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- Title
Donor Pre-Treatment with Atorvastatin Prevents Cold Preservation Injury in Isogeneic Renal Transplantation in Rats and Reduces Renal Inflammation in a Rat Model of Acute Renal Allograft Rejection.
- Authors
Goettmann, U.; Coutinho, Z. M.; Brinkkoetter, P. T.; Hoeger, S.; Karle, C.; Yard, B.; van der Woude, F. J.; Braun, C.
- Abstract
Objective: Pleiotropic effects of HMG-CoA-reductase inhibitors (statins), e.g. anti-inflammatory and immunmodulatory effects, are well recognized. Recent studies have shown that statins decrease I/R-injury in rats. The aim of the present study was to evaluate the effect of atorvastatin pre-treatment on cold preservation injury in isogeneic renal transplantation and on acute renal allograft rejection in rats. Methods: Donor rats were pre-treated with atorvastatin (ATOR: 50 mg/kg/d, n = 7) or vehicle (VEH, n = 7) daily by oral gavage 2 days prior to and on the day of explantation. After explantation one kidney was snap frozen in liquid nitrogen for determination of hemeoxygenase- 1 (HO-1) expression by light-cycler PCR and the second kidney was stored for 24 h at +4° in UW solution. For investigation of cold preservation injury kidneys of male Lewis donors were then transplanted syngeneic in bilaterally nephrectomized rats and serum creatinine was measured on days 0, 1, 3 and 5 after transplantation. In the model of acute renal allograft rejection kidneys of male Fisher rats were transplanted allogeneic in uninephrectomized Lewis rats, isogeneic vehicle treated Lewis-Lewis served as control. After 5 days all grafts were harvested for determination of monocyte infiltration and MHC II expression. Results: Pre-treatment with atorvastatin improved renal function, as measured by lower serum creatinine on days 1 and 3 after transplantation (day 1: ATOR 2.04 mg/dl vs VEH 3.10 mg/dl, p < 0.0001; day 3: ATOR 1.26 mg/dl vs VEH 3.47 mg/dl, p = 0.009; t-test) and markedly reduced monocyte infiltration (ATOR 9.48 ± 1.36 vs VEH 19.77± 1.36 pos. cells/high power field, p < 0.0001) after 24 h of cold preservation and isogeneic transplantation. Pre-treatment with atorvastatin significantly reduced monocyte infiltration (VEH 41.29 ± 3.45 vs ATOR 27.60 ± 1.88 pos. cells/high power field, p = 0.0018, ANOVA; isogeneic controls 8.97 ± 1.81 pos. cells/high power field) and MHC II positive cells (VEH 20.46 ± 1.24 vs ATOR 14.75± 1.55 pos. cells/high power field, p = 0.003, ANOVA; isogeneic controls 5.4 ± 0.76 pos. cells/high power field) 5 days after allogeneic transplantation. In donor kidneys pre-treated for 2 days with atorvastatin, a significant up-regulation of the protective enzyme HO-1 was observed compared to animals pre-treated with vehicle. Conclusions: Our data demonstrate, that donor pre-treatment with atorvastatin improves renal function and decreases renal inflammation after prolonged cold storage and isogeneic renal transplantation in rats. Additionally renal inflammation was decreased 5 days after allogeneic renal transplantation in rats. The positive effect may be related to the up-regulation of the protective enzyme HO-1 in kidney tissue by atorvastatin. This observation is of high clinical significance, since it could offer a new strategy to prevent transplantationassociated injury.
- Subjects
STATINS (Cardiovascular agents); KIDNEY transplantation; GRAFT rejection; HOMOGRAFTS; DRUG administration; DRUG dosage
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p290
- ISSN
1420-4096
- Publication type
Article