Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C.

BACKGROUND: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. OBJECTIVE: To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. DESIGN: Population-based cohort study. SETTING: Stockholm, Sweden, 2010 to 2019. PARTICIPANTS: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION: No GFR measurements. CONCLUSION: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Premorbid physical activity and prognosis after incident myocardial infarction: The atherosclerosis risk in communities study.

BACKGROUND: High to moderate levels of physical activity (PA) are associated with low risk of incident cardiovascular disease. However, it is unclear whether the benefits of PA in midlife extend to cardiovascular health following myocardial infarction (MI) in later life. METHODS: Among 1,111 Atherosclerosis Risk in Communities study participants with incident MI during Atherosclerosis Risk in Communities follow-up (mean age 73 [SD 9] years at MI, 54% men, 21% Black), PA on average 11.9 (SD 6.9) years prior to incident MI (premorbid PA) was evaluated as the average score of PA between visit 1 (1987-1989) and visit 3 (1993-1995) using a modified Baecke questionnaire. Total and domain-specific PA (sport, nonsport leisure, and work PA) was analyzed for associations with composite and individual outcomes of mortality, recurrent MI, and stroke after index MI using multivariable Cox models. RESULTS: During a median follow-up of 4.6 (IQI 1.0-10.5) years after incident MI, 823 participants (74%) developed a composite outcome. The 10-year cumulative incidence of the composite outcome was lower in the highest, as compared to the lowest tertile of premorbid total PA (56% vs. 70%, respectively). This association remained statistically significant even after adjusting for potential confounders (adjusted hazard ratio [aHR] 0.80 [0.67-0.96] for the highest vs. lowest tertile). For individual outcomes, high premorbid total PA was associated with a low risk of recurrent MI (corresponding aHR 0.64 [0.44, 0.93]). When domain-specific PA was analyzed, similar results were seen for sport and work PA. The association was strongest in the first year following MI (e.g., aHR of composite outcome 0.66 [95% CI 0.47, 0.91] for the highest vs. lowest tertile of total PA). CONCLUSIONS: Premorbid PA was associated positively with post-MI cardiovascular health. Our results demonstrate the additional prognostic advantages of PA beyond reducing the risk of incident MI.

Serum creatinine and serum cystatin C as an index of muscle mass in adults.

PURPOSE OF REVIEW: Serum creatinine reflects both muscle mass and kidney function. Serum cystatin C has recently been recommended as an additional marker for estimating kidney function, and use of both markers together may provide an index of muscle mass. This review aims to describe the biological basis for and recent research examining the relationship of these markers to muscle mass in a range of adult populations and settings. RECENT FINDINGS: This review identified 67 studies, 50 of which had direct measures of muscle mass, and almost all found relationships between serum creatinine and cystatin C and muscle mass and related outcomes. Most studies have been performed in older adults, but similar associations were found in general populations as well as in subgroups with cancer, chronic kidney disease (CKD), and other morbid conditions. Creatinine to cystatin C ratio was the measure examined the most often, but other measures showed similar associations across studies. SUMMARY: Measures of serum creatinine and cystatin C together can be an index of muscle mass. They are simple and reliable measures that can be used in clinical practice and research. Further study is needed to determine actionable threshold values for each measure and clinical utility of testing and intervention.

Glucagon-like peptide-1 receptor agonists and the risk of atrial fibrillation in adults with diabetes: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.

A Novel Creatinine Muscle Index Based on Creatinine Filtration: Associations with Frailty and Mortality.

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.

The Kidney Failure Risk Equation: Evaluation of Novel Input Variables including eGFR Estimated Using the CKD-EPI 2021 Equation in 59 Cohorts.

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.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Anemia Prevalence, Type, and Associated Risks in a Cohort of 5.0 Million Insured Patients in the United States by Level of Kidney Function.

RATIONALE & 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: Cross-sectional and prospective cohort study. SETTING & PARTICIPANTS: 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: Severity of anemia, presence of low iron test results, eGFR. OUTCOME: Incident kidney failure with replacement therapy, cardiovascular disease, coronary heart disease, stroke, heart failure, death. ANALYTICAL APPROACH: The prevalences of anemia, low iron test results, vitamin B12 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: 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.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Conventional and Novel Lipid Measures and Risk of Peripheral Artery Disease.

OBJECTIVE: The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD). Approach and Results: We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996-1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08-1.36); RLP-C, 1.18 (1.08-1.29); LDL-TG, 1.18 (1.05-1.33); HDL-C, 1.39 (1.16-1.67); and Apo-E-HDL, 1.27 (1.07-1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD. CONCLUSIONS: Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones. Graphic Abstract: A graphic abstract is available for this article.

Association of Estimated GFR Calculated Using Race-Free Equations With Kidney Failure and Mortality by Black vs Non-Black Race.

