| Abstract|| |
This study was undertaken to assess the effect of simvastatin in the reduction of panel-reactive antibody (PRA) levels in patients with end-stage renal disease (ESRD) awaiting renal transplantation. During the 1-year period from September 2007 to August 2008, 60 ESRD patients with PRA levels more than 30% were enrolled into the study. Each patient was given oral simvastatin 10 mg/day as the initial dose. After one month, in those patients who did not respond, the dose was increased to 20 mg/day. Again, at the end of two months, if there was no response, the dose was further raised to 40 mg/day of simvastatin. The appropriate response to the treatment was defined as serum PRA levels getting reduced to less than 30%. Among the 60 patients who were enrolled in the study, three cases were excluded due to side-effects of the drug and 57 patients remained in our study. The mean age was 42.8 ± 28.2 years (range 18-75). Among these, 34 (59.6%) were females. Before the study, the PRA levels were between 30 and 100 (mean ± SD: 60.4% ± 20%). After the administration of simvastatin, a significant decrease in PRA levels was seen in our patients (P < 0.0001). In patients who had baseline PRA less than 40%, the PRA dropped to below 30% in 69.2% of the cases with 10 mg simvastatin. In those who had baseline PRA more than 40%, a similar reduction was seen only in 15.9% of the cases. However, in those who did not respond initially to 10 mg of simvastatin, statistically significant reductions were seen after the administration of 20 mg and, if needed, 40 mg of simvastatin (P = 0.001). In conclusion, simvastatin can be a useful drug in ESRD patients to lower the PRA levels.
|How to cite this article:|
Zahed N, Nazemian F, Naghibi M. Evaluation of the effects of simvastatin in reduction of panel-reactive antibody (PRA) levels in patients with end-stage renal disease awaiting renal transplantation. Saudi J Kidney Dis Transpl 2012;23:306-10
|How to cite this URL:|
Zahed N, Nazemian F, Naghibi M. Evaluation of the effects of simvastatin in reduction of panel-reactive antibody (PRA) levels in patients with end-stage renal disease awaiting renal transplantation. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2015 Jan 30];23:306-10. Available from: http://www.sjkdt.org/text.asp?2012/23/2/306/93163
| Introduction|| |
Renal transplantation is now considered as the definitive and the best therapeutic modality for patients with end-stage renal disease (ESRD). ,, Renal transplantation improves both quality of life and survival in comparison with dia-lysis,  even though the survival of renal allo-graft recipients is lower than in the general population, to large part due to increased cardiovascular risks. In many cases, immunologic problems are a limitation in the use of potential donors.  For example, HLA-specific immunity developing in recipients, after transfusions, pregnancy or previous transplantations, cause positive lymphocyte cross-matches and is accompanied by hyperacute, acute and chronic rejection. Therefore, a positive lymphocyte cross-match is generally considered as a contraindication for transplantation. ,
Estimation of panel-reactive antibody (PRA) levels is performed to screen sensitized patients so as to prevent hyperacute, acute and chronic rejection caused by sensitization. Elevation of PRA levels is associated with reduction in the 1- and 5-year overall survival rates. ,, The treatment of highly sensitized recipients with immunosuppressive drugs, im-munoadsorption, immunoglobulin and plasma-pheresis is accompanied with serious side-effects, in addition to being extremely expensive.
Statins impair cholesterol production by inhibiting 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase activity, and are safe and effective in the treatment of hyperlipi-demia in transplant recipients. , Surprisingly, statins have been found to have some immu-nosuppressive roles as well and can help prevent renal graft rejection.  Experimental and clinical studies showed that HMG-CoA drugs can cause a reduction in acute and chronic rejection. ,,, In 1996, Katz-Nelson and his colleagues found that pravastatin prescription in cadaveric renal transplant recipients caused about 33% reduction in acute rejection. 
In this study, we aimed to evaluate the effects of simvastatin in the reduction of PRA levels among ESRD patients awaiting renal transplantation.
| Patients and Methods|| |
During the one year period from September 2007 to August 2008, 60 ESRD patients with PRA over 30% were enrolled in the study. To do this, first, we selected patients with PRA levels over 30% among those in the waiting list of cadaveric renal transplantation. These summed up to 123 patients. Then, using a computational random generator, we did the simple random sampling and selected 60 patients out of these 123 patients. All selected patients were undergoing hemodialysis three-times a week (four hours each time) for more than six months. Informed consent was obtained from all patients before the study, and our university ethics committee approved our study.
Baseline total cholesterol, high-density lipo-protein, low-density lipoprotein, triglyceride, blood sugar, serum glutamic oxaloacetic trans-aminase (SGOT) and serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen, creatinine, total bilirubin, serum albumin, hemoglobin and hematocrit were measured in all patients close to the time of the study.
Patients who were under 18 years or over 75 years of age, those who had been started on statin therapy even within two weeks prior to commencement of the study and those having active liver disease, chronic inflammatory disease, connective tissue disease, malignancy or a previous history of cancer or acute illness with WBC of >10,000/mm  were excluded from the study. Patients under steroid therapy with history of previous transfusion(s) or with evidence of side-effects of simvastatin were also excluded.
