BP Control and Long-Term Risk of ESRD and Mortality.

We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval [95% CI], 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD.

A within-patient analysis for time-varying risk factors of CKD progression.

Recent data suggest that nonlinear GFR trajectories are common among patients with CKD, but the modifiable risk factors underlying these changes in CKD progression rate are unknown. Analyses relating baseline risk factors to subsequent GFR decline are suboptimal because these relationships often attenuate as follow-up time increases and these analyses do not account for temporal changes in risk factors. We identified 74 participants in the African American Study of Kidney Disease and Hypertension who had both a period of rapid GFR decline and an extended period of stability during a follow-up period of ≥12 years. We performed a within-patient comparison of time-varying risk factors measured during the periods of GFR decline and stability and identified several risk factors associated with faster GFR decline: more hospitalization episodes and hospitalization days per year; higher BP, serum phosphorus, and urine protein-to-creatinine ratio; lower serum albumin and urine sodium-to-potassium ratio; slower rate of decline of serum urea nitrogen, serum creatinine, serum uric acid, and serum phosphorus; and faster rate of decline of serum hematocrit and serum bicarbonate. By allowing each patient to serve as his or her own control, this novel, within-patient analytic approach holds considerable promise as a means to identify time-varying risk factors associated with stabilization of GFR or acceleration of GFR decline.

Vitamin D deficiency in the pathogenesis of hypertension: still an unsettled question.

Vitamin D deficiency is inversely associated with blood pressure and is felt to contribute to the genesis and maintenance of hypertension. Although well demonstrated in animal studies, in many clinical studies the association between vitamin D status and blood pressure has not been consistently observed or else has been quite small. These discrepancies may relate in part to methodological differences including: patient selection, study size and duration, and, in the case of vitamin D repletion studies, differences in the vitamin D supplement used, its dose, and dosing intervals. Polymorphisms in genes regulating vitamin D activation and function may explain some of the observed inconsistencies as suggested by recent studies. The present review examines experimental and clinical studies bearing on the inverse association between blood pressure and vitamin D status and concludes that a new definition of vitamin D deficiency using additional biomarkers may better select patients with hypertension who will respond to vitamin D supplementation.

Intensive blood-pressure control in hypertensive chronic kidney disease.

BACKGROUND: In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients. METHODS: We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years. RESULTS: During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P=0.27). However, the effects differed according to the baseline level of proteinuria (P=0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P=0.01). CONCLUSIONS: In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)

The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension.

BACKGROUND: The magnitude of proteinuria is associated with a graded increase in the risk of progression to end-stage renal disease and cardiovascular events. The objective of this study was to relate baseline and early changes in proteinuria and glomerular filtration rate (GFR) to long-term progression of hypertensive nondiabetic kidney disease. METHODS: Post hoc analysis of a randomized 3 x 2 factorial trial. A total of 1094 African Americans with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were followed up for a median of 3.8 years. Participants were randomized to a mean arterial pressure goal of 102 to 107 mm Hg (usual) or 92 mm Hg or less (lower) and to initial treatment with a beta-blocker (metoprolol), an angiotensin-converting enzyme inhibitor (ramipril), or a dihydropyridine calcium channel blocker (amlodipine) RESULTS: Baseline proteinuria and GFR predicted the rgate of GFR decline. For each 10-mL/min per 1.73 m(2) lower baseline GFR, an associated mean +/- SE 0.38 +/- 0.08-mL/min per 1.73 m(2) per year greater mean GFR decline occurred, and for each 2-fold higher proteinuria level, a mean +/- SE 0.54 +/- 0.05-mL/min per 1.73 m(2) per year faster GFR decline was observed (P < .001 for both). In multivariate analysis, the effect of baseline proteinuria GFR decline persisted. Initial change in proteinuria from baseline to 6 months predicted subsequent progression, with this relationship extending to participants with baseline urinary protein levels less than 300 mg/d. CONCLUSIONS: The change in the level of proteinuria is a predictor of subsequent progression of hypertensive kidney disease at a given GFR. A prospective trial is needed to confirm this observation.

Associations of blood pressure, sunlight, and vitamin D in community-dwelling adults.

