Increased Plasma Timps Concentrations as the Negative Predictor Associated with Deterioration of Kidney Allograft Function in the Long-Term Observation

Abstract

Introduction: Chronic allograft injury (CAI) is the most frequent cause of kidney graft loss, and presents with progressive graft impairment. Chemokines, cytokines and MMPs/TIMPs system play the role in fibrosis development. The aim of the study was to assess the importance of MMPs/TIMPs, IL-6 and CCL2 (previously MCP-1) in renal transplant recipients (RTR) with long-term allograft function (over 1 year) with impaired graft function Methods: 150 RTR (male 66%, aged 49,2 ± 11,5 y.), at mean 73,4 ± 41,2 months (range 12-240) after kidney transplantation and 37 healthy volunteers (male 54%, aged 48,4 ± 14,1 y.) as controls, were assessed for plasma and urine MMP-2, MMP-9, TIMP-1, TIMP-2, IL-6 and CCL2. Investigated factors were evaluated by ELISA, and urine concentrations were standardized to urine creatinine. Depending on allograft function 45 RTR had eGFR > 60 ml/min/1,73m2, and 104 RTR had eGFR < 60 ml/min/1,73m2, respectively. The data are presented as mean ± SD or median and 95% Cl for the median. The Mann-Whitney U test (for independent samples) was applied, and differences with p < 0,05 were considered statistically significant. Results: 1. RTR compared with controls had significantly lower eGFR (48 ± 16 and 73 ± 10 ml/min/1,73m2; p = 0,0001) and increased concentrations of plasma and urine IL-6 (p = 1,8e-0,5 and p = 0,0001), MMP-9 (p = 0,0015 and p = 0,003), TIMP-1 (p = 2,2e-16 and p=3,4e-05), TIMP-2 (p = 0,003 and p = 0,02), respectively, as well as lower plasma MMP-2 (p = 7,5e-06) and urine CCL2 (p = 3,3e-05) concentrations. 2. RTR with impaired graft function (eGFR < 60 ml/min/1,73m2) compared with RTR with preserved graft function (eGFR > 60 ml/min/1,73m2) had higher median plasma TIMP-1 (165 ng/ml, 95%Cl 151 - 171 ng/ml vs 124 ng/ml, 95%Cl: 115 - 141 ng/ml; p < 0,0001) and TIMP-2 (93 ng/ml, 95%Cl: 88 - 99 ng/ml vs 79 ng/ml, 95%Cl: 76 - 88 ng/ml; p = 0,0005) concentrations and trend to higher median urine IL-6 concentration (0,9 pg/ml, 95%Cl: 0,6- 1,3 pg/ml vs 0,4 pg/ml, 95%Cl: 0,3 - 0,9 pg/ml; p = 0,054). 3. There were no significant differences in plasma and urine CCL2, MMP-2, MMP-9 and plasma IL-6 concentrations between RTR with preserved and impaired graft function. Conclusion: RTR compared with healthy controls had significantly higher plasma and urine IL-6, urine CCL2 concentrations and unsettled MMPs/TIMPs system RTR with impaired graft function had significantly increased plasma TIMP-1, TIMP-2 and trend to increased urine IL-6 concentrations compared with RTR with preserved graft function.