In each patient, we prescribed oral simvas-tatin equal to 10 mg/day. Appropriate response to the treatment was defined as serum PRA levels getting reduced to less than 30%. PRA level were measured using the microcyto-toxicity method. After one month, we checked the PRA and in those who did not respond, the drug dosage was increased to 20 mg/day. Again, at the end of two months, in patients who did not respond, we raised it further to 40 mg/day of simvastatin.
All patients were followed-up for six months and their PRA, SGOT and SGPT were checked monthly. Statistical analysis was performed using SPSS version 11.5. P-values <0.05 were considered statistically significant.
| Results|| |
Among these 60 ESRD patients with PRA over than 30%, three patients developed side-effects to simvastatin such as nausea and vomiting. These three patients were excluded from the study and the remaining 57 patients continued in the study. The mean age (±SD) of our cases was 42.8 (±28.2) years (range 18- 75). Among these, 34 (59.6%) were females and 23 (40.4%) were males.
The underlying etiology of ESRD in this group of patients were hypertension in 19 (33%) patients, diabetes mellitus in six (10.5%), glomerulonephritis in five (8.8%) and polycystic kidney disease in four (7%). The mean (±SD) values of laboratory tests are shown in [Table 1]. The mean duration of dialysis in our patients was 68.02 ± 12.44 months.
|Table 1: The mean (±SD) of laboratory tests among 57 patients with ESRD.|
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Our patients had PRA levels between 30 and 100 before the study (mean ± SD: 60.4% ± 20%). Among these, 13 (22.8%) had PRA levels between 30% and 40%. PRA levels between 41% and 50%, 51% and 60%, 61% and 70%, 71% and 80% and more than 81% were seen in 10 (17.5%), 11 (19.3%), eight (14%), eight (14%) and seven (12.3%) patients, respectively.
A significant decrease in PRA levels after administration of 10 mg simvastatin per day was seen in our study (P < 0.0001) (mean PRA level was 52.1 ± 24.3). This can easily be concluded comparing mean PRA levels of patients before and after taking simvastatin (mean PRA level of patients before taking simvastatin is more than in those after taking simvastatin). The mean ± SD levels of PRA following 20 mg and 40 mg daily administration of sim-vastatin were 45.8 ± 26.2 and 42.8 ± 25.09, respectively (P < 0.0001). We arbitrarily divided our patients into two groups according to baseline PRA levels less than and more than 40%. This level was chosen based on our protocol for immunosuppression. In our protocol, we consider patients with PRA levels less than 30% as low risk and those with PRA levels between 30% and 40% as high-risk patients for transplantation. We do not perform transplantation for patients with PRA levels higher than 40%. In patients who had baseline PRA less than 40%, the PRA dropped to below 30% in 69.2% of the cases after 10 mg simvastatin, and this was 15.9% in those who had a baseline PRA more than 40% (P = 0.001). After using 20 mg simvastatin, PRA less than 30% was seen in 69.2% and 27.3% of the cases who had baseline PRA less than 40% and higher than 40%, respectively (P = 0.001). Finally, PRA less than 30% was seen in 84.6% and 25% of the cases in these two groups after 40 mg simvastatin (P = 0.001).
| Discussion|| |
Clinical and laboratory studies have found that HMG-CoA reductase inhibitors have anti-inflammatory effects.  This is found to be independent of lipid levels, suggesting that it is not related to the lipid-lowering action of these drugs.  Statins are able to modulate T lymphocyte or natural killer (NK) cell activity. , Statins have been reported to exhibit a marked decrease in the incidence of rejection in cardiac-transplant patients.  Statins have also been reported to inhibit the B-cell activity.  Indeed, statins have been reported to decrease the rejection in heart transplant patients, and simvastatin is effective for decrease in the incidence of transplant coronary disease by decreasing cellular proliferation. 
Kreuzer et al found that statins decrease monocyte chemotaxis and also reduce their adhesion to vascular endothelial cells.  In one study, the authors reported that the acute rejection rate was decreased by about 15% in renal transplant recipients after using simvas-tatin or pravastatin in comparison with patients who did not receive these drugs.  There is some evidence that statins do decrease smooth muscle cell migration, which is a pathogenic factor in chronic rejection. ,
Monteiro et al. reported that the 1- and 5-year graft survival rates in sensitized renal transplant recipients are lower than that in non-sensitized patients.  PRA and cross-match determination are accepted as screening methods in patients who are candidates for renal transplantation. Pre-and post-transplantation PRA levels are associated with increased renal graft rejection. 
In one study conducted by Ozdemir et al in 18 cases with PRA more than 30%, the authors found that simvastatin has an immunosuppres-sive effect in transplant candidates who are PRA positive or/and cross-match positive.  In contrast to this, Ossareh et al in their study concluded that lovastatin at a dose of 20 mg/ day had no effect in PRA levels in their patients in contrast with other studies.  However, they conducted their study in only eight patients, seven of which had PRA levels equal or more than 80%.  Our findings were similar to Ozdemir et al, and we found that simvastatin is effective in reducing PRA levels, but this reduction is limited.
