Simon B. Ascher

Key Points: For the first time, we evaluated the association between kidney secretion and cardiovascular mortality in community-dwelling individuals. Worse tubular secretion was associated with a greater mortality risk, independent of eGFR, albuminuria, and other traditional risk factors. The association between worse tubular secretion and cardiovascular disease mortality was similar across major demographic categories. Background: Kidney tubular secretion is a critical mechanism for the clearance of numerous metabolites, toxins, and drugs. In populations with advanced CKD, low (worse) tubular secretion has been associated with an increased risk of cardiovascular disease (CVD). However, it remains unknown whether this relationship is also present in the general population. Methods: In this case–cohort study, we selected a 10% random subcohort ( n =1246) from the Nord-Trøndelag Health Study-3 (a Norwegian community-dwelling population cohort) and we also sampled 141 CVD death cases that occurred outside of the subcohort. We developed a summary secretion score by averaging urine-to-plasma ratios of 12 endogenous secreted solutes, with lower ratios indicating worse tubular secretion. Weighted Cox proportional hazards models were used to assess the relationship between the summary secretion score and the risk of CVD mortality. Results: The mean (SD) age was 51 (14) years, 54.4% were female, 6% had prevalent CVD, and median (interquartile range) eGFR was 99 (90–110) ml/min per 1.73 m ² at baseline. In multivariable models adjusted for demographics, CVD risk factors, eGFR, and albuminuria, each SD lower summary secretion score was associated with 27% higher risk of CVD mortality (95% confidence interval, 1.03 to 1.56). The results were similar across major demographic categories and among those with or without eGFR 30 mg/g at baseline. Conclusions: Among community-dwelling participants, lower tubular secretion is associated with increased CVD mortality independent of eGFR, albuminuria, and other CKD risk factors.

Key Points: AKI frequently occurs in the ambulatory setting, but there are no available tools to distinguish whether kidney function will recover. Plasma biomarkers reflecting kidney tubular injury and dysfunction measured at the time of AKI are associated with nonrecovery in kidney function. Measuring plasma biomarkers of kidney tubule health during ambulatory AKI episodes could be helpful in guiding treatment decisions. Background: AKI frequently occurs in the ambulatory setting, but few tools are available to distinguish whether an individual's kidney function will subsequently recover. Methods: We included 652 participants with and without CKD in the Systolic Blood Pressure Intervention Trial who experienced ambulatory AKI, defined as a rise in serum creatinine of ≥0.3 mg/dl from baseline that occurred at the 12- or 24-month study visits. Four plasma biomarkers of kidney tubule health were measured at baseline and when ambulatory AKI was detected: kidney injury molecule-1 (KIM-1), soluble TNF receptor 1 (sTNFR1) and soluble TNF receptor 2, and uromodulin. Multivariable logistic regression models were used to evaluate biomarker associations with subsequent odds of 2 , and there was an eGFR decline of 21.7±12.5 ml/min per 1.73 m ² at the time ambulatory AKI was detected. When measured at the time of ambulatory AKI, higher KIM-1 (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.14 to 1.73) and sTNFR1 (OR, 2.07; 95% CI, 1.49 to 2.88) and lower uromodulin (OR, 0.77; 95% CI, 0.63 to 0.94) were each associated with eGFR nonrecovery in multivariable models that adjusted for eGFR and albuminuria. In models that included all four plasma biomarkers, KIM-1 and sTNFR1 remained jointly associated with eGFR nonrecovery. Conclusions: Among hypertensive adults with ambulatory AKI, plasma biomarkers reflecting impaired kidney tubule health measured at the time of ambulatory AKI are associated with subsequent nonrecovery in kidney function.

