Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

BACKGROUND: In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. RESULTS: At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. CONCLUSIONS: The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.

An intervention to decrease sedentary behavior in older adults: A secondary analysis of a randomized controlled trial.

Background: Sedentary behaviors are associated with adverse health outcomes in older adults. The feasibility of behavioral interventions in this population is unclear. Methods: In the Sit Less, Interact, Move More (SLIMM) trial of 106 participants who had obesity, those randomized to the SLIMM intervention (N = 54) were instructed to replace sedentary activities with stepping. An accelerometer was used to measure physical activity. In this secondary analysis, mixed effect models were used to examine the effects of the SLIMM intervention on sedentary and stepping durations and steps/day by age (<70 and ≥ 70 years). Results: Mean ages in the <70 years (N = 47) and ≥70 years (N = 59) groups were 58 ± 11 and 78 ± 5. In the older subgroup, compared to standard-of-care (N = 29), the SLIMM intervention (N = 30) significantly increased stepping duration (13, 95%CI 1-24 min/d, p = 0.038) and steps per day (1330, 95% CI 322-2338, p = 0.01) and non-significantly decreased sedentary duration by (28,95% CI -61-5 min/d, p = 0.09). In the age <70 subgroup, there was no separation between the standard of care (N = 23) and SLIMM (N = 24) groups. Discussion: In older adults who had obesity, SLIMM intervention significantly increased stepping duration and steps per day. Interventions targeting sedentary behaviors by promoting low intensity physical activity may be feasible in this population.

Predicting hospitalization from real-world measures in patients with chronic kidney disease: A proof-of-principle study.

Objective: To investigate if in-clinic measures of physical function and real-world measures of physical behavior and mobility effort are associated with one another and to determine if they predict future hospitalization in participants with chronic kidney disease (CKD). Methods: In this secondary analysis, novel real-world measures of physical behavior and mobility effort, including the best 6-minute step count (B6SC), were derived from passively collected data from a thigh worn actigraphy sensor and compared to traditional in-clinic measures of physical function (e.g. 6-minute walk test (6MWT). Hospitalization status during 2 years of follow-up was determined from electronic health records. Correlation analyses were used to compare measures and Cox Regression analysis was used to compare measures with hospitalization. Results: One hundred and six participants were studied (69 ± 13 years, 43% women). Mean ± SD baseline measures for 6MWT was 386 ± 66 m and B6SC was 524 ± 125 steps. Forty-four hospitalization events over 224 years of total follow-up occurred. Good separation was achieved for tertiles of 6MWT, B6SC and steps/day for hospitalization events. This pattern persisted in models adjusted for demographics (6MWT: HR = 0.63 95% CI 0.43-0.93, B6SC: HR = 0.75, 95% CI 0.56-1.02 and steps/day: HR = 0.75, 95% CI 0.50-1.13) and further adjusted for morbidities (6MWT: HR = 0.54, 95% CI 0.35-0.84, B6SC: HR = 0.70, 95% CI 0.49-1.00 and steps/day: HR = 0.69, 95% CI 0.43-1.09). Conclusion: Digital health technologies can be deployed remotely, passively, and continuously to collect real-world measures of physical behavior and mobility effort that differentiate risk of hospitalization in patients with CKD.

Social Determinants of Health and Their Impact on the Black Race Coefficient in Serum Creatinine-Based Estimation of GFR: Secondary Analysis of MDRD and CRIC Studies.

BACKGROUND: The cause for differences in serum creatinine between Black and non-Black individuals incorporated into prior GFR-estimating equations is not understood. We explored whether social determinants of health can account for this difference. METHODS: We conducted a secondary analysis of baseline data of the Modification of Diet in Renal Disease and Chronic Renal Insufficiency Cohort studies ( N =1628 and 1423, respectively). Data in both study cohorts were stratified by race (Black versus non-Black). We first evaluated the extent to which the coefficient of Black race in estimating GFR from creatinine is explained by correlations of race with social determinants of health and non-GFR determinants of creatinine. Second, we evaluated whether the difference between race groups in adjusted mean creatinine can be explained by social determinants of health and non-GFR determinants of creatinine. RESULTS: In models regressing measured GFR on creatinine, age, sex, and race, the coefficient for Black race was 21% (95% confidence interval, 0.176 to 0.245) in Modification of Diet in Renal Disease and 13% (95% confidence interval, 0.097 to 0.155) in the Chronic Renal Insufficiency Cohort and was not attenuated by the addition of social determinants of health, alone or in combination. In both studies, the coefficient for Black race was larger at lower versus higher income levels. In models, regressing creatinine on measured GFR, age, and sex, mean creatinine was higher in Black versus non-Black participants in both studies, with no effect of social determinants of health. CONCLUSIONS: Adjustment for selected social determinants of health did not influence the relationship between Black race and creatinine-based estimated GFR.

