Effects of restoring normoglycemia in type 1 diabetes on inflammatory profile and renal extracellular matrix structure after simultaneous pancreas and kidney transplantation

Abstract

Aims Patients with type 1 diabetes and end-stage renal disease with simultaneous pancreas and kidney (SPK) or kidney transplants alone (KA) were recruited 9–12 years post transplantation. We investigated differences between these groups with regard to inflammatory parameters and long-term structural changes in kidneys. Methods Blood samples were analyzed by ELISA and multiplex for chemokines, cytokines, growth factors, cell adhesion molecules and matrix metalloproteinases. Kidney graft biopsies were analyzed by electron microscopy for glomerular basement membrane thickness. Heparan- and chondroitin sulfate disaccharide structures were determined by size exclusion chromatography mass–spectrometry. Results The SPK and the KA group had average glycated hemoglobin A1c (HbA1c) of 5.8% (40 mmol/mol) and 8.6% (70 mmol/mol) respectively. SPK recipients also had 16.2% lower body mass index (BMI) and 46.4% lower triglyceride levels compared with KA recipients, compatible with an improved metabolic profile in the SPK group. Plasminogen activator inhibitor (PAI-1), C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) were lower in the SPK group. In kidney graft biopsies of the KA-patients an 81.2% increase in average glomerular basement membrane thickness was observed, accompanied by alterations in heparan sulfate proteoglycan structure. In addition to a decrease in 6-O-sulfated disaccharides, an increase in non-N-sulfated disaccharides with a corresponding slight decrease in N-sulfation was found in kidney biopsies from hyperglycemic patients. Conclusions Patients with end stage renal disease subjected to KA transplantation showed impaired inflammatory profile, increased thickness of basement membranes and distinct changes in heparan sulfate structures compared with SPK recipients.

Acute exercise increases syndecan-1 and -4 serum concentrations

“…Serum syndecan is increased in response to acute vascular trauma, as we have reported for syndecan-1 during coronary artery bypass surgery [17]. We have also shown that increased serum concentrations of syndecan-1 are related to early diabetic nephropathy [18], and we observed a trend for increased syndecan-1 serum concentrations in hyperglycemic individuals compared to normoglycemic kidney transplanted patients together with increased levels of the syndecan sheddase matrix metalloproteinase MMP-9 [19]. Furthermore, we have demonstrated high expression of syndecan-4 in endothelial cells [20], and in a case-cohort study including 1500 participants from the Tromsø study, we observed that serum syndecan-4 was an independent predictor of myocardial infarction [21].…”

Matrix metalloproteinase‐9 mediated shedding of syndecan‐4 in glomerular endothelial cells

“…Syndecan shedding is increased as a response to acute vascular trauma, as we have demonstrated for syndecan‐1 . We have also documented that increased serum syndecan‐1 is related to early diabetic nephropathy, and we observed a trend for increased syndecan‐1 serum levels in the hyperglycemic group compared to normoglycemic kidney transplanted patients together with increased levels of the syndecan‐1 sheddase MMP9 . This promising potential for syndecans as markers for endothelial dysfunction is further strengthened by our most recent results generated.…”

Beneficial effect of successful simultaneous pancreas-kidney transplantation on plasma profile of metalloproteinases in type 1 diabetes mellitus patients

“…Moreover, several advanced glycation end-products were associated with plasma levels of MMP-2 and MMP-3 in T1D individuals [26]. Notably, in line with our present ndings, Reine et al described bene cial effects of successful SPK, as compared to KTA, on the kidney graft extracellular matrix structure in approximately 10-year observation in T1D patients [27]. We may hypothesize that the long-term restoration of normoglycemia results in favorable MMPs pro le, which probably re ects the slowing of vascular system damage (diabetic vasculopathy/remodeling).…”