Imbalance of metallaproteinase/tissue inhibitors of metalloproteinase system in renal transplant recipients with chronic allograft injury

Abstract

Introduction: Nowadays, renal allografts continue to be lost at the rate of 2% to 4% per year beyond the first year after transplantation due to chronic allograft injury. Excessive accumulation of extracellular matrix results from overproduction and/or defective degradation by proteolytic enzymes, among which metalloproteinases (MMPs) play a major role. The aim of this study was to assess the role of MMPs in renal transplant recipients (RTR) in the context of allograft injury or proteinuria.

Materials and methods: Plasma and urine MMP-2 and MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) were assessed by enzyme-linked immunoassay in 150 RTR including 66% males with an overall mean age of 49.2±11.5 years. The subjects were examined at a mean of 73.4±41.2 months (range=12-240) after kidney transplantation. Thirty-seven healthy volunteers including 54% male with an overall mean age of 48.4±14.1 years served as a control group.

Results: Renal transplant recipients displayed significantly decreased plasma MMP-2 activity compared with healthy controls (P<.000) probably due to increased inhibitory plasma (p) TIMP-2 activity (P=.0029), and lower plasma MMP-2:TIMP-2 index (P<.0001). Plasma MMP-9 and pTIMP-1 activities were twofold increased in RTR compared with controls (P=.0015 and P<.000) but with a nearly stable plasma MMP-9:TIMP-1 index (P=NS). There was no difference between RTR and controls according to urine (u) MMP-2 activity, but uMMP-9 was increased in RTR compared with healthy controls (P=.0032). Urine MMP-9 potential was probably diminished by increased uTIMPs (uTIMP-2, P=.017; uTIMP-1, P=.000), which contributed to graft impairment or proteinuria.

Conclusion: Our study revealed profibrotic MMP/TIMP constellations in RTR that show an imbalance in plasma MMP-2 and MMP-9 with increased plasma and urinary TIMPs. The net proteolytic potential of increased plasma and urinary MMP-9 may be diminished significantly by enhanced plasma and urine TIMP activities.