A Possible Role for Statin Therapy in Solitary Pancreas Transplantation? J.R. Scalea and M. Cooper ABSTRACT Introduction. Statin use after renal transplantation improves long-term outcome and reduces the incidence of glomerulonephritis. With both anti-inflammatory and cardioprotective effects, statins may also improve outcomes in pancreas transplantation. Methods. A retrospective review at a single institution was undertaken. Patients who underwent solitary pancreas transplantation between 2001 and 2010 were identified. Multiple data points including recipient and donor demographics, patient and graft outcomes, and early use of statins were collected. Results. Sixty-eight patients underwent solitary pancreas transplantation within the study period. Eighteen patients (26%) were already on, or were prescribed, a statin at the time of hospital discharge; the 1-year death-censored graft survival was 81.25% for those that were on statins versus 72.9% for those without (P ¼ NS). Excluding patients with early graft loss (600 days) 7.05 years Any Rejection 1.72 years 1-yr Death Censorred 81.25% Graft Survival
5.26 years 1.17 years 72.90%
.02 NS NS
without (data not shown). When individual lipid-lowering agents were evaluated, we observed that graft survival was 575 days longer for patients that received atorvastatin versus no lipid-lowering agent (data not shown; P ¼ NS). We sought to determine if statins were associated with graft failure. To evaluate this relationship we compared graft survival for patients in whom grafts failed, and stratified these results based on statin use (Fig 2). We identified no difference in rate of failure for patients on statins. DISCUSSION
There may be a role for statin therapy beyond lipid-lowering ability.6,7 If the added benefits of statin therapies are owing to the anti-inflammatory properties of these agents, patients undergoing transplantation may benefit from their use.8 Although a study of statin therapies and their role in kidney transplantation was undertaken, the authors failed to find a difference between the placebo and experimental groups because the study was underpowered.5 We retrospectively reviewed our single-center experience with pancreas transplantation and found that, for patients who did not lose their grafts early, there was a benefit to the use of statins. When we evaluated individual statins, we did not find that one was better than the other. Our results suggest that the graft survival benefit of statins was only observed in patients who had their grafts for nearly 2 years. This finding may highlight the mechanism by which statins improved outcomes. Were the effects of statins anti-inflammatory in nature, we might expect to also observe that (1) rates of acute or chronic rejection would be lower, and that (2) improvement in early, rather than late, graft function would be more dramatic. Rates
Fig 2. Comparison of Patients that Experienced Any Graft Failure: No Clinical Difference.
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of rejection were no different between the two groups, and the benefit of statins seemed to affect the longer-term outcome. A more likely explanation is that the observed effect of statins in this group was mainly owing to improvements in cardiac risk factors, rather than other statin-related properties. There are several ways to reconcile our findings. First, the difference in outcome that we were attempting to measure was likely to be very small, and our study was likely underpowered to detect a difference between our studied groups. Second, there may be an inherent bias in the group receiving statins, because these patients may have had received pre- and postoperative care, leading to improvements in longer term outcomes. Last, the improvements in cardiac risk may have been difficult to separate from the smaller improvements in immunology/inflammation. Statin therapies have revolutionized the management of cardiac risk factors. It is likely that the mechanism by which they function are multifactorial. Although there may be an anti-inflammatory benefit to the use of statins, it was not observed herein. Further studies should be undertaken to evaluate the potential utility of statin therapy in transplantation. In conclusion, the use statins in the solitary pancreas transplant patient may lead improved outcomes. Whether
SCALEA AND COOPER
this is owing to cardiovascular protection, or to other factors not associated with lipid lowering, remains unclear. REFERENCES 1. Packard C. Improving outcomes through statin therapy e a review of ongoing trials. Eur Heart J Suppl. 2004;6(suppl A): A28eA31. 2. Sato K, Nuki T, Gomita K, et al. Statins reduce endothelial cell apoptosis via inhibition of TRAIL expression on activated CD4 T cells in acute coronary syndrome. Atherosclerosis. 2010;213:33e39. 3. Takano K, Yamamoto S, Tomita K, et al. Successful treatment of acute lung injury with pitavastatin in septic mice: potential role of glucocorticoid receptor expression in alveolar macrophages. J Pharmacol Exp Ther. 2011;336(2):381e390. 4. Younas N, Wu CM, Shapiro R, et al. HMG-CoA reductase inhibitors in kidney transplant recipients receiving tacrolimus: statins not associated with improved patient or graft survival. BMC Nephrol. 2010;11:5. 5. Navaneethan SD, Perkovic V, Johnson DW, et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev. 2009;3:CD004289. 6. Cravedi P, Perico N, Remuzzi G. Non-immune interventions to protect kidney allografts in the long term. Kidney Int. 2010;119(suppl):S71eS75. 7. Ginsberg HN. Treatment for patients with the metabolic syndrome. Am J Cardiol. 2003;91:29Ee39E. 8. Martins L, Fonseca I, Dias L, et al. Cardiovascular risk factors and events in pancreas-kidney transplants. Transplant Proc. 2013;45: 1063e1065.