BACKGROUND: Hypotensive episodes detected by 24-hour ambulatory blood pressure (BP) monitoring capture daily cumulative hypotensive stress and could be clinically relevant to cognitive impairment, but this relationship remains unclear. METHODS: We included participants from the Systolic Blood Pressure Intervention Trial (receiving intensive or standard BP treatment) who had 24-hour ambulatory BP monitoring measured near the 27-month visit and subsequent biannual cognitive assessments. We evaluated the associations of hypotensive episodes (defined as systolic BP drops of ≥20 mm Hg between 2 consecutive measurements that reached Z scores, −0.249 [95% CI, −0.380 to −0.119]) and their faster declines (difference in Z score changes, −0.128 [95% CI, −0.231 to −0.026]). A consistent dose-response association was also observed for longer hypotensive duration with worse Montreal Cognitive Assessment and digit symbol coding scores. The association with digit symbol coding scores remained significant after further adjusting for 24-hour average BP and variability and was not observed for hypotension defined by clinic, orthostatic, or 24-hour average BP. Intensive BP treatment increased 24-hour hypotensive episodes and modified its association with the decline in digit symbol coding score. CONCLUSION: Twenty-four–hour hypotensive episodes were associated with worse cognitive function, especially in processing speed, and could be a novel marker for optimal BP control and dementia prevention.

Key Points: We identified three kidney health dimensions using 17 urine and plasma biomarkers across two cohorts of persons with diabetes and CKD. Worse scores for tubule injury, tubule function, and systemic inflammation/filtration were associated with a higher risk of CKD progression and death. A multibiomarker approach could help capture tubulointerstitial health in persons with diabetes and CKD. Background: Individual kidney tubule biomarkers are associated with risks of CKD progression and mortality in persons with diabetes. Integrating multiple kidney biomarkers using a latent variable method of exploratory factor analysis could define distinct dimensions of kidney health and their associations with adverse outcomes. Methods: We conducted a factor analysis of 17 candidate urine and plasma biomarkers in 1256 participants with diabetes and eGFR 2 from the Chronic Renal Insufficiency Cohort (CRIC; N=701) and the REasons for Geographic And Racial Differences in Stroke (REGARDS; N=555) studies. We used Cox proportional hazards models to evaluate the associations of identified factors with CKD progression and mortality, adjusting for baseline clinical risk factors, eGFR, and albuminuria. Results: Three factor scores comprising ten biomarkers were identified: systemic inflammation and filtration (plasma TNF receptor-1 and TNF receptor-2, plasma soluble urokinase plasminogen activator receptor, and plasma symmetric dimethylarginine), tubular function (urine EGF, urine asymmetric dimethylarginine, and urine symmetric dimethylarginine), and tubular damage (urine α-1 microglobulin, urine kidney injury molecule-1, and urine monocyte chemoattractant protein-1). In CRIC, there were 244 incident ESKD events, 102 with ≥40% eGFR decline from baseline, and 259 deaths; in REGARDS, there were 121 incident ESKD events and 462 deaths. In CRIC, lower tubular function (hazard ratio per 1-SD, 0.36; 95% confidence interval, 0.25 to 0.52) and higher tubular damage (1.45; 1.18 to 1.78) scores were independently associated with higher CKD progression risk. Associations in REGARDS were weaker but directionally consistent (tubular function score [0.81; 0.47 to 1.39] and tubular damage score [1.12; 0.73 to 1.72]). Higher tubular damage (1.47; 1.15 to 1.87) scores were associated with higher mortality risk in CRIC, but not REGARDS (1.15; 0.96 to 1.38). Higher systemic inflammation and filtration factor scores were associated with higher mortality risk in both cohorts (CRIC: 1.35; 1.07 to 1.71; REGARDS: 1.41; 1.20 to 1.65). Conclusions: Three distinct kidney health dimensions were identified, and each associated with CKD progression and/or all-cause mortality in persons with diabetes and CKD.