Influence of Baseline Diastolic Blood Pressure on the Effects of Systolic Blood Pressure Lowering on Cognitive Function in Type 2 Diabetes Mellitus.

BACKGROUND: Lowering of systolic blood pressure (SBP) in patients with low diastolic blood pressure (DBP), can further lower DBP. This can potentially decrease cerebral perfusion and cognition. We examined the influence of baseline DBP on the effect of lowering SBP on cognition. METHODS: This is a post hoc analysis of the Memory in Diabetes (MIND) substudy (N = 1,430) of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (NCT00000620). Standard neuropsychological tests (Digit Symbol Substitution Test [DSST], Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Test [RAVLT], and Stroop test) were performed at baseline and months 20 and 40. We compared the effects of intensive (goal SBP <120 mm Hg) vs. standard (goal SBP <140 mm Hg) SBP control on the changes in the 4 test scores from baseline to the averages of months 20 and 40 across the range of baseline DBP using cubic spline terms. RESULTS: Mean age was 63 ± 6 years, 55% were women and 66% White. Participates with lower baseline DBP were older, had more cardiovascular events and a longer duration of diabetes. There was no difference in the change in DSST (-0.22; 95% CI -0.97, 0.52), MMSE (-0.14; 95% CI -0.34, 0.06), RAVLT (-0.12; 95% CI -0.29, 0.06), and Stroop interference (-0.47; 95% CI -1.76, 0.82) in the intensive vs. standard SBP intervention. There was no interaction between baseline DBP and change in scores with the SBP intervention. CONCLUSIONS: Intensive SBP reduction does not adversely affect cognition, even in those with low baseline DBP.

Insulin use in chronic kidney disease and the risk of hypoglycemic events.

BACKGROUND: We examined in persons with type 2 diabetes (T2D) whether the use of insulin and the risk of serious hypoglycemic events with insulin is higher in persons with more advanced CKD. METHODS: In a national cohort of 855,133 veterans with T2D seen at Veteran Affairs clinics between Jan 1, 2008 and December 31, 2010 with at least two serum creatinine measurements, we defined insulin use from pharmacy records and serious hypoglycemic events by ICD-9/10 codes from emergency room visits or hospitalizations that occurred until December 31, 2016. RESULTS: Mean age was 66 ± 11 years and 97% were men. Mean baseline eGFR was 73 ± 22 ml/min/1.73 m2. In a multivariable Cox regression model of those without insulin use at baseline (N = 653,200), compared to eGFR ≥90 group, eGFR < 30 group had higher hazard (HR 1.80, 95% CI 1.74 to 1.88) of subsequent insulin use. In a multivariable Cox model with propensity score matching for baseline insulin use (N = 305,570), both insulin use (HR 2.34, 95% CI 2.24 to 2.44) and advanced CKD (HR 2.28, 95% CI 2.07 to 2.51 for comparison of eGFR < 30 to eGFR ≥90 ml/min/1.73 m2 groups) were associated with increased risk of subsequent serious hypoglycemic events. CONCLUSIONS AND RELEVANCE: In T2D, more advanced CKD was associated with greater insulin use. Both insulin use and advanced CKD were risk factors for serious hypoglycemic events. The safety of insulin compared to newer glycemic agents in more advanced CKD needs further study.

Influence of Baseline Diastolic Blood Pressure on the Effects of Intensive Systolic Blood Pressure Lowering on the Risk of Stroke.