BACKGROUND: Vitamin D deficiency/insufficiency is associated with hypertension. Blood pressure (BP) and circulating vitamin D concentrations vary with the seasons and distance from the equator suggesting BP varies inversely with the sunshine available (insolation) for cutaneous vitamin D photosynthesis. METHODS: To determine if the association between insolation and BP is partly explained by vitamin D, we evaluated 1104 participants in the Reasons for Racial and Geographic Differences in Stroke study whose BP and plasma 25-hydroxyvitamin D [25(OH)D] concentrations were measured. RESULTS: We found a significant inverse association between SBP and 25(OH)D concentration and an inverse association between insolation and BP in unadjusted analyses. After adjusting for other confounding variables, the association of solar insolation and BP was augmented, -0.3.5 ±â€ŠSEM 0.01 mmHg/1 SD higher solar insolation, P = 0.01. The greatest of effects of insolation on SBP were observed in whites (-5.2 ±â€ŠSEM 0.92 mmHg/1 SD higher solar insolation, P = 0.005) and in women (-3.8 ±â€ŠSEM 1.7 mmHg, P = 0.024). We found that adjusting for 25(OH)D had no effect on the association of solar insolation with SBP. CONCLUSION: We conclude that although 25(OH)D concentration is inversely associated with SBP, it did not explain the association of greater sunlight exposure with lower BP.

Relationship between ambulatory BP and clinical outcomes in patients with hypertensive CKD.

BACKGROUND AND OBJECTIVES: Abnormal ambulatory BP (ABP) profiles are commonplace in CKD, yet the prognostic value of ABP for renal and cardiovascular outcomes is uncertain. This study assessed the relationship of baseline ABP profiles with CKD progression and subsequent cardiovascular outcomes to determine the prognostic value of ABP beyond that of clinic BP measurements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 2002 and 2003, 617 African Americans with hypertensive CKD treated to a clinic BP goal of <130/80 mmHg were enrolled in this prospective, observational study. Participants were followed for a median of 5 years. Primary renal outcome was a composite of doubling of serum creatinine, ESRD, or death. The primary cardiovascular outcome was a composite of myocardial infarction, hospitalized congestive heart failure, stroke, revascularization procedures, cardiovascular death, and ESRD. RESULTS: Multivariable Cox proportional hazard analysis showed that higher 24-hour systolic BP (SBP), daytime, night-time, and clinic SBP were each associated with subsequent renal (hazard ratio, 1.17-1.28; P<0.001) and cardiovascular outcomes (hazard ratio, 1.22-1.32; P<0.001). After controlling for clinic SBP, ABP measures were predictive of renal outcomes in participants with clinic SBP <130 mmHg (P<0.05 for interaction). ABP predicted cardiovascular outcomes with no interaction based on clinic BP control. CONCLUSIONS: ABP provides additional information beyond that of multiple clinic BP measures in predicting renal and cardiovascular outcomes in African Americans with hypertensive CKD. The primary utility of ABP in these CKD patients was to identify high-risk individuals among those patients with controlled clinic BP.

Vitamin D, blood pressure, and African Americans: toward a unifying hypothesis.

Vitamin D deficiency has increasingly been recognized in the general population and especially in African Americans whose deep skin pigmentation makes vitamin D photosynthesis inefficient. Over the last decade there has been increasing interest in the role that vitamin D deficiency may play in BP modulation because many epidemiologic studies have shown an inverse association between serum vitamin D concentration and BP. There is a high prevalence of vitamin D deficiency in African Americans who also have an increased susceptibility to develop hypertension and its consequences. This paper will review the circumstances leading to vitamin D deficiency in the African American population and will also discuss how vitamin D deficiency can affect the renin-angiotensin system, free radical production, inflammatory processes, and carbohydrate tolerance that in turn influence vascular endothelial function and vascular structure producing increased vascular resistance. It will speculate that the presence of vitamin D deficiency throughout life from its earliest phases may adversely affect the microvasculature in African Americans, thereby playing a major role in the genesis and maintenance of hypertension.

Introduction to Vitamin D Symposium, March 14, 2008.

A large body of work in diverse clinical and scientific areas has accumulated that supports a role for vitamin D in multiple organ systems and physiologic and molecular processes. The vitamin D receptor is distributed ubiquitously, and by binding with its receptor, vitamin D initiates a series of events that can affect cellular proliferation and differentiation, inflammation, the immune system, and the endocrine system, including the renin-angiotensin system, insulin resistance, and lipid metabolism.

Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans.

BACKGROUND: Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. METHODS: Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. RESULTS: During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). CONCLUSION: Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.

Racial disparities in the association of foetal growth retardation to childhood blood pressure.