Similar to Urra et al's study,  which reported that the effect of IVIG to reduce the PRA levels was more in those with lower baseline PRA levels, we also found that the best benefits of simvastatin therapy were in those who had relatively lower baseline PRA levels.
It seems that, in those having PRA levels more than 30%, simvastatin may not be of much benefit to decrease the levels. But, the correct cut off level of PRA for prescribing this drug is yet not well defined, and needs to be evaluated further by more studies. One limitation of this study is that it is not a randomized sample study. We feel that randomized clinical studies are needed for better evaluation of benefits as well as complications of simvastatin in sensitized ESRD patients. In conclusion, our findings do show that sim-vastatin can be a useful drug in ESRD patients to lower the PRA levels.
| References|| |
|1.||Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998;9:2135-41. |
|2.||Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725. |
|3.||Meier-Kriesche HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. Kidney Int 2000;58:1311. |
|4.||Lentine KL, Brennan DC. Statin use after renal transplantation: a systematic quality review of trial-based evidence. Nephrol Dial Transplant 2004;19(9):2378-86. |
|5.||Matas AJ, Gillingham K, Payne WD, et al. Should I accept this kidney? Clin Transplant 2000;14:90-5. |
|6.||Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive cross-match barriers. Am J Transplant 2004;4:561. |
|7.||Monteiro F, Buelow R, Mineiro C, Rodrigues H, Kalil J. Identification of patients at high risk of graft loss by pre- and post-transplant monitoring of anti-HLA class I IgG antibodies by enzyme-linked immunosorbent assay. Trans-plantation1997;63:542-6. |
|8.||Sumitran-Holgersson S. HLA-specific alloanti-bodies and renal graft outcome. Nephrol Dial Transplant 2001;16:897-904. |
|9.||Tuncer M, Sulcymanlar G, Ersoy FF et al. Comparison of the effects of Simvastatin and pravastatin on acute rejection episodes in renal transplant patients. Transplant Proc 2000;32: 622. |
|10.||Kasiske BL, Tortorice KL, Heim-Duthoy KL, Goryance JM, Rao KV. Lovastatin treatment of hypercholesterolemia in renal transplant recipients. Transplantation 1990;49(1):95-100. |
|11.||Katznelson S, Kobashigawa JA. Dual roles of HMG-CoA reductase inhibitors in solid organ transplantation. lipid lowering and immuno-suppression. Kidney Int 1995;52(Suppl): 112- 5. |
|12.||Katznelson S, Wilkinson AH, Kobashigawa JA et al. The effect of pravastatin on acute reject-tion after kidney transplantation- a pilot study. Transplantation 1996;61:1469. |
|13.||Katznelson S. The effect of HMG-CoA reductase inhibitors on chronic allograft rejection. Contrib Nephrol 1997;120:97. |
|14.||Massy ZA, Guijarro C, Wiederkehr MR, Ma JZ, Kasiske BL. Chronic renal allograft rejection: immunologic and nonimmunologic risk factors. Kidney Int 1996;49(2):518-24. |
|15.||Nurhan Ozdemir F, Akcay A, Sezer S, et al. Effect of Simvastatin in the treatment of highly sensitized dialysis patients: the pre and post-renal transplantation follow-up outcomes. Transpl Immunol 2004;13(1):39-42. |
|16.||Yakupoglu U, Kocak H, Karatas GU, et al. Simvastatin therapy in lymphocyte cross-match-positive kidney transplantation candidates. Transplant Proc 2005;37(7):2933-5. |
|17.||Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 1990;145:244. |
|18.||Rudich SM, Mongini PK, Perez RV, et al. HMG-CoA reductase inhibitors pravastatin and Simvastatin inhibit human B-lymphocyte activation. Transplant Proc 1998;30:992. |
|19.||Kreuzer J, Bader J, Jahn L, et al. Chemotaxis of the monocyte cell line U937: dependence on cholesterol and early mevalonate pathway products. Atherosclerosis1991;90:203. |
|20.||Corsini A, Mazzotti M, Raiteri M, et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis. 1993;101(1):117-25. |
|21.||Ozdemir FN, Sezer S, Turan M, et al. The effect of Simvastatin on panel-reactive antibody and cross-match positivity. Transplant Proc 2001;33:2842-3. |
|22.||Ossareh S, Ghorbani G, Ghods AJ. Effect of HMG-CoA reductase inhibitors on reduction of panel reactivity. Transplant Proc 2003;35: 2592. |
|23.||Urra JM, de la Torre M, Alcazar R et al. Variable in vitro inhibition of HLA specific allo-antibody mediated cytotoxicity by intravenous immunoglobulin. Transplant Proc 1998;30: 4177-9. |
Nephrology Ward, Department of Internal Medicine, Imam-Reza Hospital, Mashhad, I.R.