BACKGROUND: Guidelines recommend lowering systolic blood pressure below 130 mm Hg, irrespective of previous strokes. However, there is a concern that lowering systolic blood pressure in people with low baseline diastolic blood pressure might increase the risk of stroke. METHODS: We conducted a secondary analysis of the Secondary Prevention of Small Subcortical Strokes trial that randomly assigned participants with a history of subcortical strokes to an intensive (<130 mm Hg; N=1519) or standard (130-149 mm Hg; N=1501) systolic targets. We examined the effects of blood pressure intervention on stroke and cardiovascular composite across the range of baseline diastolic blood pressure in spline regression models and tested for interaction of baseline diastolic blood pressure with the intervention on outcomes. RESULTS: Mean baseline systolic and diastolic blood pressures were 143±19 and 78±11 mm Hg, respectively. Within each baseline diastolic blood pressure tertile, the achieved diastolic was lower in the intensive versus standard arm. There were 275 stroke events over 10 889 years of follow-up. Lower baseline diastolic blood pressure was associated with increased risk of stroke in an observational spline regression model. Hazard ratios relating blood pressure intervention with the risk of stroke in the lowest (hazard ratio, 0.78 [95% CI, 0.52-1.16]) and the highest (hazard ratio, 0.80 [95% CI, 0.53-1.21]) baseline diastolic tertiles were similar (P=0.95). Results were similar for the cardiovascular composite. CONCLUSIONS: Intensive systolic control does not appear to increase the risk of stroke in those with low baseline diastolic blood pressure and prior stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00059306.

Targeting Sedentary Behavior in CKD: A Pilot and Feasibility Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: We tested the feasibility of reducing sedentary behavior common in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We carried out a Sit Less, Interact, Move More intervention in a 24-week parallel-group, randomized controlled trial in patients with stages 2-5 CKD. In the intervention group (n=54), accelerometry performed at baseline and repeated every 4 weeks was used to develop and monitor adherence to individualized plans targeting sedentary and stepping durations. The control group (n=52) was provided national physical activity recommendations; accelerometry was performed at baseline and every 8 weeks. Between-groups changes from baseline to the average follow-up values at weeks 8, 16, and 24 of the sedentary and stepping durations were the coprimary end points. RESULTS: The mean age was 69±13 years. Fourteen percent were on dialysis or received a kidney transplant. Eight percent of the control group and 17% of the intervention group were lost to follow-up. Sedentary and stepping durations did not change in the control group. Within the intervention group, the maximum decrease in sedentary duration (-43; 95% confidence interval, -69 to -17 min/d) and increase in stepping duration (16; 95% confidence interval, 7 to 24 min/d) and the number of steps per day (1265; 95% confidence interval, 518 to 2012) were seen at week 20. These attenuated at week 24. In mixed effects models, overall treatment effects between groups on sedentary (-17; 95% confidence interval, -43 to 8 min/d) and stepping (6; 95% confidence interval, -3 to 15 min/d) durations and the number of steps per day, a secondary end point (652; 95% confidence interval, -146 to 1449), were not significantly different. The intervention significantly reduced secondary end points of body mass index (-1.1; 95% confidence interval, -1.9 to -0.3 kg/m2) and body fat percentage (-2.1%; 95% confidence interval, -4.4% to -0.2%). CONCLUSIONS: It is feasible to reduce sedentary duration and increase stepping duration in patients with CKD, but these were not sustained. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: National Health and Nutrition Examination Survey (NHANES), NCT02970123.

Modification of the effects of intensive systolic blood pressure control on kidney outcomes by baseline body mass index.

AIM: Obesity and intensive systolic blood pressure (SBP) control are independently associated with greater risk of acute kidney injury (AKI) and incident chronic kidney disease (CKD). We examined whether baseline body mass index (BMI) modifies the effects of intensive SBP lowering on AKI or incident CKD. METHODS: The systolic blood pressure intervention trial (SPRINT) randomized 9361 participants with high blood pressure to an SBP target of either <120 mm Hg or < 140 mm Hg. In a secondary analysis of 9210 SPRINT participants with a baseline BMI of ≥18.5 and < 50 kg/m2 , we examined the interactions of baseline BMI and SPRINT SBP intervention on subsequent AKI and incident CKD. RESULTS: Each 5 kg/m2 increase in baseline BMI was associated with higher risk of AKI (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.01 to 1.25) and incident CKD (HR 1.17, 95% CI 1.01 to 1.32). Intensive SBP control increased the risk of AKI (HR 1.68, 95% CI 1.22-2.11) and incident CKD (HR 3.49, 95% CI 2.47-4.94). The increased risk of AKI with intensive SBP control was consistent across the baseline BMI spectrum (linear interaction p = 0.55); however, the risk of incident CKD with SPRINT intervention increased with higher BMI (linear interaction p = 0.043). CONCLUSION: The increased risk of adverse kidney events seen with intensive SBP control in the SPRINT persisted across the baseline BMI spectrum. A higher baseline BMI was associated with an augmented risk of incident CKD with intensive SBP control.

