Simultaneous pancreas-kidney transplantation in patients with type 1 diabetes reverses elevated MBL levels in association with MBL2 genotype and VEGF expression

Abstract

Aims/hypothesis: High levels of circulating mannan-binding lectin (MBL) are associated with the development of diabetic nephropathy and hyperglycaemia-induced vasculopathy. Here, we aimed to assess the effect of glycaemic control on circulating levels of MBL and the relationship of these levels with vascular damage.

Methods: We assessed MBL levels and corresponding MBL2 genotype, together with vascular endothelial growth factor (VEGF) levels as a marker of vascular damage, in type 1 diabetes patients with diabetic nephropathy before and after simultaneous pancreas-kidney (SPK) transplantation. We included diabetic nephropathy patients (n = 21), SPK patients (n = 37), healthy controls (n = 19), type 1 diabetes patients (n = 15) and diabetic nephropathy patients receiving only a kidney transplant (n = 15). Fourteen diabetic nephropathy patients were followed up for 12 months after SPK.

Results: We found elevated circulating MBL levels in diabetic nephropathy patients, and a trend towards elevated circulating MBL levels in type 1 diabetes patients, compared with healthy control individuals. MBL levels in SPK patients completely normalised and our data indicate that this predominantly occurs in patients with a polymorphism in the MBL2 gene. By contrast, MBL levels in kidney transplant only patients remained elevated, suggesting that glycaemic control but not reversal of renal failure is associated with decreased MBL levels. In line, levels of glucose and HbA1c, but not creatinine levels and estimated GFR, were correlated with MBL levels. VEGF levels were associated with levels of MBL and HbA1c in an MBL-polymorphism-dependent manner.

Conclusions/interpretation: Taken together, circulating MBL levels are associated with diabetic nephropathy and are dependent on glycaemic control, possibly in an MBL2-genotype-dependent manner.

Keywords: Diabetic nephropathy; MBL; Mannan-binding lectin; Simultaneous pancreas–kidney transplantation; Type 1 diabetes; VEGF; Vascular injury.

Fig. 1

SPK in patients with type 1 diabetes reverses elevated MBL levels in association with MBL2 genotype and VEGF expression. (a) Circulating MBL levels are increased in diabetic nephropathy (DN) patients and normalise after SPK. (b) Data in (a) presented as a bar graph. (c) Subdivision of polymorphisms per patient group suggests that predominantly patients with a polymorphism in the MBL2 gene show normalisation of MBL levels after SPK. The scale is presented as a log₁₀ scale. For an explanation of the different genotypes please refer to the ‘MBL2 genotyping’ section of the Methods. (d) Circulating MBL levels in DN patients who received SPK and were followed up longitudinally before transplantation (D0), and 1, 6 and 12 months (M) after SPK. (e) VEGF levels plotted for DN and SPK groups divided by patients with wild-type MBL or MBL polymorphism carriers. *p < 0.05. Data are presented as mean + SEM. Co, control groups of healthy volunteers; DM, type 1 diabetes patients with an eGFR of ≥30 ml min⁻¹ 1.73 m⁻²; DN, type 1 diabetic patients with diabetic nephropathy; KTx, diabetic nephropathy patients with a functioning kidney graft; SPK, patients who received SPK in the past