Background: The optimal blood pressure (BP) target for older adults with hypertension remains controversial, particularly among those with advanced age, frailty, or polypharmacy. This study estimated the individualized net benefit of intensive BP lowering among community‐dwelling older adults in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods: Among 5143 SPRINT participants age ≥ 65 years, Cox models were internally validated to predict an absolute difference in risk between treating to a systolic BP target of < 120 versus < 140 mm Hg for all‐cause death, cardiovascular outcomes, cognitive outcomes, and serious adverse events. Treatment effects were combined using simulated preference weights into individualized net benefits, representing the weighted sum of risk differences across outcomes. Net benefits were compared across categories of age (65–74 vs. ≥ 75 years), SPRINT‐derived frailty status (fit, less fit, and frail), and polypharmacy (≥ 5 medications). Results: When simulating preferences for participants who view the benefits of BP lowering (reduction in death, cardiovascular events, and cognitive impairment) as much more important than treatment‐related harms (e.g., acute kidney injury and syncope), the median net benefit from intensive BP lowering was 4 percentage points (IQR: 3–6), and 100% had a positive net benefit favoring intensive BP lowering. When simulating benefits and harms to have similar, intermediate importance, the median net benefit was 1 percentage point (IQR: 0–2), and 85% had a positive net benefit. Participants with advanced age and frailty had greater net benefits from intensive BP lowering despite experiencing more harm in both simulations, and those with polypharmacy had greater net benefits when benefits were viewed as much more important than harms ( p < 0.001 for all comparisons). Conclusions: Among community‐dwelling older adults with hypertension in SPRINT, almost all participants had a net benefit that favored a systolic BP target of < 120 mm Hg, but the magnitude of net benefit varied according to estimated risks and simulated preferences.

Background: Physician use of stigmatizing language in the clinical documentation of hospitalized adults with opioid use is common. However, patient factors associated with stigmatizing language in this setting remain poorly characterized. Objective: This study aimed to determine whether specific demographic factors and clinical outcomes are associated with the presence of stigmatizing language by physicians in the clinical documentation of encounters with opioid-related ICD-10 (International Statistical Classification of Diseases, Tenth Revision) codes. Methods: Hospital encounters with one or more associated opioid-related ICD-10 admission diagnoses on the hospital medicine service during the 2020 calendar year were analyzed for the presence of stigmatizing language in history and physical and discharge summaries. Multivariable adjusted logistic regression models were used to determine associations of age, race, gender, medication for addiction treatment use, against medical advice discharge, homelessness, comorbid polysubstance use, comorbid psychiatric disorder, comorbid chronic pain, cost, and 30-day readmission with the presence of stigmatizing language. Results: A total of 221 encounters were identified, of which 64 (29%) encounters had stigmatizing language present in physician documentation. Most stigmatizing language was due to use of “substance abuse” rather than the preferred term “substance use” (63/66 instances). Polysubstance use and homelessness were independently associated with the presence of stigmatizing language (adjusted odds ratio [aOR] 7.83; 95% CI 3.42-19.24 and aOR 2.44; 95% CI 1.03-5.90) when controlling for chronic pain and other covariates. Conclusions: Among hospital medicine encounters with an opioid-related diagnosis, stigmatizing language by physicians in clinical documentation was common and independently associated with comorbid polysubstance use and homelessness.

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00–1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50–0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80–1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72–1.13]; P _interaction =0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were −2.9% (−4.4%, −1.3%), −0.2% (−3.0%, 2.6%), and −1.9% (−6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.

Background: There are no shared decision‐making frameworks for selecting blood pressure (BP) targets for individuals with hypertension. This study addressed whether results from the SPRINT (Systolic Blood Pressure Intervention Trial) could be tailored to individuals using predicted risks and simulated preferences. Methods and Results: Among 8202 SPRINT participants, Cox models were developed and internally validated to predict each individual's absolute difference in risk from intensive versus standard BP lowering for cardiovascular events, cognitive impairment, death, and serious adverse events (AEs). Individual treatment effects were combined using simulated preference weights into a net benefit, which represents a weighted sum of risk differences across outcomes. Net benefits were compared among those above versus below the median AE risk. In simulations for which cardiovascular, cognitive, and death events had much greater weight than the AEs of BP lowering, the median net benefit was 3.3 percentage points (interquartile range [IQR], 2.0–5.7), and 100% of participants had a net benefit favoring intensive BP lowering. When simulating benefits and harms to have similar weights, the median net benefit was 0.8 percentage points (IQR, 0.2–2.2), and 87% had a positive net benefit. Compared with participants at lower risk of AEs from BP lowering, those at higher risk had a greater net benefit from intensive BP lowering despite experiencing more AEs ( P <0.001 in both simulations). Conclusions: Most SPRINT participants had a predicted net benefit that favored intensive BP lowering, but the degree of net benefit varied considerably. Tailoring BP targets using each patient's risks and preferences may provide more refined BP target recommendations.