Chronic kidney disease, atherosclerotic plaque characteristics on carotid magnetic resonance imaging, and cardiovascular outcomes.

BACKGROUND: It is unclear whether faster progression of atherosclerosis explains the higher risk of cardiovascular events in CKD. The objectives of this study were to 1. Characterize the associations of CKD with presence and morphology of atherosclerotic plaques on carotid magnetic resonance imaging (MRI) and 2. Examine the associations of baseline CKD and carotid atherosclerotic plaques with subsequent cardiovascular events. METHODS: In a subgroup (N = 465) of Systolic Blood Pressure Intervention Trial. (SPRINT) participants, we measured carotid plaque presence and morphology at baseline and after 30-months with MRI. We examined the associations of CKD (baseline eGFR < 60 ml/min/1.73m2) with progression of carotid plaques and the SPRINT cardiovascular endpoint. RESULTS: One hundred and ninety six (42%) participants had CKD. Baseline eGFR in the non-CKD and CKD subgroups were 77 ± 14 and 49 ± 8 ml/min/1.73 m2, respectively. Lipid rich necrotic-core plaque was present in 137 (29.5%) participants. In 323 participants with both baseline and follow-up MRI measurements of maximum wall thickness, CKD was not associated with progression of maximum wall thickness (OR 0.62, 95% CI 0.36 to 1.07, p = 0.082). In 96 participants with necrotic core plaque at baseline and with a valid follow-up MRI, CKD was associated with lower odds of progression of necrotic core plaque (OR 0.41, 95% CI 0.17 to 0.95, p = 0.039). There were 28 cardiovascular events over 1764 person-years of follow-up. In separate Cox models, necrotic core plaque (HR 2.59, 95% CI 1.15 to 5.85) but not plaque defined by maximum wall thickness or presence of a plaque component (HR 1.79, 95% CI 0.73 to 4.43) was associated with cardiovascular events. Independent of necrotic core plaque, CKD (HR 3.35, 95% CI 1.40 to 7.99) was associated with cardiovascular events. CONCLUSIONS: Presence of necrotic core in carotid plaque rather than the presence of plaque per se was associated with increased risk of cardiovascular events. We did not find CKD to be associated with faster progression of necrotic core plaques, although both were independently associated with cardiovascular events. Thus, CKD may contribute to cardiovascular disease principally via mechanisms other than atherosclerosis such as arterial media calcification or stiffening. TRIAL REGISTRATION: NCT01475747 , registered on November 21, 2011.

Effects of Intensive Blood Pressure Control in Patients with and without Albuminuria: Post Hoc Analyses from SPRINT.

BACKGROUND AND OBJECTIVES: It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). RESULTS: Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. CONCLUSIONS: Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

The Influence of Baseline Diastolic Blood Pressure on the Effects of Intensive Blood Pressure Lowering on Cardiovascular Outcomes and All-Cause Mortality in Type 2 Diabetes.

OBJECTIVE: To examine whether low baseline diastolic blood pressure (DBP) modifies the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP), a two-by-two factorial randomized controlled trial, examined effects of SBP (<120 vs. <140 mmHg) and glycemic (HbA1c <6% vs. 7.0-7.9% [<42 vs. 53-63 mmol/mol]) control on cardiovascular events in T2DM (N = 4,731). We examined whether effects of SBP control on cardiovascular composite were modified by baseline DBP and glycemic control. RESULTS: Intensive SBP lowering decreased the risk of the cardiovascular composite (hazard ratio [HR] 0.76 [95% CI 0.59-0.98]) in the standard glycemic arm but not in the intensive glycemic arm (HR 1.06 [95% CI 0.81-1.40]). Spline regression models relating the effects of the intervention on the cardiovascular composite across the range of baseline DBP did not show evidence of effect modification by low baseline DBP for the cardiovascular composite in the standard or intensive glycemic arms. The relation between the effect of the intensive SBP intervention and baseline DBP was similar between glycemic arms for the cardiovascular composite three-way interaction (P = 0.83). CONCLUSIONS: In persons with T2DM, intensive SBP lowering decreased the risk of cardiovascular composite end point irrespective of baseline DBP in the setting of standard glycemic control. Hence, low baseline DBP should not be an impediment to intensive SBP lowering in patients with T2DM treated with guideline-recommended standard glycemic control.

