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.

Concordance between clinical outcomes in the Systolic Blood Pressure Intervention Trial and in the electronic health record.

BACKGROUND: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. METHODS: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. RESULTS: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. CONCLUSIONS: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

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.

Obstacles and opportunities in managing coexisting obesity and CKD: Report of a scientific workshop cosponsored by the National Kidney Foundation and The Obesity Society.

The National Kidney Foundation (NKF) and The Obesity Society (TOS) cosponsored a multispecialty international workshop in April 2021 to advance the understanding and management of obesity in adults with chronic kidney disease (CKD). The underlying rationale for the workshop was the accumulating evidence that obesity is a major contributor to CKD and adverse outcomes in individuals with CKD, and that effective treatment of obesity, including lifestyle intervention, weight loss medications, and metabolic surgery, can have beneficial effects. The attendees included a range of experts in the areas of kidney disease, obesity medicine, endocrinology, diabetes, bariatric/metabolic surgery, endoscopy, transplant surgery, and nutrition, as well as patients with obesity and CKD. The group identified strategies to increase patient and provider engagement in obesity management, outlined a collaborative action plan to engage nephrologists and obesity medicine experts in obesity management, and identified research opportunities to address gaps in knowledge about the interaction between obesity and kidney disease. The workshop's conclusions help lay the groundwork for development of an effective, scientifically based, and multidisciplinary approach to the management of obesity in people with CKD.

Obstacles and Opportunities in Managing Coexisting Obesity and CKD: Report of a Scientific Workshop Cosponsored by the National Kidney Foundation and The Obesity Society.

The National Kidney Foundation (NKF) and The Obesity Society (TOS) cosponsored a multispecialty international workshop in April 2021 to advance the understanding and management of obesity in adults with chronic kidney disease (CKD). The underlying rationale for the workshop was the accumulating evidence that obesity is a major contributor to CKD and adverse outcomes in individuals with CKD, and that effective treatment of obesity, including lifestyle intervention, weight loss medications, and metabolic surgery, can have beneficial effects. The attendees included a range of experts in the areas of kidney disease, obesity medicine, endocrinology, diabetes, bariatric/metabolic surgery, endoscopy, transplant surgery, and nutrition, as well as patients with obesity and CKD. The group identified strategies to increase patient and provider engagement in obesity management, outlined a collaborative action plan to engage nephrologists and obesity medicine experts in obesity management, and identified research opportunities to address gaps in knowledge about the interaction between obesity and kidney disease. The workshop's conclusions help lay the groundwork for development of an effective, scientifically based, and multidisciplinary approach to the management of obesity in people with CKD.

Intensive Versus Standard Blood Pressure Lowering and Days Free of Cardiovascular Events and Serious Adverse Events: a Post Hoc Analysis of Systolic Blood Pressure Intervention Trial.

BACKGROUND: Communication of the benefits and harms of blood pressure lowering strategy is crucial for shared decision-making. OBJECTIVES: To quantify the effect of intensive versus standard systolic blood pressure lowering in terms of the number of event-free days DESIGN: Post hoc analysis of the Systolic Blood Pressure Intervention Trial PARTICIPANTS: A total of 9361 adults 50 years or older without diabetes or stroke who had a systolic blood pressure of 130-180 mmHg and elevated cardiovascular risk INTERVENTIONS: Intensive (systolic blood pressure goal <120 mmHg) versus standard blood pressure lowering (<140 mmHg) MAIN MEASURES: Days free of major adverse cardiovascular events (MACE), serious adverse events (SAE), and monitored adverse events (hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, or acute kidney injury) over a median follow-up of 3.33 years KEY RESULTS: The intensive treatment group gained 14.7 more MACE-free days over 4 years (difference, 14.7 [95% confidence interval: 5.1, 24.4] days) than the standard treatment group. The benefit of the intensive treatment varied by cognitive function (normal: difference, 40.7 [13.0, 68.4] days; moderate-to-severe impairment: difference, -15.0 [-56.5, 26.4] days; p-for-interaction=0.009) and self-rated health (excellent: difference, -22.7 [-51.5, 6.1] days; poor: difference, 156.1 [31.1, 281.2] days; p-for-interaction=0.001). The mean overall SAE-free days were not significantly different between the treatments (difference, -14.8 [-35.3, 5.7] days). However, the intensive treatment group had 28.5 fewer monitored adverse event-free days than the standard treatment group (difference, -28.5 [-40.3, -16.7] days), with significant variations by frailty status (non-frail: difference, 38.8 [8.4, 69.2] days; frail: difference, -15.5 [-46.6, 15.7] days) and self-rated health (excellent: difference, -12.9 [-45.5, 19.7] days; poor: difference, 180.6 [72.9, 288.4] days; p-for-interaction <0.001). CONCLUSIONS: Over 4 years, intensive systolic blood pressure lowering provides, on average, 14.7 more MACE-free days than standard treatment, without any difference in SAE-free days. Whether this time-based effect summary improves shared decision-making remains to be elucidated. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01206062.

