Faculty Bibliography

BACKGROUND:Potentially inappropriate medication (PIM) use is an important public health problem, particularly among older adults who may need multiple pharmacologic therapies for various chronic conditions. As socioeconomic status (SES) affects the quality of healthcare that individuals receive, SES may be associated with the use of PIM in older adults. This study aimed to determine whether low SES is associated with increased use of PIM. METHODS:We studied 4927 participants (aged 66-90 years) who were on at least one medication at visit five (2011-2013) of the Atherosclerosis Risk in Communities Study. We created a cumulative SES score categorized as high (7-9), middle (3-6), and low (0-2) based on education, income, and area deprivation index. We use multivariable logistic regression to examine the associations between SES and use of two or more PIM for older adults, defined by the 2019 Beers Criteria. RESULTS:A total of 31.0% and 6.9% of the participants used one or more PIM and two or more PIM, respectively. After adjusting for demographic characteristics and insurance type, low cumulative SES score was associated with significantly greater use of two or more PIM (odds ratio [OR] = 1.83 [95% confidence interval (CI) 1.18-2.86]), as was middle cumulative SES score (OR = 1.40 [95% CI 1.06-1.83]), compared to high cumulative SES score. The results remained significant after further adjusting for comorbidities and medication burden for low cumulative SES score (OR = 1.66 [95%CI 1.02-2.71]). CONCLUSIONS:We found that lower SES was associated with greater use of PIM among older adults independent of their medication burden and comorbidities, suggesting socioeconomic disparities in quality of medication management. Focused efforts targeting older adults with low SES to reduce PIM use may be needed to prevent adverse drug events.

SIGNIFICANCE STATEMENT:Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. This paper describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C. CMI was moderately associated with frailty among older adults. A significantly higher proportion of individuals with weak grip strength were in the lowest tertile of CMI. The index was also associated with mortality. These results are consistent with the hypothesis that creatinine filtration may be an index of muscle mass, which may have utility in clinical practice. BACKGROUND:Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. METHODS:This study describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C in a community-based sample of older adults from the Atherosclerosis Risk in Communities Study. Analyses included 4639 participants who attended visit 5 (2011-2013) and 12,786 participants who attended visit 2 (1990-1992). CMI was defined as creatinine filtration (the product of serum creatinine times eGFR on the basis of cystatin C) and was analyzed in sex-specific tertiles. Cross-sectional associations of CMI with a frailty trichotomy, defined by the number (robust [0]/prefrail [1-2]/frail [3-5]) of five frailty components (weight loss, slowness, exhaustion, weakness, and low physical activity), were studied using polychotomous logistic regression and binary logistic regression with each frailty component. Cox regression was used to estimate associations of CMI at visit 5 and visit 2 with mortality. Models were adjusted for demographics, clinical variables, and comorbid conditions. RESULTS:CMI (tertile 1 versus 3) was moderately associated with frailty (visit 5: adjusted odds ratio 4.23 [95% confidence interval (CI), 2.02 to 8.87] in men and 2.34 [95% CI, 1.41 to 3.89] in women) and with mortality (visit 5: adjusted hazard ratio 1.45 [95% CI, 1.08 to 1.94] in men and 1.55 [95% CI, 1.13 to 2.12] in women; similar results were seen at visit 2). CONCLUSION:Lower CMI was associated with frailty and increased mortality, two clinical outcomes known to be associated with decreased muscle mass. Creatinine filtration may be an index of muscle mass and have utility in clinical practice, particularly at low levels.

SIGNIFICANCE STATEMENT:The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict 2- and 5-year risk of kidney failure in populations with eGFR <60 ml/min per 1.73 m 2 . However, the CKD-EPI 2021 creatinine equation for eGFR is now recommended for use but has not been fully tested in the context of KFRE. In 59 cohorts comprising 312,424 patients with CKD, the authors assessed the predictive performance and calibration associated with the use of the CKD-EPI 2021 equation and whether additional variables and accounting for the competing risk of death improves the KFRE's performance. The KFRE generally performed well using the CKD-EPI 2021 eGFR in populations with eGFR <45 ml/min per 1.73 m 2 and was not improved by adding the 2-year prior eGFR slope and cardiovascular comorbidities. BACKGROUND:The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR <60 ml/min per 1.73 m 2 . METHODS:Using 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EPI 2021 creatinine equation for eGFR, substituting 1-year average ACR for single-measure ACR and 1-year average eGFR in participants with high eGFR variability, and adding 2-year prior eGFR slope and cardiovascular comorbidities. We also assessed calibration of the KFRE in subgroups of eGFR and age before and after accounting for the competing risk of death. RESULTS:The KFRE remained accurate and well calibrated overall using the CKD-EPI 2021 eGFR equation. The other modifications did not improve KFRE performance. In subgroups of eGFR 45-59 ml/min per 1.73 m 2 and in older adults using the 5-year time horizon, the KFRE demonstrated systematic underprediction and overprediction, respectively. We developed and tested a new model with a spline term in eGFR and incorporating the competing risk of mortality, resulting in more accurate calibration in those specific subgroups but not overall. CONCLUSIONS:The original KFRE is generally accurate for eGFR <45 ml/min per 1.73 m 2 when using the CKD-EPI 2021 equation. Incorporating competing risk methodology and splines for eGFR may improve calibration in low-risk settings with longer time horizons. Including historical averages, eGFR slopes, or a competing risk design did not meaningfully alter KFRE performance in most circumstances.