BACKGROUND: Foetal growth retardation (FGR), defined as less than the 10th percentile of birth weight for gestational age, is reported to be an important contributor to hypertension and cardiovascular disease in children and adults, but findings are not consistent. For this reason we re-examined the role of FGR in childhood blood pressure. METHODS: We performed univariate and multivariate analyses on data gathered from 262 children, age 5 years, born to mothers at risk for pre-term delivery or FGR infant. The characteristics of the mothers and the children were evaluated using Student's t-test. Rates and proportions were compared using either chi-square or Fisher's exact test. Linear regression models evaluated the effect of birth weight and body mass index on systolic and diastolic blood pressure. Multivariate linear regression was used to model the effects of FGR, gestational age, body mass index, race, gender, maternal smoking, maternal gestational diabetes on blood pressure while adjusting for possible confounders. RESULTS: Systolic blood pressure was inversely associated with birth weight in white children while a small direct association was noted in African Americans. Body mass index was positively associated with systolic blood pressure in both groups. Multiple linear regression analyses showed FGR and early gestational age were associated with higher blood pressure in white but not African American children, accounting for a 13.2 mmHg difference between FGR and appropriate for gestational age groups. Blood pressure in African Americans was strongly affected by maternal gestational diabetes and smoking. CONCLUSIONS: Birth weight influences childhood blood pressure but the effects may vary depending on ethnic group. The relative importance of birth weight on blood pressure may depend on other prenatal and post-partum risks.

Racial differences in renal arteriolar structure in children with minimal change nephropathy.

BACKGROUND: African Americans are at increased risk for hypertension and chronic renal disease. Some data suggest this results from renal microvascular disease. The aim of this study was to determine if renal vascular changes were more pronounced in African Americans, were independent of blood pressure, and occurred in early childhood. METHODS: We performed morphometric analysis on small cortical arteries and arterioles from 44 renal biopsies done in African American and white children (mean age 8.4 +/- SD 5.0 years) with minimal change nephropathy. Outer and inner vessel diameters were measured and wall:lumen and wall:outer diameter ratios (WT/OD) calculated. Clinical data on blood pressure, steroid use, serum creatinine, gender, age, and proteinuria were abstracted by chart review. A z score for systolic and diastolic blood pressure was calculated. Follow-up clinical data were available for 11 children. Data were compared using analysis of covariance (ANCOVA) and t test for paired data. RESULTS: Lumen diameters of African Americans were 3.1 microm (23%) smaller that those of white children (P = 0.024). Similarly, their WT/OD was greater than in the whites, 0.31+/-0.03 vs. 0.28 +/- 0.02 (P= 0.048). These changes were independent of age, steroid use, systolic blood pressure and diastolic blood pressure z scores. Follow-up data showed a rise in serum creatinine (>50%) in five patients, +1.42 +/- 0.79 mg/dL (P = 0.016), of whom four were African American. There was no change in blood pressure. CONCLUSION: The renal arterioles of African American children with minimal change nephropathy exhibit significantly smaller lumens and thicker walls than white children. The changes occur very early in life and are independent of age, blood pressure, and steroid use. Such changes may contribute to the African American predisposition to chronic renal disease and hypertension.

Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.

CONTEXT: Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD. OBJECTIVE: To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension. DESIGN: Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998. SETTING AND PARTICIPANTS: A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years. INTERVENTIONS: Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual; n = 554) or 92 mm Hg or less (lower; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d; n = 217). Open-label agents were added to achieve the assigned BP goals. MAIN OUTCOME MEASURES: Rate of change in GFR (GFR slope); clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified: lower vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol. RESULTS: Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2%; 95% confidence interval [CI], -22% to 21%; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38%; P =.04) and 38% (95% CI, 14%-56%; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups. CONCLUSIONS: No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline.

The rationale and design of the AASK cohort study.

Hypertensive kidney disease commonly progresses. The primary objective of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study is to determine prospectively the course of kidney function and risk factors for kidney disease progression in African Americans with hypertensive kidney disease who receive recommended anti-hypertensive therapy. The AASK Cohort Study is a prospective, observational study that is an extension of the AASK trial. The AASK trial tested the effects of three medications used as initial anti-hypertensive therapy (ramipril, metoprolol, and amlodipine) and two levels of BP control. Of the 1094 trial participants, approximately 650 to 700 individuals who have not reached ESRD will likely enroll in the Cohort Study. Risk factors to be studied include environmental, genetic, physiologic, and socioeconomic variables. The primary renal outcome is a composite clinical outcome defined by doubling of serum creatinine, ESRD, or death. Medication treatment for hypertension, beginning with the angiotensin converting enzyme inhibitor ramipril, is offered to all participants. In this fashion, the study directly controls two of the major determinants of kidney disease progression: treatment of hypertension and use of renoprotective, anti-hypertensive medication. The minimum duration of follow-up in the Cohort Study is 5 yr (total of 9 to 12 yr, including the period of the AASK trial). Ultimately, data from the AASK Cohort Study should enhance our understanding of the risk factors and processes that determine the progression of kidney disease. Such results might eventually lead to new strategies that delay or prevent ESRD.