Effect of Intensive versus Standard BP Control on AKI and Subsequent Cardiovascular Outcomes and Mortality: Findings from the SPRINT EHR Study.

Background: Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality. Methods: We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality. Results: A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD. Conclusions: Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control.

Urinary Sulfate, Kidney Failure, and Death in CKD: The African American Study of Kidney Disease and Hypertension.

Background: Sulfur is an important mineral element whose principal source is animal protein. Animal protein contributes to the daily acid load, which is associated with poor outcomes in individuals with chronic kidney disease (CKD). We hypothesized that higher urinary sulfate, as a reflection of the daily acid load, is associated with a greater risk of death and CKD progression. Methods: Urinary sulfate was measured in 1057 African American Study of Kidney Disease and Hypertension (AASK) participants at baseline. Participants were categorized by tertiles of daily sulfate excretion. The longitudinal outcome of interest was the composite of death, dialysis, or 50% reduction in measured glomerular filtration rate (GFR). Multivariable adjusted Cox regression models were fit to relate the composite outcome to daily sulfate excretion using the lowest tertile as the reference. Results: Participants in the highest urinary sulfate tertile were more likely to be men and have a higher body mass index, protein intake, measured GFR, and urinary ammonium and phosphate excretion, and lower urinary protein/creatinine. Compared with those in the lowest tertile of sulfate, those in the highest tertile had a 44% lower hazard (95% CI, 0.37 to 0.84), and those in the middle tertile had a 27% lower hazard (95% CI, 0.55 to 0.96) of death, dialysis, or 50% reduction in measured GFR during follow-up after adjusting for demographics, GFR, protein intake, and other potential confounders. Protein intake was not associated with risk of these events. Conclusions: Higher urinary sulfate excretion is associated with more favorable outcomes in Blacks who have CKD attributed to hypertension.

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.

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.

KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD.

The Kidney Disease Outcomes Quality Initiative (KDOQI) convened a work group to review the 2021 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the management of blood pressure in chronic kidney disease (CKD). This commentary is the product of that work group and presents the recommendations and practice points from the KDIGO guideline in the context of US clinical practice. A critical addition to the KDIGO guideline is the recommendation for accurate assessment of blood pressure using standardized office blood pressure measurement. In the general adult population with CKD, KDIGO recommends a goal systolic blood pressure less than 120 mm Hg on the basis of results from the Systolic Blood Pressure Intervention Trial (SPRINT) and secondary analyses of the Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) trial. The KDOQI work group agreed with most of the recommendations while highlighting the weak evidence base especially for patients with diabetes and advanced CKD.

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure.

RATIONALE & OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering. OUTCOMES: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV). RESULTS: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction). LIMITATIONS: Measurement variability due to multisite design. CONCLUSIONS: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease. FUNDING: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062.

SPRINT Revisited: Updated Results and Implications.

The SPRINT (Systolic Blood Pressure Intervention Trial) results have influenced clinical practice but have also generated discussion regarding the validity, generalizability, and importance of the findings. Following the SPRINT primary results manuscript in 2015, additional results and analyses of the data have addressed these concerns. The primary objective of this article is to respond to key questions that have been raised.