Long-term visit-to-visit variability in hemoglobin A1c and kidney-related outcomes in persons with diabetes

Rationale & Objective: To characterize associations between long-term visit-to-visit variability of hemoglobin A(1c) (HbA(1c)) and risk of adverse kidney outcomes in patients with diabetes.Study Design: Observational study.Setting & Participants: 93,598 adults with diabetes undergoing routine care in Stockholm, Sweden.Exposures and Predictors: Categories of baseline and time-varying HbA(1c) variability score (HVS, the percentage of total HbA(1c) measures that vary by >0.5% [5.5 mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group.Outcome: Chronic kidney disease (CKD) progression (composite of >50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations ac-cording to KDIGO criteria), and worsening of albuminuria.Analytical Approach: Multivariable Cox proportional hazards regression.Results: Compared with persons showing low HbA(1c) variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA(1c). For example, for patients with a baseline HbA(1c) variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.3 6] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA(1c) or alternative metrics of variability.Limitations: Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration.Conclusions: Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria.Clinical epidemiolog

Particulate matter and albuminuria, glomerular filtration rate, and incident ckd

Background and objectives Exposure to particulate matter (PM),2.5 mm in aerodynamic diameter (PM2.5) has been linked to detrimental health effects. This study aimed to describe the relationship between long-term PM2.5 exposure and kidney disease, including eGFR, level of albuminuria, and incident CKD. Design, setting, participants, & measurements The study included 10,997 participants from the Atherosclerosis Risk in Communities cohort who were followed from 1996–1998 through 2016. Monthly mean PM2.5 concentrations (mg/m3 ) were estimated at geocoded participant addresses using geographic information system–based, spatiotemporal generalized additive mixed models—including geospatial covariates such as land use—and then averaged over the 12-month period preceding participant examination. Covariate-adjusted, cross-sectional associations of PM2.5, baseline eGFR, and urinary albumin-creatinine ratio (UACR) were estimated using linear regression. PM2.5 and incident CKD (defined as follow-up eGFR,60 ml/min per 1.73 m2 with $25% eGFR decline relative to baseline, CKD-related hospitalization or death based on International Classification of Diseases 9/10 codes, or development of ESKD) associations were estimated using Cox proportional hazards regression. Modeling was stratified by study site, and stratum-specific estimates were combined using random-effects meta-analyses. Results Baseline mean participant age was 63 (66) years and eGFR was 86 (616) ml/min per 1.73 m2. There was no significant PM2.5-eGFR association at baseline. Each 1-mg/m3 higher annual average PM2.5 was associated with higher UACR after adjusting for demographics, socioeconomic status, and clinical covariates (percentage difference, 6.6%; 95% confidence interval [95% CI], 2.6% to 10.7%). Each 1-mg/m3 higher annual average PM2.5 was associated with a significantly higher risk of incident CKD (hazard ratio, 1.05; 95% CI, 1.01 to 1.10). Conclusions Exposure to higher annual average PM2.5 concentrations was associated with a higher level of albuminuria and higher risk for incident CKD in a community-based cohort

Association Between Midlife Obesity and Kidney Function Trajectories: The Atherosclerosis Risk in Communities (ARIC) Study

Rationale & Objective: Obesity has been related to risk for chronic kidney disease. However, the associations of different measures of midlife obesity with long-term kidney function trajectories and whether they differ by sex and race are unknown. Study Design: Observational study. Setting & Participants: 13,496 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Predictors: Midlife obesity status as measured by body mass index (BMI), waist-to-hip ratio, and predicted percent fat at baseline. Outcomes: Estimated glomerular filtration rate (eGFR) calculated using serum creatinine level measured at 5 study visits, and incident kidney failure with replacement therapy (KFRT). Analytical Approach: Mixed models with random intercepts and random slopes for eGFR. Cox proportional hazards models for KFRT. Results: Baseline mean age was 54 years, median eGFR was 103 mL/min/1.73 m2, and median BMI was 27 kg/m2. Over 30 years of follow-up, midlife obesity measures were associated with eGFR decline in White and Black women but not consistently in men. Adjusted for age, center, smoking, and coronary heart disease, the differences in eGFR slope per 1-SD higher BMI, waist-to-hip ratio, and predicted percent fat were 0.09 (95% CI, −0.18 to 0.36), −0.25 (95% CI, −0.50 to 0.01), and −0.14 (95% CI, −0.41 to 0.13) mL/min/1.73 m2 per decade for White men; −0.91 (95% CI, −1.15 to −0.67), −0.82 (95% CI, −1.06 to −0.58), and −1.02 (95% CI, −1.26 to −0.78) mL/min/1.73 m2 per decade for White women; −0.70 (95% CI, −1.54 to 0.14), −1.60 (95% CI, −2.42 to −0.78), and −1.24 (95% CI, −2.08 to −0.40) mL/min/1.73 m2 per decade for Black men; and −1.24 (95% CI, −2.08 to −0.40), −1.50 (95% CI, −2.05 to −0.95), and −1.43 (95% CI, −2.00 to −0.86) mL/min/1.73 m2 per decade for Black women. Obesity indicators were independently associated with risk for KFRT for all sex-race groups except White men. Limitations: Loss to follow-up during 3 decades of follow-up with 5 eGFR assessments. Conclusions: Obesity status is a risk factor for future decline in kidney function and development of KFRT in Black and White women, with less consistent associations among men

