Serum transferrin predicts end-stage Renal Disease in Type 2 Diabetes Mellitus patients

Abstract

Background: To investigate the relationship between serum iron status and renal outcome in patients with type 2 diabetes mellitus (T2DM). Methods: Chinese patients (n=111) with T2DM and biopsy-proven diabetic nephropathy (DN) were surveyed in a longitudinal, retrospective study. Serum iron, total iron-binding capacity, ferritin, and transferrin were measured at the time of renal biopsy. Iron deposition and transferrin staining were performed with renal biopsy specimens of DN patients and potential kidney donors. End-stage renal disease (ESRD) was the end-point. ESRD was defined as an estimated glomerular filtration rate <15 mL/min/1.73 m² or the need for chronic renal replacement therapy. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for the influence of serum iron metabolism on ESRD. Results: During a median follow up of 30.9 months, 66 (59.5%) patients progressed to ESRD. After adjusting for age, sex, baseline systolic blood pressure, renal functions, hemoglobin, HbA1c, and pathological findings, lower serum transferrin concentrations were significantly associated with higher ESRD in multivariate models. Compared with patients in the highest transferrin quartile (≥1.65 g/L), patients in the lowest quartile (≤1.15 g/L) had multivariable-adjusted HR (95% confidence interval) of 7.36 (1.40-38.65) for ESRD. Moreover, tubular epithelial cells in DN exhibited a higher deposition of iron and transferrin expression compared with healthy controls. Conclusions: Low serum transferrin concentration was associated with diabetic ESRD in patients with T2DM. Free iron nephrotoxicity and poor nutritional status with accumulated iron or transferrin deposition might contribute to ESRD.

Keywords: diabetic nephropathy; end-stage renal disease; iron nephrotoxicity; transferrin.

Figure 1

Flowcharts of patients in this study.

Figure 2

Univariate (a) and multivariate (b, c) Cox proportional hazard models by serum iron status at the renal endpoint. Model 1: adjusted for age, sex, estimated glomerular filtration rate, proteinuria, hemoglobin, and HbA1c. Model 2: adjusted for the above plus pathological parameters including Renal Pathology Society diabetic nephropathy class, tubular atrophy and interstitial fibrosis, interstitial inflammation, arteriosclerosis, and arteriolar hyalinosis. Abbreviations: HR, hazard ratio; CI, confidence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation; Ref, reference.

Figure 2

Univariate (a) and multivariate (b, c) Cox proportional hazard models by serum iron status at the renal endpoint. Model 1: adjusted for age, sex, estimated glomerular filtration rate, proteinuria, hemoglobin, and HbA1c. Model 2: adjusted for the above plus pathological parameters including Renal Pathology Society diabetic nephropathy class, tubular atrophy and interstitial fibrosis, interstitial inflammation, arteriosclerosis, and arteriolar hyalinosis. Abbreviations: HR, hazard ratio; CI, confidence interval; TIBC, total iron-binding capacity; TSAT, transferrin saturation; Ref, reference.

Figure 3

Transferrin and iron staining in kidney biopsy specimens. (a) Tissue transferrin (red arrows) by immunohistochemistry in normal kidney tissue, diabetic kidney tissue with microalbuminuria or macroalbuminuria. 200×, Bar=50 μm. (b) Quantification of the transferrin staining shows a significant increase in diabetic kidney tissue compared with normal kidney tissue (*p <0 001, compared with control group). Experiments were performed with ten participants for each group, and the results are expressed as mean ± SD. (c) Tissue iron deposition (black arrows) by Perl's staining in normal kidney tissue and diabetic kidney tissue. 200×, Bar=50 μm.