RATIONALE & OBJECTIVE:Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR. STUDY DESIGN:Cross-sectional study nested in a cohort study. SETTING & PARTICIPANTS:1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. PREDICTORS:-microglobulin (B2M). OUTCOMES:Brain volume reduction, infarcts, microhemorrhages, white matter lesions. ANALYTICAL APPROACH:Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. RESULTS:Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient: -0.07 [95% CI, -0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient: -0.08 [95% CI, -0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex. LIMITATIONS:No inference about longitudinal effects due to cross-sectional design. CONCLUSIONS:We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

AIM/OBJECTIVE:We sought to evaluate the performance of glycated albumin (GA) as a measure of hyperglycemia in pregnant women. METHODS:We used data from 555 pregnant women aged 20-40 years who participated in NHANES 1999-2004 and did not report a pre-pregnancy diagnosis of diabetes. We used Pearson's correlations and evaluated the area under the curve (AUC) for GA to detect elevated concentrations of random glucose, HbA1c, or fasting glucose (subset). We compared results to 1607 nonpregnant women aged 20-40 without diabetes. RESULTS:In pregnant women, 1.9 % had HbA1c ≥ 39 mmol/mol (≥5.7 %), 9.1 % had random glucose ≥ 5.3 mmol/L (≥95 mg/dL), and 10.7 % had fasting glucose ≥ 5.3 mmol/L. In pregnancy, GA was poorly correlated with HbA1c (r = 0.08) and random glucose (r = 0.17). BMI was positively associated with HbA1c (r = 0.33) and random glucose (r = 0.25) but was inversely associated with GA (r = -0.27). GA had poor discrimination for detecting hyperglycemia in pregnant women, defined as HbA1c ≥ 39 mmol/mol (AUC = 0.634) or random glucose ≥ 5.3 mmol/L (AUC = 0.628). Similar patterns were observed among nonpregnant women. CONCLUSIONS:GA is not a sensitive test to screen for hyperglycemia in pregnancy. GA was inversely associated with adiposity in pregnant women without diabetes. Pregnancy-related weight gain may complicate interpretation of repeated GA measurements.

RATIONALE & OBJECTIVE/OBJECTIVE:Anemia is common in chronic kidney disease (CKD); although anemia is associated with adverse outcomes, the available treatments are not ideal. We characterized the burden, risk factors for, and risks associated with anemia by estimated glomerular filtration rate (eGFR) and hemoglobin level. STUDY DESIGN/METHODS:Cross-sectional and prospective cohort study. SETTING & PARTICIPANTS/METHODS:Outpatient data from 5,004,957 individuals across 57 health care centers in the United States from 2016 to 2019, extracted from the Optum Labs Data Warehouse. EXPOSURE/METHODS:Severity of anemia, presence of low iron test results, eGFR. OUTCOME/RESULTS:Incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, death. ANALYTICAL APPROACH/METHODS:deficiency, and erythropoiesis-stimulating agent (ESA) use, stratified by sex and eGFR, were characterized. Polychotomous logistic regression was used to estimate the adjusted odds ratios of different hemoglobin levels across eGFR. Cox proportional hazards regression was used to calculate adjusted hazard ratios for adverse outcomes across hemoglobin level. RESULTS:The mean age was 54 years, and 42% were male. Lower eGFR was very strongly associated with increased prevalence of anemia, even after adjustment. Although iron studies were checked infrequently in patients with anemia, low iron test results were highly prevalent in those tested: 60.4% and 81.3% of men and women, respectively. ESA use was uncommon, with a prevalence of use of<4%. Lower hemoglobin was independently associated with increased risk of incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, and death. LIMITATIONS/CONCLUSIONS:Reliance on ICD codes for medical diagnoses, death information obtained from claims data, observational study. CONCLUSIONS:Severe anemia was common and strongly associated with lower eGFR and multiple adverse outcomes. Low-iron test results were highly prevalent in those tested despite iron studies being checked infrequently. ESA use in nondialysis CKD patients was uncommon.

AIMS/OBJECTIVE:The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach. METHODS:In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. RESULTS:In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. CONCLUSION/CONCLUSIONS:Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.