNA levels were significantly upregulated at 45 and 66+/-1 compared with 27, 100+/-4, and 140 days (term approximately 150 days). V1a mRNA levels were much lower in fetal membranes in which no significant difference across gestation was observed. In situ hybridization histochemistry localized V1a gene expression in the maternal component of the placenta similar to the receptor-binding studies using 125I-labeled [d(CH2)5, sarcosine7] vasopressin. No AVP gene expression was observed in the placenta and fetal membranes, which eliminates local AVP production. This increase in V1a expression at 45 and 66+/-1 days of gestation correlates with the period of maximal placental growth in the sheep and suggests that AVP and V1a receptors may play a hitherto unrecognized role in placental growth, differentiation, and/or function, particularly in the deleterious effects of heat stress, early in pregnancy, on fetal growth.
Biology of Reproduction 09/2003; 69(2):679-86. · 4.01 Impact Factor
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ABSTRACT: In the Southeast United States, African Americans have an estimated incidence of hypertension and end-stage renal disease (ESRD) that is five times greater than Caucasians. Higher rates of low birth weight (LBW) among African Americans is suggested to predispose African Americans to the higher risk, possibly by reducing the number of glomeruli that develop in the kidney. This study investigates the relationships between age, race, gender, total glomerular number (Nglom), mean glomerular volume (Vglom), body surface area (BSA), and birth weight.
Stereologic estimates of Nglom and Vglom were obtained using the physical disector/fractionator combination for autopsy kidneys from 37 African Americans and 19 Caucasians.
Nglom was normally distributed and ranged from 227,327 to 1,825,380, an 8.0-fold difference. A direct linear relationship was observed between Nglom and birth weight (r = 0.423, P = 0.0012) with a regression coefficient that predicted an increase of 257,426 glomeruli per kilogram increase in birth weight (alpha = 0.050:0.908). Among adults there was a 4.9-fold range in Vglom, and in adults, Vglom was strongly and inversely correlated with Nglom (r =-0.640, P = 0.000002). Adult Vglom showed no significant correlation with BSA for males (r = -0.0150, P = 0.936), although it did for females (r = 0.606, P = 0.022). No racial differences in average Nglom or Vglom were observed.
Birth weight is a strong determinant of Nglom and thereby of glomerular size in the postnatal kidney. The findings support the hypothesis that LBW by impairing nephron development is a risk factor for hypertension and ESRD in adulthood.
Kidney International 07/2003; 63(6):2113-22. · 6.61 Impact Factor
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ABSTRACT: In sheep, placental size is maximal by midgestation, but blood flow continues to increase until term. No nerves are present and ANG II is thought to be a major regulator of vascular tone. We hypothesized that angiotensin type 2 receptors (AT(2)) would predominate over type 1 (AT(1)) until late in gestation and be primarily expressed in the vasculature. Real-time PCR, hybridization histochemistry, and ligand-binding studies were performed on placentae and fetal membranes at 27, 45, 66 +/- 1, 100 +/- 4, 130, and 140 days of gestation (term approximately 150 days) to determine quantitative changes and localization. The maximum level of AT(1) expression occurred in the 45-day placenta and was located predominantly in the maternal stromal cells. AT(1) receptors were expressed in the endothelial cells of the chorion in the first half of pregnancy, where later in gestation, both AT(1) and AT(2) receptors were predominant in blood vessels. These results suggest that ANG II, via the AT(1) receptor, may have hitherto unsuspected important roles in the growth/function on the ovine placenta during the maximal growth phase.
AJP Regulatory Integrative and Comparative Physiology 11/2002; 283(4):R972-82. · 3.34 Impact Factor
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ABSTRACT: Unilateral nephrectomy of the adult animal results in compensatory renal growth but does not involve formation of new nephrons. It is not clear whether compensatory growth can occur during the period of active nephrogenesis in utero and if so, whether more nephrons can be formed. Male ovine fetuses (n = 20) underwent unilateral nephrectomy (n = 10) or sham nephrectomy (n = 10) at 100 d of gestation (term, 150 d). After 27 to 34 d, ewes and fetuses were killed and the right kidney of each fetus was removed and weighed. The wet weight of the right kidney was greater in the unilaterally nephrectomized fetuses (16.3 +/- 1.3 g compared with 12.2 +/- 0.7 g; mean +/- SEM, P < 0.05) as was the kidney to body weight ratio (5.2 +/- 0.3 g/kg compared with 3.8 +/- 0.2 g/kg; P < 0.001). Nephron number in the right kidney was estimated by an unbiased stereologic technique. There was a 45% increase in the number of nephrons in the kidneys from unilaterally nephrectomized animals compared with the kidneys from sham-operated animals (530,763 +/- 37,136 nephrons in the unilaterally nephrectomized group compared with 365,672 +/- 36,016 nephrons in the sham-operated group; P < 0.01). Mean glomerular volume was lower in the unilaterally nephrectomized group; however, total glomerular volume per kidney was not different between groups. This study demonstrates that there is a significant amount of compensatory growth and nephron endowment in a remaining kidney after unilateral nephrectomy during the period of active nephrogenesis in the sheep. This is the first time such events have been shown to occur in utero.
Journal of the American Society of Nephrology 02/2002; 13(2):406-10. · 9.66 Impact Factor
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