Faculty Bibliography

BACKGROUND/UNASSIGNED:Urinary albumin-creatinine ratio (UACR) and urinary protein-creatinine ratio (UPCR) are both used in clinical practice to diagnose and monitor chronic kidney disease (CKD). Which measure exhibits stronger associations with clinical outcomes and whether this varies by patient characteristics are unknown. OBJECTIVE/UNASSIGNED:To assess and compare the performance of UACR and UPCR across CKD-related clinical outcomes. DESIGN/UNASSIGNED:Individual patient-level meta-analysis. SETTING/UNASSIGNED:38 research and clinical cohorts. PARTICIPANTS/UNASSIGNED:148 994 participants with same-day measurements of UACR and UPCR. MEASUREMENTS/UNASSIGNED:, and glomerular disease. RESULTS/UNASSIGNED:, diabetes, and glomerular disease. Associations between UACR and UPCR were generally similar for cardiovascular outcomes but favored UACR in subgroups with moderately to severely elevated UACR. LIMITATION/UNASSIGNED:Assessment of UACR and UPCR in spot urine samples. CONCLUSION/UNASSIGNED:Overall, UACR was more strongly associated with kidney failure than UPCR (particularly in subgroups with higher UACR), supporting the use of UACR rather than UPCR to diagnose and risk-stratify patients. PRIMARY FUNDING SOURCE/UNASSIGNED:National Kidney Foundation and National Institute of Diabetes and Digestive and Kidney Diseases.

IMPORTANCE/UNASSIGNED:Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear. OBJECTIVES/UNASSIGNED:To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes. DATA SOURCES/UNASSIGNED:Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC). STUDY SELECTION/UNASSIGNED:Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy. RESULTS/UNASSIGNED:A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.

BACKGROUND:Prior prediction equations for heart failure (HF) omitted cardiac biomarkers and used select populations. We assessed the added value of NT-proBNP (NT-terminal pro-brain natriuretic peptide) and hsTnT (high-sensitivity troponin T) as predictors of HF, across a broad population, including participants with chronic kidney disease or atherosclerotic cardiovascular disease. METHODS:Among 41 427 individuals free of HF from 9 prospective cohort studies, we performed an individual-participant data meta-analysis, quantifying the associations of NT-proBNP and hsTnT with incident HF when added to a clinical model. Changes in Harrel's C-statistic with and without NT-proBNP or hsTnT were estimated within each cohort and then pooled using random effects meta-analysis. RESULTS:<0.001). CONCLUSIONS:NT-proBNP improved risk discrimination of incident HF when added to traditional HF risk factors, even in individuals with chronic kidney disease and atherosclerotic cardiovascular disease. The contribution of hsTnT was modest. Measurement of NT-proBNP may help identify individuals at risk of HF.

BACKGROUND:Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results. METHODS:This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure. RESULTS:Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06-1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis. DISCUSSION/CONCLUSIONS:Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

BACKGROUND:Few studies have comprehensively examined health outcomes among older caregivers. We aimed to describe older caregivers and characterize risks for mortality and hospitalization compared to non-caregivers. METHODS:Caregiving status and characteristics were determined for Atherosclerosis Risk in Communities (ARIC) Study participants via a one-time telephone assessment in 2015. All-cause mortality was identified from active surveillance, state records, and linkage to the National Death Index through December 31, 2021. Hospitalizations were identified from active cohort surveillance. Cox proportional hazard models assessed risks of mortality and hospitalization. RESULTS:Among 5,239 ARIC participants [mean age: 75.4 (SD 5.1) years; female: 60.0%; Black: 18.9%], 427 (8.2%) reported caregiving. Caregivers were generally female and younger as compared to non-caregivers. Most caregivers provided care for their spouse (55.0%) and 28.3% reported spending >40 hours/week on caregiving activities. Caregivers had modestly better cognitive scores but were similar to non-caregivers in the number of comorbidities and self-rated health. During a mean 5.4 (SD 1.3) years of follow-up, caregivers had a lower risk of mortality than non-caregivers (18.7% vs. 23.8%), although not statistically significant in fully adjusted time-to-event models (hazard ratio [HR]=0.84; 95%CI:0.67-1.06). Caregivers and non-caregivers had similar risk of hospitalization (63.5% vs. 64.9%; HR = 1.00; 95%CI:0.89-1.14). CONCLUSIONS:Older caregivers provide substantial care while facing their own health challenges. Despite similar baseline comorbidity burdens as non-caregivers, caregivers had a lower risk of all-cause mortality over the 6 years of follow-up. Future studies should examine the potential protective factors of caregiving in older age to inform caregiver support initiatives for older adults providing care.