Baseline Diastolic Blood Pressure and Cardiovascular Outcomes in SPRINT Participants with Chronic Kidney Disease.

Background: We sought to determine whether intensive systolic BP (SBP) lowering was harmful in Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD (eGFR<60 ml/min per 1.73 m2) and lower baseline diastolic BP (DBP). Methods: We related baseline DBP with the SPRINT primary composite end point (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or cardiovascular death) and all-cause death. We examined the effect of intensive SBP lowering on these outcomes across the range of baseline DBPs using Cox regression with treatment by baseline DBP interaction terms. Results: Among 2646 SPRINT participants with CKD, lower baseline DBP was associated with a higher adjusted hazard of the primary composite end point and all-cause death. For example, participants with baseline DBP of 61 mm Hg (mean baseline DBP in the lowest tertile) experienced a 37% (95% CI, 7% to 75%) higher hazard of the primary outcome relative to participants with baseline DBP of 75 mm Hg (mean baseline DBP for overall). The benefit of intensive SBP lowering was consistent across a range of baseline DBPs on rates of the primary composite end point (linear interaction P value =0.56) and all-cause death (linear interaction P value =0.20). Conclusions: Among SPRINT participants with baseline CKD, lower DBP was associated with higher rates of the primary composite end point and all-cause death. However, DBP did not seem to modify the benefit of intensive SBP lowering on the primary composite end point or all-cause death. Our results suggest that lower DBP should not necessarily impede more intensive SBP lowering in patients with mild to moderate CKD.

Implications of Early Decline in eGFR due to Intensive BP Control for Cardiovascular Outcomes in SPRINT.

BACKGROUND: The Systolic BP Intervention Trial (SPRINT) found that intensive versus standard systolic BP control (targeting <120 or <140 mm Hg, respectively) reduced the risks of death and major cardiovascular events in persons with elevated cardiovascular disease risk. However, the intensive intervention was associated with an early decline in eGFR, and the clinical implications of this early decline are unclear. METHODS: In a post hoc analysis of SPRINT, we defined change in eGFR as the percentage change in eGFR at 6 months compared with baseline. We performed causal mediation analyses to separate the overall effects of the randomized systolic BP intervention on the SPRINT primary cardiovascular composite and all-cause mortality into indirect effects (mediated by percentage change in eGFR) and direct effects (mediated through pathways other than percentage change in eGFR). RESULTS: About 10.3% of the 4270 participants in the intensive group had a ≥20% eGFR decline versus 4.4% of the 4256 participants in the standard arm (P<0.001). After the 6-month visit, there were 591 cardiovascular composite events during 27,849 person-years of follow-up. The hazard ratios for total effect, direct effect, and indirect effect of the intervention on the cardiovascular composite were 0.67 (95% confidence interval [95% CI], 0.56 to 0.78), 0.68 (95% CI, 0.57 to 0.79), and 0.99 (95% CI, 0.95 to 1.03), respectively. All-cause mortality results were similar. CONCLUSIONS: Although intensive systolic BP lowering resulted in greater early decline in eGFR, there was no evidence that the reduction in eGFR owing to intensive systolic BP lowering attenuated the beneficial effects of this intervention on cardiovascular events or all-cause mortality.

Influence of Prediabetes on the Effects of Intensive Systolic Blood Pressure Control on Kidney Events.