Accuracy of GFR estimating equations in patients with discordances between creatinine and cystatin C-based estimations

Background Cystatin C is recommended as a confirmatory test to eGFR when more precise estimates are needed for clinical decision making. Although eGFR on the basis of both creatinine and cystatin (eGFR(cr-cys)) is the most accurate estimate in research studies, it is uncertain whether this is true in real-world settings, particularly when there are large discordances between eGFR based on creatinine (eGFR(cr)) and that based on cystatin C (eGFR(cys))Methods We included 6185 adults referred for measured GFR (mGFR) using plasma clearance of iohexol in Stockholm, Sweden, who had 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance. The performance of eGFR(cr), eGFR(cys), and eGFR(cr-cys) was assessed against mGFR with median bias, P-30, and correct classification of GFR categories. We stratified analyses within three categories: eGFR(cys) at least 20% lower than eGFR(cr) (eGFR(cys)eGFR(cr)).Results eGFR(cr) and eGFR(cys) were similar in 4226 (45%) samples, and among these samples all three estimating equations performed similarly. By contrast, eGFR(cr-cys) was much more accurate in cases of discordance. For example, when eGFR(cys)eGFR(cr) (8% of samples), the median biases were -4.5, 8.4, and 1.4 ml/min per 1.73m(2). The findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer.Conclusions When eGFR(cr) and eGFR(cys) are highly discordant in clinical practice, eGFR(cr-cys) is more accurate than either eGFR(cr) or eGFR(cys).Clinical epidemiolog

Albuminuria, lung function decline, and risk of incident chronic obstructive pulmonary disease the NHLBI pooled cohorts study

Rationale: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD. Objectives: To test whether albuminuria was associated with lung function decline and incident CLRDs. Methods: Six U.S. population–based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications. Measurements and Main Results: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV 1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV 1 decline (95% confidence interval [CI], 0.86–4.76%; P = 0.0047), 11.02% greater FEV 1 /FVC decline (95% CI, 4.43–17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2–31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18–34%, P, 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease. Conclusions: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population–based sample

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Hemoglobin, Albuminuria, and Kidney Function in Cardiovascular Risk: The ARIC (Atherosclerosis Risk in Communities) Study

Background--Reduced estimated glomerular filtration rate (eGFR) and elevated urinary albumin-to-creatinine ratio (ACR) individually increase risk of cardiovascular disease (CVD). We hypothesized that these associations are stronger among people with abnormal (both low and high) hemoglobin levels. Methods and Results--Using 5801 participants with available hemoglobin measures of the ARIC (Atherosclerosis Risk in Community) study in 1996-1998, we explored the cross-sectional association of eGFR and ACR with hemoglobin levels and their longitudinal associations with CVD (heart failure, coronary heart disease, and stroke) risk through 2013. At baseline, 8.8% had anemia ( < 13 g/dL in men and < 12 g/dL in women) and 7.2% had high hemoglobin (≥16 g/dL in men and ≥15 g/dL in women). The adjusted prevalence ratio of anemia was 2.12 (95% confidence interval, 1.59-2.82) for eGFR 30 to 59 compared with ≥90 mL/ min per 1.73 m 2 and 1.45 (1.07-1.95) for ACR ≥30 compared with < 10 mg/g. ACR ≥30 mg/g was also associated with high hemoglobin (prevalence ratio, 1.57 [1.12-2.19] compared with < 10 mg/g). During follow-up, there were 1069 incident CVDs among 5098 CVD-free participants at baseline. In multivariable Cox models, lower eGFR, higher ACR, and anemia were each independently associated with CVD risk, with the association of low eGFR being slightly stronger in anemia (P-for-interaction, 0.072). There was no hemoglobin-ACR interaction; however, when CVD subtypes were analyzed separately, risk of coronary heart disease and stroke associated with high ACR was slightly stronger in high hemoglobin (P-for-interaction, 0.074). Conclusions--Kidney function, albuminuria, and anemia were correlated and independently associated with CVD risk. Correlation and potential interaction for atherosclerotic CVD between albuminuria and high hemoglobin deserve further investigation

Removing race from the CKD-EPI equation and its impact on prognosis in a predominantly White European population

Background While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations. Methods We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation. Results Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9-4.8) mL/min/1.73 m(2), which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a-G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation. Conclusions Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes.Clinical epidemiolog