BACKGROUND:Our understanding of traditional atherosclerotic risk factors is based predominantly on one-time measurements and associations with adverse cardiovascular outcomes. OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate the contribution of mid- to late-life cumulative risk factor exposure to healthy arterial aging, represented by a persistent coronary artery calcium (CAC) score of zero. METHODS:Among 2,044 community-dwelling, participants free of coronary heart disease from the ARIC (Atherosclerosis Risk in Communities) study, the associations of ∼30-year time-weighted average mid- to late-life (starting at a median age of 49 years in 1987-1989) traditional atherosclerotic risk factors (cholesterol, systolic blood pressure, fasting glucose, and smoking) with late-life (median age 80 years in 2018-2019) CAC 0 were evaluated. RESULTS:A total of 204 participants (10.0%) had CAC 0, and they tended to have more favorable mid- to late-life average risk factor profiles than those with CAC: lower total cholesterol, especially <160 mg/dL; lower systolic blood pressure, especially <125 mm Hg; and higher high-density lipoprotein cholesterol, especially >45 mg/dL. The association was less evident for fasting glucose, with no increased probability of CAC 0 at <95 mg/dL. Never smoking was associated with a 5.7 (95% CI: 2.3-16.7) times greater odds of CAC 0 vs smoking throughout mid- to late-life. Within sex-race groups, average modifiable risk factors predicted substantial differences in CAC 0 probability (eg, for a Black woman, 53% vs 0.4% for a low vs high risk factor profile, respectively). CONCLUSIONS:Favorable average risk factor profiles at mid- to late-life were associated with a greater probability of CAC 0 at older age. These results highlight the importance of maintaining a healthy risk factor profile from mid- to late-life, with implications for public health promotion and policy.

AIMS/OBJECTIVE:Carotid-femoral pulse wave velocity (cfPWV) is a representative measure of central arterial stiffness and an independent predictor of cardiovascular disease (CVD). Femoral-ankle PWV (faPWV) represents peripheral arterial stiffness, but its association with CVD has not been specifically investigated. METHODS:We analyzed 3,402 ARIC participants without prior coronary heart disease (CHD), heart failure (HF), or stroke at Visit 5 (2011-13) (mean age 74.8 [4.9] years, 36.1% male, 22.0% Black). faPWV and cfPWV were measured by Omron VP-1000 Plus. The primary outcome was CVD (CHD, HF, and stroke). We used multivariable Cox proportional hazards models. RESULTS:During a median 9.0-year follow-up, 607 CVD events occurred. Overall, faPWV showed an inverse association with CVD, with hazard ratio (HR) for top vs. bottom quartile 0.80 (95%CI 0.64-1.01) and p-for-trend 0.017 in Model 1 (demographically adjusted) and HR 0.86 (0.68-1.09) and p-for-trend 0.096 in Model 2 (further adjusted for CVD risk factors). In contrast, cfPWV was positively associated with CVD in both Models (HR for top vs. bottom quartile 1.22 [0.95-1.56], p-for-trend=0.043 in Model 2). The ratio of cfPWV to faPWV ("cf-fa ratio") showed a stronger association with CVD (HR 1.37 [1.07-1.74], p-for-trend=0.005) than cfPWV. Examining CVD subtypes, the significant contrast in Model 2 was cf-fa ratio and HF. CONCLUSIONS:faPWV showed a borderline significant inverse association with CVD, and cf-fa ratio appeared more strongly associated with CVD than cfPWV. Our findings indicate distinct prognostic implications of central vs. peripheral arterial stiffness and support cf-fa ratio as an alternative measure for CVD risk assessment.

