Faculty Bibliography

BACKGROUND:The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS:We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS/RESULTS:The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION/CONCLUSIONS:Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING/BACKGROUND:US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.

BACKGROUND:Equivalence of laboratory tests over time is important for longitudinal studies. Even a small systematic difference (bias) can result in substantial misclassification. METHODS:We selected 200 Atherosclerosis Risk in Communities Study participants attending all 5 study visits over 25 years. Eight analytes were remeasured in 2011-2013 from stored blood samples from multiple visits: creatinine, uric acid, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and high-sensitivity C-reactive protein. Original values were recalibrated to remeasured values with Deming regression. Differences >10% were considered to reflect substantial bias, and correction equations were applied to affected analytes in the total study population. We examined trends in chronic kidney disease (CKD) pre- and postrecalibration. RESULTS:Repeat measures were highly correlated with original values [Pearson r > 0.85 after removing outliers (median 4.5% of paired measurements)], but 2 of 8 analytes (creatinine and uric acid) had differences >10%. Original values of creatinine and uric acid were recalibrated to current values with correction equations. CKD prevalence differed substantially after recalibration of creatinine (visits 1, 2, 4, and 5 prerecalibration: 21.7%, 36.1%, 3.5%, and 29.4%, respectively; postrecalibration: 1.3%, 2.2%, 6.4%, and 29.4%). For HDL cholesterol, the current direct enzymatic method differed substantially from magnesium dextran precipitation used during visits 1-4. CONCLUSIONS:Analytes remeasured in samples stored for approximately 25 years were highly correlated with original values, but 2 of the 8 analytes showed substantial bias at multiple visits. Laboratory recalibration improved reproducibility of test results across visits and resulted in substantial differences in CKD prevalence. We demonstrate the importance of consistent recalibration of laboratory assays in a cohort study.

BACKGROUND:Chronic kidney disease progression is a risk factor for end-stage renal disease (ESRD). A 57% decline in creatinine-based estimated glomerular filtration rate (eGFRcr) is an established surrogate outcome for ESRD in clinical trials, and a 30% decrease recently has been proposed as a surrogate end point. However, it is unclear whether change in novel filtration marker levels provides additional information for ESRD risk to change in eGFRcr. STUDY DESIGN/METHODS:Cohort study. SETTING & PARTICIPANTS/METHODS:Atherosclerosis Risk in Communities (ARIC) Study participants from 4 US communities. PREDICTORS/METHODS:Percent change in levels of filtration markers (eGFRcr, cystatin C-based eGFR [eGFRcys], the inverse of β2-microglobulin concentration [1/B2M]) over a 6-year period. OUTCOME/RESULTS:Incident ESRD. MEASUREMENTS/METHODS:Cox proportional hazards regression with adjustment for demographics, kidney disease risk factors, and first measurement of eGFRcr. RESULTS:During a median follow-up of 13 years, there were 142 incident ESRD cases. In adjusted analysis, declines > 30% in eGFRcr, eGFRcys, and 1/B2M were associated significantly with ESRD compared with stable concentrations of filtration markers (HRs of 19.96 [95% CI, 11.73-33.96], 16.67 [95% CI, 10.27-27.06], and 22.53 [95% CI, 13.20-38.43], respectively). Using the average of declines in the 3 markers, >30% decline conferred higher ESRD risk than that for eGFRcr alone (HR, 31.97 [95% CI, 19.40-52.70; P=0.03] vs eGFRcr). LIMITATIONS/CONCLUSIONS:Measurement error could influence estimation of change in filtration marker levels. CONCLUSIONS:A >30% decline in kidney function assessed using novel filtration markers is associated strongly with ESRD, suggesting the potential utility of measuring change in cystatin C and B2M levels in settings in which improved outcome ascertainment is needed, such as clinical trials.

BACKGROUND:A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. STUDY DESIGN/METHODS:Longitudinal cohort study. SETTING & PARTICIPANTS/METHODS:250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). PREDICTORS/METHODS:Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C level (eGFRcys). OUTCOMES & MEASUREMENTS/METHODS:Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). RESULTS:During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. LIMITATIONS/CONCLUSIONS:Small sample size, single measurements of markers. CONCLUSIONS:In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population.