Importance: At a given estimated glomerular filtration rate (eGFR), individuals who are Black have higher rates of mortality and kidney failure with replacement therapy (KFRT) compared with those who are non-Black. Whether the recently adopted eGFR equations without race preserve racial differences in risk of mortality and KFRT at a given eGFR is unknown. Objective: To assess whether eGFR equations with and without race and cystatin C document racial differences in risk of KFRT and mortality in populations including Black and non-Black participants. Design, Setting, and Participants: Retrospective individual-level data analysis of 62 011 participants from 5 general population and 3 chronic kidney disease (CKD) US-based cohorts with serum creatinine, cystatin C, and follow-up for KFRT and mortality from 1988 to 2018. Exposures: Chronic Kidney Disease Epidemiology Collaboration equation with serum creatinine (eGFRcr with and without race), cystatin C (eGFRcys without race), or both markers (eGFRcr-cys without race). Main Outcomes and Measures: The prevalence of decreased eGFR at baseline and hazard ratios of KFRT and mortality in Black vs non-Black participants were calculated, adjusted for age and sex. Analyses were performed within each cohort and with random-effect meta-analyses of the models. Results: Among 62 011 participants (20 773 Black and 41 238 non-Black; mean age, 63 years; 53% women), the prevalence ratio (95% CI; percent prevalences) of eGFR less than 60 mL/min/1.73 m2 comparing Black with non-Black participants was 0.98 (95% CI, 0.93-1.03; 11% vs 12%) for eGFRcr with race, 0.95 (95% CI, 0.91-0.98; 17% vs 18%) for eGFRcys, and 1.2 (95% CI, 1.2-1.3; 13% vs 11%) for eGFRcr-cys but was 1.8 (95% CI, 1.7-1.8; 15% vs 9%) for eGFRcr without race. During a mean follow-up of 13 years, 8% and 4% of Black and non-Black participants experienced KFRT and 34% and 39% died, respectively. Decreased eGFR was associated with significantly greater risk of both outcomes for all equations. At an eGFR of 60 mL/min/1.73 m2, the hazard ratios for KFRT comparing Black with non-Black participants were 2.8 (95% CI, 1.6-4.9) for eGFRcr with race, 3.0 (95% CI, 1.5-5.8) for eGFRcys, and 2.8 (95% CI, 1.4-5.4) for eGFRcr-cys vs 1.3 (95% CI, 0.8-2.1) for eGFRcr without race. The 5-year absolute risk differences for KFRT comparing Black with non-Black participants were 1.4% (95% CI, 0.2%-2.6%) for eGFRcr with race, 1.1% (95% CI, 0.2%-1.9%) for eGFRcys, and 1.3% (95% CI, 0%-2.6%) for eGFRcr-cys vs 0.37% (95% CI, -0.32% to 1.05%) for eGFRcr without race. Similar patterns were observed for mortality. Conclusions and Relevance: In this retrospective analysis of 8 US cohorts including Black and non-Black individuals, the eGFR equation without race that included creatinine and cystatin C, but not the eGFR equation without race that included creatinine without cystatin C, demonstrated racial differences in the risk of KFRT and mortality throughout the range of eGFR. The eGFRcr-cys equation may be preferable to the eGFRcr equation without race for assessing racial differences in the risk of KFRT and mortality associated with low eGFR.

Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 14,537 participants aged 45 to 64 years. PREDICTORS: Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. OUTCOMES: Incident CKD defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). LIMITATIONS: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded. CONCLUSIONS: Highly active participants had lower risk for developing CKD compared with inactive participants.

Fibrosis and Inflammatory Markers and Long-Term Risk of Peripheral Artery Disease: The ARIC Study.

OBJECTIVE: Inflammatory markers, such as hs-CRP (high-sensitivity C-reactive protein), have been reported to be related to peripheral artery disease (PAD). Galectin-3, a biomarker of fibrosis, has been linked to vascular remodeling and atherogenesis. However, its prospective association with incident PAD is unknown; as is the influence of inflammation on the association between galectin-3 and PAD. Approach and Results: In 9851 Atherosclerosis Risk in Communities Study participants free of PAD at baseline (1996-1998), we quantified the association of galactin-3 and hs-CRP with incident PAD (hospitalizations with PAD diagnosis [International Classification of Diseases-Ninth Revision: 440.2-440.4] or leg revascularization [eg, International Classification of Diseases-Ninth Revision: 38.18]) as well as its severe form, critical limb ischemia (PAD cases with resting pain, ulcer, gangrene, or leg amputation) using Cox models. Over a median follow-up of 17.4 years, there were 316 cases of PAD including 119 critical limb ischemia cases. Log-transformed galectin-3 was associated with incident PAD (adjusted hazard ratio, 1.17 [1.05-1.31] per 1 SD increment) and critical limb ischemia (1.25 [1.05-1.49] per 1 SD increment). The association was slightly attenuated after further adjusting for hs-CRP (1.14 [1.02-1.27] and 1.22 [1.02-1.45], respectively). Log-transformed hs-CRP demonstrated robust associations with PAD and critical limb ischemia even after adjusting for galectin-3 (adjusted hazard ratio per 1 SD increment 1.34 [1.18-1.52] and 1.34 [1.09-1.65], respectively). The addition of galectin-3 and hs-CRP to traditional atherosclerotic predictors (C statistic of the base model 0.843 [0.815-0.871]) improved the risk prediction of PAD (ΔC statistics, 0.011 [0.002-0.020]). CONCLUSIONS: Galectin-3 and hs-CRP were independently associated with incident PAD in the general population, supporting the involvement of fibrosis and inflammation in the pathophysiology of PAD.

