Background: Serum bicarbonate varies over time in chronic kidney disease ( CKD ) patients, and this variability may portend poor cardiovascular outcomes. The aim of this study was to conduct a time‐updated longitudinal analysis to evaluate the association of serum bicarbonate with long‐term clinical outcomes: heart failure, atherosclerotic events, renal events (halving of estimated glomerular filtration rate [ eGFR ] or end‐stage renal disease), and mortality. Methods and Results: Serum bicarbonate was measured annually, in 3586 participants with CKD , enrolled in the Chronic Renal Insufficiency Cohort ( CRIC ) study. Marginal structural models were created to allow for integration of all available bicarbonate measurements and proper adjustment for time‐dependent confounding. During the 6 years follow‐up, 512 participants developed congestive heart failure (26/1000 person‐years) and 749 developed renal events (37/1000 person‐years). The risk of heart failure and death was significantly higher for participants who maintained serum bicarbonate >26 mmol/L for the entire duration of follow‐up (hazard ratio [ HR ] 1.66; 95% confidence interval [ CI ], 1.23 to 2.23, and HR 1.36, 95% CI 1.02 to 1.82, respectively) compared with participants who kept their bicarbonate 22 to 26 mmol/L, after adjusting for demographics, co‐morbidities, medications including diuretics, eGFR, and proteinuria. Participants who maintained serum bicarbonate <22 mmol/L had almost a 2‐fold increased risk of renal disease progression ( HR 1.97; 95% CI , 1.50 to 2.57) compared with participants with bicarbonate 22 to 26 mmol/L. Conclusion: In this large CKD cohort, persistent serum bicarbonate >26 mmol/L was associated with increased risk of heart failure events and mortality. Further studies are needed to determine the optimal range of serum bicarbonate in CKD to prevent adverse clinical outcomes.

Background and objectives: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2–4. Design, setting, participants, & measurements: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T₅₀) from primary to secondary calciprotein particles, with lower T₅₀ corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T₅₀ with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. Results: The mean T₅₀ was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T₅₀ was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T₅₀, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T₅₀, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T₅₀, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T₅₀, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T₅₀ was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. Conclusions: Among patients with CKD stages 2–4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3

Background and objectives: Cognitive function worsens as kidney function declines, but mechanisms contributing to this association are not completely understood. Metabolic acidosis, a common complication of CKD, leads to neural networks overexcitation and is involved in cerebral autoregulation. We aimed to evaluate the association between serum bicarbonate concentration as a measure of metabolic acidosis, and cognitive function in hypertensive adults with and without CKD. Design, setting, participants, & measurements: Five cognitive summary scores were measured (global cognitive function, executive function, memory, attention/concentration, and language) in 2853 participants in the Systolic BP Intervention Trial (SPRINT). Multivariable linear regression models adjusted for demographics, comorbidities, systolic BP, medications, eGFR and albuminuria evaluated the cross-sectional association between bicarbonate and cognition at SPRINT baseline. In a subset (n=681) who underwent brain magnetic resonance imaging, the models were adjusted for white matter hyperintensity volume, vascular reactivity, and cerebral blood flow. Results: The mean age (SD) was 68 (8.5) years. Global cognitive and executive functions were positively associated with serum bicarbonate (estimate [SEM]: 0.014 [0.006]; P=0.01, and 0.018 [0.006]; P=0.003, respectively). Each 1 mEq/L lower bicarbonate level had a similar association with global cognitive and executive function as being 4.3 and 5.4 months older, respectively. The association with global cognition persisted after magnetic resonance imaging findings adjustment (estimate [SEM]: 0.03 [0.01]; P=0.01). There was no association between serum bicarbonate level and memory, attention/concentration, and language. Conclusions: In a large cohort of hypertensive adults, higher serum bicarbonate levels were independently associated with better global cognitive and executive performance. (ClinicalTrials.gov: NCT01206062).

Summary: Background and objectives: Cardiovascular disease is the most common cause of death in CKD. This study evaluated whether electrocardiogram (ECG) abnormalities are predictors of cardiovascular death in CKD. Design, setting, participants, & measurements: The Cardiovascular Health Study limited database (1989–2005) was used to identify a cohort with CKD at baseline (estimated GFR < 60 mL/min per 1.73 m²). The patients were categorized as having major, minor, or no ECG abnormalities. Rates of adjudicated cardiovascular events and mortality were compared among the groups using proportional hazards regression models. Results: A total of 1192 participants had CKD at baseline; mean age ± SD was 74.7±6.2 years. Of these patients, 452 (38.8%) had major, 346 (29.7%) had minor, and 367 (31.5%) had no ECG abnormalities. Participants with estimated GFR < 60 mL/min per 1.73 m² were more likely to have ECG abnormalities at baseline (adjusted prevalence odds ratio, 1.23 [95% confidence interval (CI), 1.06–1.43]) than those with GFR ≥ 60 mL/min per 1.73 m². During mean follow-up of 10.3±3.8 years, 814 (68.3%) participants died. Compared with participants without ECG abnormalities, participants with major abnormalities had the highest risk for cardiovascular events and death; adjusted hazard ratios were 2.15 (95% CI, 1.56–2.98) and 2.27 (95% CI, 1.56–3.30), respectively. For minor ECG abnormalities, hazard ratios were 1.24 (95% CI, 0.91–1.70) and 1.48 (95% CI, 1.00–2.18), respectively. Conclusions: In patients with CKD, major ECG abnormalities are frequently present and predict a significantly higher risk for death and adverse cardiovascular outcomes.

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4⁺ T cell count after antiretroviral therapy (ART). INRs have low CD4⁺ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4⁺ T cell cycling (Ki67⁺). Here, we report the findings that memory CD4⁺ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4⁺ T cell counts. In vitro PCS or IS blocked CD4⁺ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4⁺ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4⁺ T cell recovery during ART and may contribute to CD4⁺ T cell lymphopenia characteristic of INRs.