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.

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.

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.

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.

A trial of 2 strategies to reduce nocturnal blood pressure in blacks with chronic kidney disease.

The objective of our study was to determine the effects of 2 antihypertensive drug dose schedules (PM dose and add-on dose) on nocturnal blood pressure (BP) in comparison with usual therapy (AM dose) in blacks with hypertensive chronic kidney disease and controlled office BP. In a 3-period, crossover trial, former participants of the African American Study of Kidney Disease were assigned to receive the following 3 regimens, each lasting 6 weeks, presented in random order: AM dose (once-daily antihypertensive medications taken in the morning), PM dose (once-daily antihypertensives taken at bedtime), and add-on dose (once-daily antihypertensives taken in the morning and an additional antihypertensive medication before bedtime [diltiazem 60-120 mg, hydralazine 25 mg, or additional ramipril 5 mg]). Ambulatory BP monitoring was performed at the end of each period. The primary outcome was nocturnal systolic BP. Mean age of the study population (n=147) was 65.4 years, 64% were men, and mean estimated glomerular filtration rate was 44.9 mL/min per 1.73 m(2). At the end of each period, mean (SE) nocturnal systolic BP was 125.6 (1.2) mm Hg in the AM dose, 123.9 (1.2) mm Hg in the PM dose, and 123.5 (1.2) mm Hg in the add-on dose. None of the pairwise differences in nocturnal, 24-hour, and daytime systolic BP was statistically significant. Among blacks with hypertensive chronic kidney disease, neither PM (bedtime) dosing of once-daily antihypertensive nor the addition of drugs taken at bedtime significantly reduced nocturnal BP compared with morning dosing of antihypertensive medications.

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.

Kidney function can improve in patients with hypertensive CKD.

The typical assumption is that patients with CKD will have progressive nephropathy. Methodological issues, such as measurement error and regression to the mean, have made it difficult to document whether kidney function might improve in some patients. Here, we used data from 12 years of follow-up in the African American Study of Kidney Disease and Hypertension to determine whether some patients with CKD can experience a sustained improvement in GFR. We calculated estimated GFR (eGFR) based on serum creatinine measurements during both the trial and cohort phases. We defined clearly improved patients as those with positive eGFR slopes that we could not explain by random measurement variation under Bayesian mixed-effects models. Of 949 patients with at least three follow-up eGFR measurements, 31 (3.3%) demonstrated clearly positive eGFR slopes. The mean slope among these patients was +1.06 (0.12) ml/min per 1.73 m(2) per yr, compared with -2.45 (0.07) ml/min per 1.73 m(2) per yr among the remaining patients. During the trial phase, 24 (77%) of these 31 patients also had clearly positive slopes of (125)I-iothalamate-measured GFR during the trial phase. Low levels of proteinuria at baseline and randomization to the lower BP goal (mean arterial pressure ≤92 mmHg) associated with improved eGFR. In conclusion, the extended follow-up from this study provides strong evidence that kidney function can improve in some patients with hypertensive CKD.

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.)

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.

Disparate estimates of hypertension control from ambulatory and clinic blood pressure measurements in hypertensive kidney disease.

Ambulatory blood pressure (ABP) monitoring provides unique information about day-night patterns of blood pressure (BP). The objectives of this article were to describe ABP patterns in African Americans with hypertensive kidney disease, to examine the joint distribution of clinic BP and ABP, and to determine associations of hypertensive target organ damage with clinic BP and ABP. This study is a cross-sectional analysis of baseline data from the African American Study of Kidney Disease Cohort Study. Masked hypertension was defined by elevated daytime (>or= 135/85 mm Hg) or elevated nighttime (>or= 120/70 mm Hg) ABP in those with controlled clinic BP (<140/90 mm Hg); nondipping was defined by a

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.

Prevalence and correlates of left ventricular hypertrophy in the African American Study of Kidney Disease Cohort Study.