IMPORTANCE/UNASSIGNED:Characterizing population-level changes in type 1 diabetes (T1D) management can inform public health policies and interventions. OBJECTIVE/UNASSIGNED:To characterize trends and disparities in glycemic control and use of diabetes technology among US youths and adults with T1D. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This serial, cross-sectional analysis used the Optum Labs Data Warehouse, a national, deidentified database of electronic health records, to identify US youths (aged <18 years) and adults (aged ≥18 years) with T1D. Data were obtained from records from January 1, 2009, to December 31, 2023. EXPOSURES/UNASSIGNED:Calendar years divided into 3-year study periods from 2009 to 2011 to 2021 to 2023. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Glycemic control (mean hemoglobin A1c level, <7%) and use of diabetes technology (continuous glucose monitoring systems and/or insulin pumps) were defined using laboratory data and prescriptions, procedures, and diagnoses codes from electronic health records. RESULTS/UNASSIGNED:A total of 186 590 participants with T1D was identified (mean [SD] age, 40 [19] years; 96 766 [52%] male; 12 493 [7%] Hispanic, 2819 [2%] non-Hispanic Asian, 21 459 [12%] non-Hispanic Black, and 141 847 [76%] non-Hispanic White). Of these, 26 853 participants were youths (mean [SD] age, 12 [4] years; 14 060 [52%] male; 19 822 [74%] non-Hispanic White) and 159 737 were adults (mean [SD] age, 45 [16] years; 82 706 [52%] male; 122 025 [76%] non-Hispanic White). From the 2009-2011 to 2021-2023 study periods, the prevalence of glycemic control (mean hemoglobin A1c level <7%) increased from 7% (95% CI, 7%-8%) to 19% (95% CI, 19%-20%) in youths (P < .001 for trend) and 21% (95% CI, 21%-22%) to 28% (95% CI, 28%-29%) in adults (P < .001 for trend). During this same period, there was a substantial increase in the percentage of patients using continuous glucose monitoring (4% to 82% for youths; 5% to 57% for adults), insulin pumps (16% to 50% for youths; 11% to 29% for adults), and both devices concurrently (1% to 47% for youths; 1% to 22% for adults) (P < .001 for trend for all). The prevalence of glycemic control and use of diabetes technology were lowest in Hispanic, non-Hispanic Black, and Medicaid-insured youths and adults, and differences persisted or increased over time. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cross-sectional study, there was a rapid increase in the use of diabetes technology and notable improvements in glycemic control among youths and adults with T1D during the past 15 years. Nonetheless, the prevalence of glycemic control remained low, and racial, ethnic, and socioeconomic differences grew over time.

BACKGROUND/UNASSIGNED:Infections are a major cause of hospitalization in people with chronic kidney disease (CKD), with incidence similar to cardiovascular disease, yet the risk of infection has not been systematically studied across stages of CKD. METHODS/UNASSIGNED:We conducted a meta-analysis of individual participant data including 1,246,912 individuals across 47 cohorts in the CKD Prognosis Consortium, with information on estimated glomerular filtration rate based on serum creatinine (eGFRcr) and urinary albuminuria (ACR) (or proteinuria converted to ACR), to examine the association of eGFR and ACR with the risk of hospitalization with infection. Outcomes were ascertained through diagnostic codes on hospital discharge records relevant to acute infections (i.e., upper and lower respiratory tract, urinary tract, skin and soft tissue, musculoskeletal, gastrointestinal tract, genital, nervous system, and cardiovascular system infections, and sepsis). Follow-up was censored on December 31, 2019 or on the last date of cohort follow-up, whichever was earlier. Multivariable Cox models were used to estimate hazard ratios (HRs). FINDINGS/UNASSIGNED:in eGFR and 1.48 [1.44-1.53] per 8-fold increase in ACR). INTERPRETATION/UNASSIGNED:Lower kidney function and higher albuminuria were independently associated with higher risk of infection. The risk was elevated even in mild to moderate CKD, with the highest risk seen in the most advanced stage of CKD. Infection prevention measures should target individuals across all CKD stages. FUNDING/UNASSIGNED:US National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases.

RATIONALE & OBJECTIVE/OBJECTIVE:Arterial stiffness is associated with prevalent chronic kidney disease (CKD). Whether arterial stiffness is prospectively associated with incident CKD is inconclusive. STUDY DESIGN/METHODS:Longitudinal cohort study. SETTING & PARTICIPANTS/METHODS:Using data from the Atherosclerosis Risk in Communities (ARIC) Study, the primary analysis included 3,161 participants without prevalent CKD at visit 5; a secondary analysis studied 4,341 participants with any estimated glomerular filtration rate (eGFR) record across visits 5 to 7. EXPOSURE/METHODS:Carotid-femoral pulse wave velocity (cfPWV), heart-femoral PWV (hfPWV), heart-ankle PWV (haPWV), brachial-ankle PWV (baPWV), heart-carotid PWV (hcPWV), and femoral-ankle PWV (faPWV). OUTCOMES/RESULTS:accompanied by >25% decline eGFR or CKD hospitalization. Secondary analysis - eGFR slope. ANALYTICAL APPROACH/METHODS:Primary analysis - Cox regression models to calculate hazard ratio (HR). Secondary analysis - multilevel mixed effects models to estimate the eGFR slope across visits. RESULTS:/year [95% CI, -0.56 to -0.33] in Q4 versus -0.37 [95% CI, -0.48 to -0.26] in Q1). All p-value <0.05. faPWV was not associated with incident CKD or eGFR slope. LIMITATIONS/CONCLUSIONS:Residual confounding. CONCLUSIONS:Greater arterial stiffness, especially higher cfPWV, hfPWV, and haPWV, was prospectively associated with a higher risk of incident CKD and faster decline in eGFR among community-dwelling older adults, supporting a pathophysiological contribution of arterial stiffness to the development of CKD.