Effect of Long-term Exercise Training on Physical Performance and Cardiorespiratory Function in Adults With CKD: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: The safety and efficacy of long-term exercise training in reducing physical functional loss in older adults with advanced CKD and comorbidity is uncertain. STUDY DESIGN: Multicenter, parallel group, randomized controlled trial. SETTINGS & PARTICIPANTS: Adults 55 years and older with estimated glomerular filtration rate (eGFR) of 15 to <45 mL/min/1.73 m2 enrolled from centers in Baltimore and Boston. INTERVENTION: Twelve months of in-center supervised exercise training incorporating majority aerobic but also muscle strengthening activities or a group health education control intervention, randomly assigned in 1:1 ratio. OUTCOME: Primary outcomes were cardiorespiratory fitness and submaximal gait at 6 and 12 months quantified by peak oxygen consumption (Vo2peak) on graded exercise treadmill test and distance walked on the 6-minute walk test, respectively. Secondary outcomes were changes in lower extremity function, eGFR, albuminuria, glycemia, blood pressure, and body mass index. RESULTS: Among 99 participants, the mean age was 68 years, 62% were African American, and the mean eGFR was 33 mL/min/1.73 m2; 59% had diabetes, and 29% had coronary artery disease. Among those randomized to exercise, 59% of exercise sessions were attended in the initial 6 months. Exercise was well tolerated without excess occurrence of adverse events. At 6 months, aerobic capacity was higher among exercise participants (17.9 ± 5.5 vs 15.9 ± 7.0 mL/kg/min, P = 0.03), but the differences were not sustained at 12 months. The 6-minute walk distance improved more in the exercise group (adjusted difference: 98 feet [P = 0.02; P = 0.03 for treatment-by-time interaction]). The exercise group had greater improvements on the Timed Up and Go Test (P = 0.04) but not the Short Physical Performance Battery (P = 0.8). LIMITATIONS: Planned sample size was not reached. Loss to follow-up and dropout were greater than anticipated. CONCLUSIONS: Among adults aged ≥55 years with CKD stages 3b-4 and a high level of medical comorbidity, a 12-month program of in-center aerobic and resistance exercise training was safe and associated with improvements in physical functioning. FUNDING: Government grants (National Institutes of Health). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01462097.

Longitudinal Changes in Cardiac Troponin and Risk of Heart Failure Among Black Adults.

BACKGROUND: Among Black adults, high-sensitivity cardiac troponin I (hs-cTnI) is associated with heart failure (HF) risk. The association of longitudinal changes in hs-cTnI with risk of incident HF, HF with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively), among Black adults is not well-established. METHODS AND RESULTS: This study included Black participants from the Jackson Heart Study with available hs-cTnI data at visits 1 (2000-2004) and 2 (2005-2008) and no history of cardiovascular disease. Cox models were used to evaluate associations of categories of longitudinal change in hs-cTnI with incident HF risk. Among 2423 participants, 11.6% had incident elevation in hs-cTnI at visit 2, and 16.9% had stable or improved elevation (≤50% increase in hs-cTnI), and 4.0% had worsened hs-cTnI elevation (>50% increase). Over a median follow-up of 12.0 years, there were 139 incident HF hospitalizations (64 HFrEF, 58 HFpEF). Compared with participants without an elevated hs-cTnI, those with incident, stable or improved, or worsened hs-cTnI elevation had higher HF risk (adjusted hazard ratio 3.20 [95% confidence interval, 1.92-5.33]; adjusted hazard ratio 2.40, [95% confidence interval, 1.47-3.92]; and adjusted hazard ratio 8.10, [95% confidence interval, 4.74-13.83], respectively). Similar patterns of association were observed for risk of HFrEF and HFpEF. CONCLUSIONS: Among Black adults, an increase in hs-cTnI levels on follow-up was associated with a higher HF risk. LAY SUMMARY: The present study included 2423 Black adults from the Jackson Heart Study with available biomarkers of cardiac injury and no history of cardiovascular disease at visits 1 and 2. The majority of participants did not have evidence of cardiac injury at both visits (67.5%), 11.6% had evidence of cardiac injury only on follow-up, 14.5% had stable elevations, 4.0% had worsened elevations, and 2.4% had improved elevations of cardiac injury biomarkers during follow-up. Compared with participants without evidence of cardiac injury, those with new, stable, and worsened levels of cardiac injury had a higher risk of developing heart failure. TWEET: Among Black adults, persistent or worsening subclinical myocardial injury is associated with an elevated risk of HF.

Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD.

RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease. EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOME: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH: We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m2, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m2 decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]). LIMITATIONS: Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting. CONCLUSIONS: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study.

BACKGROUND: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. METHODS: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) <6 ng/L and NT-proBNP (N-terminal pro-B-type natriuretic peptide) <100 pg/mL), and those with ECG-LVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF. RESULTS: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1-3.5) in those with malignant LVH and 0.9 (95% CI, 0.6-1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. CONCLUSIONS: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD).

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.73 m2, in a 1:1 ratio to receive metformin or placebo twice daily. Primary outcomes were medication safety and tolerability. Secondary outcomes included estimated GFR decline, and total kidney volume growth. Thirty-eight metformin and 39 placebo participants still received study product at 24-months. Twenty-one participants in the metformin arm reduced drug dose due to inability to tolerate, compared with 14 in the placebo arm (not significant). Proportions of participants experiencing serious adverse events was similar between the groups. The Gastrointestinal Symptoms Rating Scale score was low at baseline and did not significantly change over time. The annual change for estimated GFR was -1.71 with metformin and -3.07 ml/min/1.73m2 per year with placebo (mean difference 1.37 {-0.70, 3.44} ml/min/1.73m2), while mean annual percent change in height-adjusted total kidney volume was 3.87% in metformin and 2.16% per year in placebo, (mean difference 1.68% {-2.11, 5.62}). Thus, metformin in adults with ADPKD was found to be safe and tolerable while slightly reducing estimated GFR decline but not to a significant degree. Hence, evaluation of efficacy requires a larger trial, with sufficient power to detect differences in endpoints.

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. STUDY DESIGN: A multicenter, prospective, cohort study. SETTING & PARTICIPANTS: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. EXPOSURES: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). OUTCOMES: Incident heart failure, myocardial infarction, and stroke events. ANALYTICAL APPROACH: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. RESULTS: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. LIMITATIONS: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. CONCLUSIONS: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.

Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease.

BACKGROUND: Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD. METHODS: We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors. RESULTS: In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters. CONCLUSIONS: hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.

Incorporation of Biomarkers Into Risk Assessment for Allocation of Antihypertensive Medication According to the 2017 ACC/AHA High Blood Pressure Guideline: A Pooled Cohort Analysis.

BACKGROUND: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. METHODS: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/<100 mm Hg) were further stratified by biomarker status. Cumulative incidence rates for CV event (atherosclerotic cardiovascular disease or heart failure), and the corresponding 10-year number needed to treat to prevent 1 event with intensive BP lowering (to target systolic BP <120 mm Hg), were estimated for BP and biomarker-based subgroups. RESULTS: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP <160/100 mm Hg, those with versus without an elevated biomarker had a 10-year CV incidence rate of 15.1% and 7.9%, with a 10-year number needed to treat to prevent 1 event of 26 and 49, respectively. CONCLUSIONS: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

Hyperkalemia in patients with chronic renal failure.

Although hyperkalemia is much more common in patients with chronic kidney disease (CKD), the reported frequency of hyperkalemia varies markedly across studies, primarily due to differences in the ascertainment of hyperkalemia and the severity of CKD. Major risk factors for hyperkalemia among CKD patients include lower estimated glomerular filtration rate (eGFR), use of renin-angiotensin-aldosterone system inhibitors (RAASis), diabetes, older age and male gender. The use of two drugs to inhibit RAAS in diabetic CKD markedly increases the risk of hyperkalemia, as demonstrated in large multicenter clinical trials. Hyperkalemia has consistently been associated with an increased risk of adverse events compared with normokalemia, including all-cause mortality and cardiovascular morbidity and mortality. This risk is not explained by differences in comorbidity or estimated GFR, nor concomitant metabolic abnormalities such as acidosis among those with hyperkalemia. Sodium polystyrene sulfonate has been used commonly for decades to treat hyperkalemia in CKD patients, but without any high-quality clinical data to support its efficacy and with an increased risk of rare but serious colonic complications. The newer oral potassium-binding agents, patiromer and sodium zirconium cyclosilicate, have been shown to be effective and safe for the non-emergent treatment of hyperkalemia in CKD patients, including patients treated with RAASis. Although the long-term use of these medications may permit continuation of RAASis in CKD patients with hyperkalemia, the overall impact of this approach (as compared with down-titration of RAASis and/or up-titration of diuretics) on long-term morbidity, mortality and quality of life remains uncertain.