African Americans with hypertensive renal disease represent a high-risk population for cardiovascular events. Although left ventricular hypertrophy is a strong predictor of adverse cardiac outcome, the prevalence and associated factors of left ventricular hypertrophy in this patient population are not well described. The African American Study of Kidney Disease Cohort Study is a prospective, observational study that is an extension of the African American Study of Kidney Disease randomized clinical trial that was conducted from 1994 to 2001 in African Americans with hypertension and mild-to-moderate renal dysfunction. Echocardiograms and 24-hour ambulatory blood pressure monitoring were performed at the baseline visit of the cohort. Of 691 patients enrolled in the cohort study, 599 patients had interpretable baseline echocardiograms and ambulatory blood pressure data. Left ventricular hypertrophy was defined using a cut point for left ventricular mass index >49.2 g/m(2.7) in men and >46.7 m/m(2.7) in women. The majority of patients had left ventricular hypertrophy (66.7% of men and 73.9% of women). In a multiple regression analysis, higher average day and nighttime systolic blood pressure, younger age, and lower predicted glomerular filtration rate were associated with left ventricular hypertrophy, but albuminuria was not. These data demonstrate a striking prevalence of left ventricular hypertrophy in the African American Study of Kidney Disease Cohort and identify potential targets for prevention and therapeutic intervention in this high-risk patient population.

Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular (CV) events. METHODS: We randomly assigned 1,094 African Americans with hypertensive nephrosclerosis (glomerular filtration rate [GFR], 20 to 65 mL/min/1.73 m(2) [0.33 to 1.08 mL/s]) to initial antihypertensive treatment with either: (1) a beta-blocker, metoprolol; (2) an angiotensin-converting enzyme inhibitor, ramipril; or (3) a dihydropyridine calcium channel blocker, amlodipine, and either a usual-blood pressure (BP) or low-BP treatment goal. Using a design powered to detect renal outcome differences, we compared the effect of treatment on the CV event rate (cardiac death, myocardial infarction, stroke, and heart failure) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes. RESULTS: Thirty-one patients died of CV disease (0.7%/patient-year), and 149 patients experienced at least 1 CV outcome (3.3%/patient-year). Overall, 202 CV events (4.5%/patient-year) occurred. The CV outcome rate was not related significantly to randomized interventions. In multivariable analyses, 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age, sex, baseline GFR, and baseline proteinuria group: pulse pressure, duration of hypertension, abnormal electrocardiogram result, non-high-density lipoprotein cholesterol level, serum urea nitrogen level, urine protein-creatinine ratio, urine sodium-potassium ratio, and annual income less than 15,000 dollars. CONCLUSION: Neither randomized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events, possibly because of limited power. However, this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort.

Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease.

Patients with chronic kidney disease have an increased risk for progression to ESRD. The purpose of this study was to examine factors that predict increased risk for adverse renal outcomes. Cox regression was performed to assess the potential of 38 baseline risk factors to predict the clinical renal composite outcome of 50% or 25-ml/min per 1.73 m(2) GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m(2)). Patients were trial participants who had been randomly assigned to one of two BP goals and to one of three antihypertensive regimens and followed for a range of 3 to 6.4 yr. In unadjusted and adjusted analyses, baseline proteinuria was consistently associated with an increased risk for adverse renal outcomes, even at low levels of proteinuria. The relationship of proteinuria with adverse renal outcomes also was evident in analyses that were stratified by level of GFR, which itself was associated with adverse renal outcomes but only at levels <40 ml/min. Other factors that were significantly associated with increased renal events after adjustment for baseline GFR, age, and gender, both with and without adjustment for baseline proteinuria, included serum creatinine, urea nitrogen, and phosphorus. In black patients with hypertensive nephrosclerosis, increased proteinuria, reduced GFR, and elevated levels of serum creatinine, urea nitrogen and phosphorus were directly associated with adverse clinical renal events. These findings identify a subset of this high-risk population that might benefit from even more aggressive treatment.

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.

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.

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.