Use of cystatin C to inform metformin eligibility among adult veterans with diabetes.

AimsRecommendations for metformin use are dependent on eGFR category: eGFR >45 ml/min/1.73 m2 - "first-line agent"; eGFR 30-44 - "use with caution"; eGFR<30 - "do not use". Misclassification of metformin eligibility by creatinine-based MDRD GFR estimates (eGFRcr) may contribute to its misuse. We investigated the impact of cystatin c estimates of GFR (eGFRcys) on metformin eligibility.MethodsIn a consecutive cohort of 550 Veterans with diabetes, metformin use and eligibility were assessed by eGFR category, using eGFRcr and eGFRcys. Discrepancy in eligibility was defined as cases where eGFRcr and eGFRcys categories (<30, 30-44, 45-60, and >60 ml/min/1.73 m2) differed with an absolute difference in eGFR of >5 ml/min/1.73 m2. We modeled predictors of metformin use and eGFR category discrepancy with multivariable relative risk regression and multinomial logistic regression.ResultsSubjects were 95% male, median age 68, and racially diverse (45% White, 22% Black, 11% Asian, 22% unknown). Metformin use decreased with severity of eGFRcr category, from 63% in eGFRcr >60 to 3% in eGFRcr <30. eGFRcys reclassified 20% of Veterans into different eGFR categories. Factors associated with a more severe eGFRcys category compared to eGFRcr were older age (aOR = 2.21 per decade, 1.44-1.82), higher BMI (aOR = 1.04 per kg/m2, 1.01-1.08) and albuminuria >30 mg/g (aOR = 1.81, 1.20-2.73).ConclusionsMetformin use is low among Veterans with CKD. eGFRcys may serve as a confirmatory estimate of kidney function to allow safe use of metformin among patients with CKD, particularly among older individuals and those with albuminuria

Racial/ethnic heterogeneity in associations of blood pressure and incident cardiovascular disease by functional status in a prospective cohort: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES:Research has demonstrated that the association between high blood pressure and outcomes is attenuated among older adults with functional limitations, compared with healthier elders. However, it is not known whether these patterns vary by racial/ethnic group. We evaluated race/ethnicity-specific patterns of effect modification in the association between blood pressure and incident cardiovascular disease (CVD) by functional status. SETTING:We used data from the Multi-Ethnic Study of Atherosclerosis (2002-2004, with an average of 8.8 years of follow-up for incident CVD). We assessed effect modification of systolic blood pressure and cardiovascular outcomes by self-reported physical limitations and by age. PARTICIPANTS:The study included 6117 participants (aged 46 to 87; 40% white, 27% black, 22% Hispanic and 12% Chinese) who did not have CVD at the second study examination (when self-reported physical limitations were assessed). OUTCOME MEASURES:Incident CVD was defined as an incident myocardial infarction, coronary revascularisation, resuscitated cardiac arrest, angina, stroke (fatal or non-fatal) or death from CVD. RESULTS:We observed weaker associations between systolic blood pressure (SBP) and CVD among white adults with physical limitations (incident rate ratio (IRR) per 10 mm Hg higher SBP: 1.09 (95% CI 0.99 to 1.20)) than those without physical limitations (IRR 1.29 (1.19, 1.40); P value for interaction <0.01). We found a similar pattern among black adults. Poor precision among the estimates for Hispanic or Chinese participants limited the findings in these groups. The attenuated associations were consistent across both multiplicative and additive scales, though physical limitations showed clearer patterns than age on an additive scale. CONCLUSION:Attenuated associations between high blood pressure and incident CVD were observed for blacks and whites with poor function, though small sample sizes remain a limitation for identifying differences among Hispanic or Chinese participants. Identifying the characteristics that distinguish those in whom higher SBP is associated with less risk of morbidity or mortality may inform our understanding of the consequences of hypertension among older adults

Association of Tenofovir Use With Risk of Incident Heart Failure in HIV-Infected Patients.

BackgroundThe antiretroviral medication, tenofovir disoproxil fumarate (TDF), is used by most human immunodeficiency virus-infected persons in the United States despite higher risks of chronic kidney disease. Although chronic kidney disease is a strong risk factor for heart failure (HF), the association of TDF with incident HF is unclear.Methods and resultsWe identified 21 435 human immunodeficiency virus-infected patients in the United States Veterans Health Administration actively using antiretrovirals between 2002 and 2011. We excluded patients with a prior diagnosis of HF. TDF was analyzed categorically (current, past, or never use) and continuously (per year of use). Proportional hazards regression and fully adjusted marginal structural models were used to determine the association of TDF exposure with risk of incident HF after adjustment for demographic, human immunodeficiency virus-related, and cardiovascular risk factors. During follow-up, 438 incident HF events occurred. Unadjusted 5-year event rates for current, past, and never users of TDF were 0.9 (95%CI 0.7-1.1), 1.7 (1.4-2.2), and 4.5 (3.9-5.0), respectively. In fully adjusted analyses, HF risk was markedly lower in current TDF users (HR=0.68; 95%CI 0.53-0.86) compared with never users. Among current TDF users, each additional year of TDF exposure was associated with a 21% lower risk of incident HF (95%CI: 0.68-0.92). When limited to antiretroviral-naive patients, HF risk remained lower in current TDF users (HR=0.53; 95%CI 0.36-0.78) compared to never users.ConclusionsAmong a large national cohort of human immunodeficiency virus-infected patients, TDF use was strongly associated with lower risk of incident HF. These findings warrant confirmation in other populations, both with TDF and the recently approved tenofovir alafenamide fumarate

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi-Ethnic Study of Atherosclerosis).

BACKGROUND:APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self-identified black participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS AND RESULTS:Cross-sectional associations of APOL1 genotypes (high-risk=2 alleles; low-risk=0 or 1 allele) with coronary artery calcification, carotid-intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C-based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high-risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid-intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high-risk group was 82% more likely to develop incident heart failure compared with the low-risk group (95% confidence interval, 1.01-3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00-3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03-3.35) slightly attenuated this association. The APOL1 high-risk genotypes were not significantly associated with other clinical CVD outcomes. CONCLUSIONS:Among blacks without baseline CVD, the APOL1 high-risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD

Association of urinary uromodulin with kidney function decline and mortality: the health ABC study .

BackgroundUrine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes.MethodsUsing a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression.ResultsThe median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment.ConclusionHigher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.


Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk.</p> <p>Methods</p> <p>In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race.</p> <p>Results</p> <p>Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88).</p> <p>Conclusions</p> <p>This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations.</p