Conversion of Urine Protein-Creatinine Ratio or Urine Dipstick Protein to Urine Albumin-Creatinine Ratio for Use in Chronic Kidney Disease Screening and Prognosis : An Individual Participant-Based Meta-analysis.

BACKGROUND: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead. OBJECTIVE: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging. DESIGN: Individual participant-based meta-analysis. SETTING: 12 research and 21 clinical cohorts. PARTICIPANTS: 919 383 adults with same-day measures of ACR and PCR or dipstick protein. MEASUREMENTS: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g). RESULTS: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR. LIMITATION: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample. CONCLUSION: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation.

The FDA Metformin Label Change and Racial and Sex Disparities in Metformin Prescription among Patients with CKD.

BACKGROUND: In 2016, the Food and Drug Administration (FDA) changed labeling regarding metformin contraindications in patients with diabetes and CKD from using serum creatinine-based thresholds to using eGFR-based thresholds. Because race and sex affect serum creatinine levels independently of GFR, the earlier creatinine-based contraindication may have inadvertently caused racial and sex disparities in metformin prescription among patients with low eGFR. METHODS: In an analysis of 15,946 Black and White primary care patients with diabetes and eGFR≥30 ml/min per 1.73 m2 in a large health system (the primary cohort), we assessed the association of race and sex with metformin prescription across eGFR level before and after the FDA label change. For a replication cohort, we meta-analyzed data from 36 cohorts with 1,051,723 patients from OptumLabs Data Warehouse. RESULTS: In the primary cohort, before the label change, Black patients with eGFR of 30-44 ml/min per 1.73 m2 were prescribed metformin less often than White counterparts (adjusted prevalence ratio [aPR], 0.65; 95% confidence interval [95% CI], 0.52 to 0.82); this disparity was significantly attenuated after the label change (aPR, 0.90; 95% CI, 0.74 to 1.09; P value for interaction by period =0.04). Results were consistent in the replication cohorts. Men with eGFR of 30-44 ml/min per 1.73 m2 received metformin prescriptions less often than women counterparts before the label change; this was nonsignificantly attenuated after the label change, but we found significant attenuation in the replication cohorts (aPRpre-label change, 0.76; 95% CI, 0.73 to 0.79; aPRpost-label change, 0.85; 95% CI, 0.83 to 0.88; P value for interaction by period <0.001). CONCLUSIONS: The metformin label change to an eGFR-based contraindication may have reduced racial and sex disparities in metformin prescription in moderate kidney dysfunction.

Albuminuria, Kidney Function, and Cancer Risk in the Community.

Few studies have comprehensively investigated the association of 2 key kidney disease measures, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), with cancer incidence. In 8,935 participants at the baseline (1996-1998) from the Atherosclerosis Risk in Communities study, we quantified the associations of eGFR (based on creatinine and cystatin C) and ACR with cancer risk using Cox regression models adjusted for potential confounders. Due to changing guidelines for prostate cancer screening during the follow-up period, we investigated overall cancer, overall nonprostate cancer, and site-specific cancer. During a median follow-up of 14.7 years, 2,030 incident cancer cases occurred. In demographically adjusted models, low eGFR and high ACR were associated with cancer incidence (both overall and overall nonprostate cancer). These associations were attenuated after adjusting for other shared risk factors, with a significant association remaining only for ACR (≥103 compared with 5 mg/g) and overall nonprostate cancer. For site-specific cancer, only high ACR showed a significant association with lung and urinary tract cancers. Of these, the association between ACR and lung cancer appeared most robust in several sensitivity analyses. Kidney disease measures, particularly high ACR, were independently associated with cancer risk. The association between ACR and lung cancer was uniquely robust, warranting future studies to explore potential mechanisms.

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

Evaluating Glomerular Filtration Rate Slope as a Surrogate End Point for ESKD in Clinical Trials: An Individual Participant Meta-Analysis of Observational Data.

BACKGROUND: Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR. METHODS: To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m2 and 122,664 participants with eGFR<60 ml/min per 1.73 m2 from 14 cohorts followed for an average of 4.2 years. RESULTS: Slower eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m2 (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m2 (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m2 per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%. CONCLUSIONS: Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m2, but those with the highest risk would be expected to benefit the most.