Left ventricular hypertrophy in a contemporary cohort of autosomal dominant polycystic kidney disease patients.

BACKGROUND: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) often develop hypertension in childhood or early adulthood. Although this could result in left ventricular hypertrophy (LVH), a major risk factor for cardiovascular morbidity and mortality, prior studies of LVH in ADPKD have yielded conflicting results. We estimated the prevalence of LVH using consensus echocardiography criteria and examined the independent association of ADPKD severity with LV mass in a contemporary cohort of ADPKD patients. METHODS: Adults with ADPKD and eGFR> 15 ml/min/1.73m2 were enrolled in a single-center study. Left Ventricular Mass (LVM) was quantified using 2D echocardiography, and LVH was defined using gender-specific cut-points of LVM and LVM indexed to body surface area (LVMI) from consensus guidelines. Total Kidney Volume (TKV) was quantified using Magnetic Resonance Imaging, and GFR was estimated from serum creatinine using the CKD-Epi equation. Multiple linear regression was used to estimate the association of TKV and eGFR with LVM and LVMI, adjusting for potential confounders. RESULTS: Among 126 participants (78% with hypertension), median age was 46 years, median eGFR 63 ml/min/1.73 m2, and median [IQR] systolic blood pressure was 125 [116-133] mmHg. Prevalence of LVH was 21.4% as defined by LVMI and was not significantly different (p = 0.8) between those with and without HTN, and was similar (21.4%) after excluding those (N = 21) with known cardiac disease. Greater TKV and lower eGFR were directly correlated with greater LVMI (p = .016 and p < .001, respectively). In multiple linear regression models accounting for potential confounders including blood pressure, greater TKV was positively associated with LVM ([Formula: see text] =0.19, p = 0.04). CONCLUSIONS: In a contemporary cohort of ADPKD patients with well-controlled blood pressure, the prevalence of LVH is high, and ADPKD severity as reflected by TKV is independently associated with greater LV mass. These results may suggest a relationship between ADPKD pathophysiology and increased LV mass.

Cardiac function assessed by myocardial deformation in adult polycystic kidney disease patients.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease. METHODS: A total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group. RESULTS: There was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and ß-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and ß-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and ß-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only ß-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant. CONCLUSION: Higher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.

High-Sensitive Cardiac Troponin T as an Early Biochemical Signature for Clinical and Subclinical Heart Failure: MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND: Although small elevations of high-sensitive cardiac troponin T (hs-cTnT) are associated with incident heart failure (HF) in the general population, the underlying mechanisms are not well defined. Evaluating the association of hs-cTnT with replacement fibrosis and progression of structural heart disease before symptoms is fundamental to understanding the potential of this biomarker in a HF prevention strategy. METHODS: We measured hs-cTnT at baseline among 4986 participants in MESA (Multi-Ethnic Study of Atherosclerosis), a cohort initially free of overt cardiovascular disease (CVD). Cardiac magnetic resonance imaging was performed at baseline. Repeat cardiac magnetic resonance was performed 10 years later among 2831 participants who remained free of interim CVD events; of these, 1723 received gadolinium-enhanced cardiac magnetic resonance for characterization of replacement fibrosis by late gadolinium enhancement. Progression of subclinical CVD was defined by 10-year change in left ventricular structure and function. Associations of hs-cTnT with incident HF, CV-related mortality, and coronary heart disease were estimated using Cox regression models. RESULTS: Late gadolinium enhancement for replacement fibrosis was detectable in 6.3% participants without interim CVD events by follow-up cardiac magnetic resonance. A graded association was observed between higher baseline hs-cTnT categories and late gadolinium enhancement (≥7.42 ng/L versus 12% (highest category versus

Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts.

BACKGROUND: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. METHODS: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). RESULTS: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (P<0.05 for each). When the 5 tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (P=0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06-0.08, P<0.001) and category free net reclassification improvement (0.47; 95% CI, 0.38-0.56; P=0.003) were observed, and the model was well calibrated (χ2=12.2, P=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4-2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3-4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4-6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2-10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. CONCLUSIONS: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

