Filtration Markers as Predictors of ESRD and Mortality in Southwestern American Indians With Type 2 Diabetes

Abstract

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 Longitudinal cohort study. Setting & Participants 250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). Predictors Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C (eGFRcys). Outcomes & Measurements 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 to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C-statistics, continuous net reclassification improvement (NRI), and relative integrated discrimination improvement (rIDI). Results During median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP 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 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 to established markers increased the C statistic for mortality but only weakly when assessed by either continuous NRI or rIDI; none were improved for ESRD by the addition of these markers. Limitations Small sample size, single measures of markers. Conclusions In Pima Indians with type 2 diabetes, BTP, and to a lesser extent B2M, was associated with ESRD. B2M was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M in a multi-marker approach leads to improved risk prediction for mortality in this population..

Serum β-Trace Protein and β2-Microglobulin as Predictors of ESRD, Mortality, and Cardiovascular Disease in Adults With CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study

“…7 , 9 Similarly, in hemodialysis patients higher BTP was reported to be associated with increased mortality risk over a median follow-up of 3.3 years. 8 Three prior studies measured both BTP and B2M in addition to the established filtration markers creatinine and cystatin C, allowing for comparisons of ESRD, 5,17 mortality, 5,6,17 or cardiovascular risk 5 across all markers, as well as for comparisons to mGFR in Southwestern American Indians with type 2 diabetes. 17 Two prior studies reported on ESRD.…”

“…8 Three prior studies measured both BTP and B2M in addition to the established filtration markers creatinine and cystatin C, allowing for comparisons of ESRD, 5,17 mortality, 5,6,17 or cardiovascular risk 5 across all markers, as well as for comparisons to mGFR in Southwestern American Indians with type 2 diabetes. 17 Two prior studies reported on ESRD. In the Atherosclerosis Risk in Communities (ARIC) Study higher BTP and B2M levels were associated with increased ESRD risk and associations were both stronger than observed with eGFRcr.…”

“…5 In Pima Indians with type 2 diabetes, higher BTP and B2M were associated with increased ESRD risk and were of similar magnitude as eGFRcr. 17 Three prior studies reported on mortality. 5,6,17 In ARIC and the Third National Health and Nutrition Examination Survey (NHANES III), BTP and B2M were independent predictors of all-cause mortality with associations of greater magnitude than observed for eGFRcr and with stronger associations observed for B2M than BTP.…”

“…17 Three prior studies reported on mortality. 5,6,17 In ARIC and the Third National Health and Nutrition Examination Survey (NHANES III), BTP and B2M were independent predictors of all-cause mortality with associations of greater magnitude than observed for eGFRcr and with stronger associations observed for B2M than BTP. 5,6 Consistent with this observation, B2M, but not BTP, was associated with all-cause mortality risk in Pima Indians with type 2 diabetes.…”

Prognostic Value of Tubulointerstitial Lesions, Urinary N-Acetyl-β-D-Glucosaminidase, and Urinary β2-Microglobulin in Patients with Type 2 Diabetes and Biopsy–Proven Diabetic Nephropathy

“…This difference may be explained by the limited accuracy of urinary markers because of several potential influences on marker levels, such as metal irons, urine pH, and complications (6,(34)(35)(36). Moreover, recent studies have shown that addition of these markers to known promoters of progression does not significantly improve prediction of the risk of ESRD in patients with relatively early DN (3,37), although both NAG and b2-MG are thought of as early markers of interstitial injury in DN (6). Almost 90% of our subjects had overt proteinuria and a reduced eGFR at baseline, and the influence of these interstitial markers on the primary end point was markedly reduced after adjustment for baseline UP and eGFR.…”