Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development

Abstract

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.

Keywords: diabetes; diabetic nephropathy; microalbuminuria.

Figure 1

Odds ratios for early renal decline from univariate and multivariable logistic analyses. For correlation matrix among the examined baseline variables see Supplementary Table 1. The multivariable model includes 10 variables, all listed in the Figure. The detailed results of logistic regression are shown in Supplementary Table 2. Plot of odds ratios for each variable; open diamond indicates odds ratio in univariate, and closed diamond indicates odds ratio in multivariable logistic regression; 95% confidence intervals as shown as whiskers. Vertical line indicates the null effect. For easy clinical interpretability the odds ratios were calculated for 1% increase in HbA1c; 2 kg/m² increase in BMI; 10 mmHg increase in systolic blood pressure; 20 ml/min increase in eGFR; and 1-quartile increase for the remaining covariates. The 1^st quartile, median and 3^rd quartile of these markers are as follows: TNFR1 - 1127, 1250 and 1602 pg/ml; FGF23 - 43, 56, and 72 pg/ml; ACR - 3, 9 and 36 ug/mg; KIM-1cr - 5, 27, 58 pg/mg; EGF/MCP-1 - 23, 41 and 79 ng/pg.

Figure 2

ROC curves for the multi-marker risk score of early renal decline in type 2 diabetes (T2D, training cohort, solid black line) and type 1 diabetes (T1D, validation cohort dotted grey line). The T1D cohort characteristics are provided in the Supplemental Material.