A Randomized Clinical Trial of Metformin to Treat Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Metformin inhibits cyclic AMP generation and activates AMP-activated protein kinase (AMPK), which inhibits the cystic fibrosis transmembrane conductance regulator and Mammalian Target of Rapamycin pathways. Together these effects may reduce cyst growth in autosomal dominant polycystic kidney disease (ADPKD). METHODS: A phase II, double-blinded randomized placebo-controlled trial of 26 months duration. Participants will include nondiabetic adults (n = 96) aged 18-60 years, with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 and ADPKD, recruited from university-based practices in Baltimore and Boston. Participants will be randomized in 1: 1 ratio to metformin or placebo at 500 mg once daily, increased every 2 weeks to a maximum of 1,000 mg twice daily as tolerated. Dose is decreased if eGFR falls to 30-45 mL/min/1.73 m2 and discontinued at eGFR < 30 mL/min/1.73 m2. RESULTS: The primary outcomes are safety, assessed by the rates of hypoglycemia, elevated lactic acid levels, adverse events, and tolerability assessed by the Gastrointestinal Severity Rating Scale and maximum tolerated dose of study medication. Secondary outcomes include changes in total kidney and liver volumes, pain, and health-related quality of life, and changes in urinary metabolomic biomarkers. CONCLUSIONS: Results of this trial will provide important information on the feasibility, safety, and tolerability of long-term use of metformin in patients with -ADPKD and provide preliminary information regarding its efficacy in slowing disease progression. Furthermore, results may support or refute the hypothesis that metformin effects on disease progression are mediated through the activation of the AMPK pathway. These results will be essential for the justification and design of a full-scale efficacy trial.

Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis.

BACKGROUND: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction. AIM: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates. METHODS: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines. RESULTS: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism. CONCLUSIONS: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

Loss of executive function after dialysis initiation in adults with chronic kidney disease.

The association of dialysis initiation with changes in cognitive function among patients with advanced chronic kidney disease is poorly described. To better define this, we enrolled participants with advanced chronic kidney disease from the Chronic Renal Insufficiency Cohort in a prospective study of cognitive function. Eligible participants had a glomerular filtration rate of 20 ml/min/1.73m2 or less, or dialysis initiation within the past two years. We evaluated cognitive function by a validated telephone battery at regular intervals over two years and analyzed test scores as z scores. Of 212 participants, 123 did not transition to dialysis during follow-up, 37 transitioned to dialysis after baseline, and 52 transitioned to dialysis prior to baseline. In adjusted analyses, the transition to dialysis was associated with a significant loss of executive function, but no significant changes in global cognition or memory. The estimated net difference in cognitive z scores at two years for participants who transitioned to dialysis during follow-up compared to participants who did not transition to dialysis was -0.01 (95% confidence interval -0.13, 0.11) for global cognition, -0.24 (-0.51, 0.03) for memory, and -0.33 (-0.60, -0.07) for executive function. Thus, among adults with advanced chronic kidney disease, dialysis initiation was associated with loss of executive function with no change in other aspects of cognition. Larger studies are needed to evaluate cognition during dialysis initiation.

Differential Associations of Socioeconomic Status With Global Brain Volumes and White Matter Lesions in African American and White Adults: the HANDLS SCAN Study.

OBJECTIVE: The aim of the study was to examine interactive relations of race and socioeconomic status (SES) to magnetic resonance imaging (MRI)-assessed global brain outcomes with previously demonstrated prognostic significance for stroke, dementia, and mortality. METHODS: Participants were 147 African Americans (AAs) and whites (ages 33-71 years; 43% AA; 56% female; 26% below poverty) in the Healthy Aging in Neighborhoods of Diversity across the Life Span SCAN substudy. Cranial MRI was conducted using a 3.0 T unit. White matter (WM) lesion volumes and total brain, gray matter, and WM volumes were computed. An SES composite was derived from education and poverty status. RESULTS: Significant interactions of race and SES were observed for WM lesion volume (b = 1.38; η = 0.036; p = .028), total brain (b = 86.72; η = 0.042; p < .001), gray matter (b = 40.16; η = 0.032; p = .003), and WM (b = 46.56; η = 0.050; p < .001). AA participants with low SES exhibited significantly greater WM lesion volumes than white participants with low SES. White participants with higher SES had greater brain volumes than all other groups (albeit within normal range). CONCLUSIONS: Low SES was associated with greater WM pathology-a marker for increased stroke risk-in AAs. Higher SES was associated with greater total brain volume-a putative global indicator of brain health and predictor of mortality-in whites. Findings may reflect environmental and interpersonal stressors encountered by AAs and those of lower SES and could relate to disproportionate rates of stroke, dementia, and mortality.

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines.

BACKGROUND & AIMS: Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis. METHODS: From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, ß-trace protein, ß2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy. RESULTS: After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004). CONCLUSIONS: We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.