BACKGROUND: More than one-third of US adults have prediabetes, which is typically accompanied by hypertension. METHODS: We examined whether prediabetes modified the effects of intensive systolic blood pressure (SBP) lowering on the incidence of chronic kidney disease (CKD) and acute kidney injury (AKI) events in a post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). Diabetes was a SPRINT exclusion criterion. We defined normoglycemia and prediabetes as fasting plasma glucose <100 mg/dl and ≥100 mg/dl, respectively. RESULTS: Of the 9,323 participants included in this analysis, 3,898 (41.8%) had prediabetes and the rest (5,425) had normoglycemia. In participants with baseline estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, incident CKD was defined as a ≥30% decline in eGFR to below 60 ml/min/1.73 m2 with repeat confirmation. AKI events were identified clinically. In the non-CKD participants (n = 6,678), there were 164 incident CKD events. The hazard ratios (HRs) for incident CKD for intensive SBP goal (<120 mm Hg) vs. standard SBP goal (<140 mm Hg) in the normoglycemia (HR: 3.25, 95% CI: 2.03, 5.19) and prediabetes (HR: 3.90, 95% CI: 2.17, 7.02) groups were similar (interaction P value 0.64). In the entire analytic cohort (N = 9,323), there were 310 AKI events. AKI HRs for intensive vs. standard SBP in the normoglycemia (HR: 1.59, 95% CI: 1.17, 2.15) and prediabetes (HR: 1.74, 95% CI: 1.22, 2.48) groups were also similar (interaction P value 0.71). CONCLUSIONS: Prediabetes was highly prevalent, but there was no evidence that prediabetes modified the effects of SPRINT intervention on kidney events.CLINICAL TRIALS REGISTRATIONNCT01206062.

Effects of Intensive Systolic Blood Pressure Lowering on Cardiovascular Events and Mortality in Patients With Type 2 Diabetes Mellitus on Standard Glycemic Control and in Those Without Diabetes Mellitus: Reconciling Results From ACCORD BP and SPRINT.

Background Intensive systolic blood pressure ( SBP ) lowering significantly reduced cardiovascular disease ( CVD ) events in SPRINT (Systolic Blood Pressure Intervention Trial) but not in ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure). Methods and Results SPRINT tested the effects of intensive (<120 mm Hg) versus standard (<140 mm Hg) SBP goals on CVD events and all-cause mortality. Using 2×2 factorial design, ACCORD BP tested the same SBP intervention in addition to an intensive versus standard glycemia intervention. We compared the effects of intensive SBP lowering on the composite CVD end point and all-cause mortality in SPRINT with its effects within each of the glycemia arms in ACCORD BP . Intensive SBP lowering decreased the hazard of the composite CVD end point similarly in SPRINT (hazard ratio: 0.75; 95% confidence interval, 0.64-0.89) and in the ACCORD BP standard glycemia arm (hazard ratio: 0.77; 95% confidence interval, 0.63-0.95; interaction P=0.87). However, the effect of intensive SBP lowering on the composite CVD end point in the ACCORD BP intensive glycemia arm (hazard ratio: 1.04; 95% confidence interval, 0.83-1.29) was significantly different from SPRINT (interaction P=0.023). Patterns were similar for all-cause mortality. Conclusions The effects of intensive SBP control on CVD events and all-cause mortality were similar in patients without diabetes mellitus and in those with diabetes mellitus on standard glycemic control. An interaction between intensive SBP lowering and intensive glycemic control may have masked beneficial effects of intensive SBP lowering in ACCORD BP . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01206062, NCT 00000620.

Self-reported Intentional Weight Loss and Risk of Death in Moderate Chronic Kidney Disease in the United States.

OBJECTIVE: We hypothesized that intentional weight loss is associated with lower mortality risk, whereas unintentional weight loss is associated with higher mortality risk in chronic kidney disease (CKD). DESIGN AND METHODS: We examined this hypothesis in 872 participants with age >20 years, body mass index ≥ 25 kg/m2 and CKD from 1999-2004 National Health and Nutrition Examination Survey who reported their 1 year prior and current weights and the intent to lose weight. We examined the association of self-reported intentional versus unintentional weight loss with all-cause mortality. Participants with no intent to lose weight and no change in weight were the reference group. A multivariable Cox regression model was used to relate mortality with intentional and unintentional weight losses after adjustment for demographics and comorbidity. RESULTS: There were 446 deaths over 6271 years of follow-up. Compared to the reference group, intentional weight loss of 5% to <10% (hazard ratio (HR) 1.22, 95% confidence interval (CI): 0.74-1.99), intentional weight loss of ≥10% (HR 1.53, 95% CI: 0.75-3.12), and unintentional weight loss of 5% to <10% (HR 1.11, 95% CI: 0.71-1.75) were not associated with mortality; however, unintentional weight loss of ≥10% (HR 1.66, 95% CI: 1.06-2.58) was significantly associated with higher risk of mortality. Retrospective design and self-reported weight loss were the limitations. CONCLUSIONS: Intentional weight loss in CKD participants was not associated with lower mortality risk. This might reflect residual confounding. Mechanistic and interventional studies are warranted to determine the effects of intentional weight loss in CKD.