5.26 years 1.17 years 72.90%
.02 NS NS
without (data not shown). When individual lipid-lowering agents were evaluated, we observed that graft survival was 575 days longer for patients that received atorvastatin versus no lipid-lowering agent (data not shown; P ¼ NS). We sought to determine if statins were associated with graft failure. To evaluate this relationship we compared graft survival for patients in whom grafts failed, and stratified these results based on statin use (Fig 2). We identified no difference in rate of failure for patients on statins. DISCUSSION
There may be a role for statin therapy beyond lipid-lowering ability.6,7 If the added benefits of statin therapies are owing to the anti-inflammatory properties of these agents, patients undergoing transplantation may benefit from their use.8 Although a study of statin therapies and their role in kidney transplantation was undertaken, the authors failed to find a difference between the placebo and experimental groups because the study was underpowered.5 We retrospectively reviewed our single-center experience with pancreas transplantation and found that, for patients who did not lose their grafts early, there was a benefit to the use of statins. When we evaluated individual statins, we did not find that one was better than the other. Our results suggest that the graft survival benefit of statins was only observed in patients who had their grafts for nearly 2 years. This finding may highlight the mechanism by which statins improved outcomes. Were the effects of statins anti-inflammatory in nature, we might expect to also observe that (1) rates of acute or chronic rejection would be lower, and that (2) improvement in early, rather than late, graft function would be more dramatic. Rates
Fig 2. Comparison of Patients that Experienced Any Graft Failure: No Clinical Difference.
3350
of rejection were no different between the two groups, and the benefit of statins seemed to affect the longer-term outcome. A more likely explanation is that the observed effect of statins in this group was mainly owing to improvements in cardiac risk factors, rather than other statin-related properties. There are several ways to reconcile our findings. First, the difference in outcome that we were attempting to measure was likely to be very small, and our study was likely underpowered to detect a difference between our studied groups. Second, there may be an inherent bias in the group receiving statins, because these patients may have had received pre- and postoperative care, leading to improvements in longer term outcomes. Last, the improvements in cardiac risk may have been difficult to separate from the smaller improvements in immunology/inflammation. Statin therapies have revolutionized the management of cardiac risk factors. It is likely that the mechanism by which they function are multifactorial. Although there may be an anti-inflammatory benefit to the use of statins, it was not observed herein. Further studies should be undertaken to evaluate the potential utility of statin therapy in transplantation. In conclusion, the use statins in the solitary pancreas transplant patient may lead improved outcomes. Whether
SCALEA AND COOPER
this is owing to cardiovascular protection, or to other factors not associated with lipid lowering, remains unclear. REFERENCES 1. Packard C. Improving outcomes through statin therapy e a review of ongoing trials. Eur Heart J Suppl. 2004;6(suppl A): A28eA31. 2. Sato K, Nuki T, Gomita K, et al. Statins reduce endothelial cell apoptosis via inhibition of TRAIL expression on activated CD4 T cells in acute coronary syndrome. Atherosclerosis. 2010;213:33e39. 3. Takano K, Yamamoto S, Tomita K, et al. Successful treatment of acute lung injury with pitavastatin in septic mice: potential role of glucocorticoid receptor expression in alveolar macrophages. J Pharmacol Exp Ther. 2011;336(2):381e390. 4. Younas N, Wu CM, Shapiro R, et al. HMG-CoA reductase inhibitors in kidney transplant recipients receiving tacrolimus: statins not associated with improved patient or graft survival. BMC Nephrol. 2010;11:5. 5. Navaneethan SD, Perkovic V, Johnson DW, et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev. 2009;3:CD004289. 6. Cravedi P, Perico N, Remuzzi G. Non-immune interventions to protect kidney allografts in the long term. Kidney Int. 2010;119(suppl):S71eS75. 7. Ginsberg HN. Treatment for patients with the metabolic syndrome. Am J Cardiol. 2003;91:29Ee39E. 8. Martins L, Fonseca I, Dias L, et al. Cardiovascular risk factors and events in pancreas-kidney transplants. Transplant Proc. 2013;45: 1063e1065.
