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Immunosuppression impact on long-term cardiovascular complications after liver transplantation
The American Journal of Surgery 183 (2002) 595–599
Scientific paper
Immunosuppression impact on long-term cardiovascular complications after liver transplantation John M. Rabkin M.D.a,*, Christopher L. Corless, M.D., Ph.D.b, Hugo R. Rosen, M.D.c, Ali J. Olyaei, Pharm.D.a a
Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, 3181 SW Sam Jackson Park Rd. L590, Portland, Oregon 97201-3098, USA b Department of Pathology Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, OR, USA c Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, OR, USA Manuscript received December 14, 2001; revised manuscript January 17, 2002 Presented at the 88th Annual Meeting of the North Pacific Surgical Association, Victoria, British Columbia, November 8 –11, 2001
Abstract Background: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. Objective: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. Methods: Eighty-seven sequential patients (CSA: n ⫽ 50, mean age 48 years, M/F 32/18; and FK-506: n ⫽ 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were ⱖ18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. Results: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P ⬍ 0.05), HTN (62% versus 38%, P ⬍ 0.05), HLIP (14% versus 5%, P ⫽ 0.08), and cardiovascular disease (18% versus 0%, P ⬍ 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. Conclusion: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease. © 2002 Excerpta Medica, Inc. All rights reserved. Keywords: Liver transplantation; Cardiovascular complications; Nephrotoxicity
Cardiovascular disease is the major cause of mortality in the United States. It accounts for crude an annual death rate of 200 per 100,000 population and $91 billion dollars of annual health care expenditures [1]. Cardiovascular complications also account for a majority of the morbidity and mortality posttransplantation [2–5]. The incidence of cardiovascular disease is much higher in transplant recipients * Corresponding author. Tel.: ⫹1-503-494-7810; fax: ⫹1503-4945292. E-mail address: [email protected]
than in the general population. For example, the annual cardiovascular mortality rate is increased from 0.28% for the general population to 0.54% in renal transplant recipients where it accounts for 55% of the overall mortality [1]. Up to 10% of the late mortality in the liver transplant patient population has been ascribed to cardiovascular disease [6]. Furthermore, the overall rate for cardiovascular disease may be underestimated as a result of incomplete or indeterminate death reports. Despite the prevalence of cardiovascular disease in transplant patients, most of the focus posttransplantation has been on rejection or early postoperative compli-
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cations such as infections or metabolic abnormalities with little attention paid to long-term cardiovascular complications. Established risk factors for cardiovascular disease include hypertension, hyperlipidemia, diabetes mellitus, renal insufficiency, obesity, family history of cardiovascular disease, advanced age, African-American race, male gender and tobacco abuse [7–9]. In renal transplantation hypertension, diabetes mellitus, age, family history, tobacco use and total serum cholesterol ⬎200 mg/dL or HDL ⬍35 mg/dL have been established as independent risk factors for cardiovascular disease [3,10,11]. The relationship between the required immunosuppressive medications, particularly the calcinerin inhibitors, these risk factors, and cardiovascular disease, has been outlined in renal transplant patients [12, 13]. Several investigators have sought to characterize the relationship of immunosuppressive medications to cardiovascular risk factors in liver transplantation. For example, Neal et al [14] have shown that liver transplant recipients receiving tacrolimus have improved lipid profiles compared with those receiving cyclosporine based immunosuppression. Manzarbetia et al [15] have also demonstrated that cyclosporine has been associated with significantly higher triglyceride levels while tacrolimus has been associated with a moderate reduction in cholesterol and low density lipoprotein but has had no affect on triglycerides and high density lipoprotein. The significance of this lower incidence of hyperlipidemia on long-term cardiovascular complications and the possible impact of appropriate pharmacologic modifications has yet to be studied in liver transplantation. Therefore, this study is designed to evaluate the effect of two different immunosuppressive regimens, cyclosporine or tacrolimus, on the incidence of cardiovascular risk factors and disease in liver transplant patients.
Methods Records of liver transplant recipients from the Oregon Health Sciences University, Portland Veterans Affairs Medical Center Liver Transplant Program were retrospectively reviewed. Outpatient charts, hospitalization records, and physician communication notes were reviewed along with the liver transplant database. Pretransplant recipient information including age at transplant, gender, race, diagnosis for transplant, and renal function was collected. The preexisting diagnosis of hypertension, hyperlipidemia, diabetes mellitus or cardiovascular disease was also screened for. No patients with a pretransplant diagnosis of hypertension or hyperlipidemia were identified. Included were sequential adult (⬎18 years) patients beginning in 1994 treated with a cyclosporine-based immunosuppressive regimen who survived 3 years and had complete follow-up during that time frame. One hundred and 33 cyclosporine treated patients were reviewed to obtain 50 analyzable cases (41 deaths, 42
incomplete). An additional 53 patient records of recipients transplanted beginning in 1997 after a change in baseline immunosuppression from cyclosporine to tacrolimus were reviewed to obtain 37 analyzable cases (12 deaths/4 incomplete). All patients over age 50, with a history of alcoholic cirrhosis or prior history of cardiovascular disease or cardiac events underwent a complete cardiac consultation including an echocardiogram with additional cardiac evaluation as indicated; no patients with significant abnormal findings or prior cardiac history were included in the study. Data at 3 years posttransplantation reflective of diagnoses of hypertension, hyperlipidemia, diabetes mellitus, renal function, obesity, and cumulative cardiac events was collected. In addition, patients succumbing during the 3 year study period and their cause of death were recorded. Hypertension was defined as a diastolic blood pressure ⬎90 mm/Hg, a systolic blood pressure ⬎160 mm/Hg or the initiation of new antihypertensive agents posttransplantation continued at 3 years posttransplantation. Hyperlipidemia was defined as a total serum cholesterol ⬎250 mg/dL or the initiation of a cholesterol-lowering agent posttransplantation. New onset diabetes mellitus was defined as an untreated fasting glucose ⬎200 mg/dL, new use of an oral hypoglycemic agent, or new insulin dependence at 3 years posttransplantation. Obesity was based on an indicated diagnosis; no accompanying body mass index was calculated. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dL or more when the baseline was less than 1.5 mg/dL or 1.0 mg/dL increase or more when the baseline value was greater than 1.5 mg/dL. Graft rejection was documented by allograft biopsy. Cardiovascular disease was defined as the need for cardiac revascularization or a cardiovascular or cerebrovascular event including myocardial infarction, unstable angina, cardiac dysrhythmia, congestive heart failure, carotid stenosis and/or stroke during the three year study period. Congestive heart failure was defined as evidence of cardiogenic pulmonary edema, inability to perform significant physical activity or documented presence of American Heart Association heart failure classification criteria. Stroke was defined as a sudden nonconvulsive focal neurologic deficit including thrombosis, embolism, or hemorrhage. Statistical analyses were performed using SPSS statistical software. A reported standard deviation including an alpha error of 0.05 and a beta error of 0.2 was used.
Results A total of 186 patient records were reviewed, 133 patients treated with cyclosporine and 53 treated with tacrolimus. Of the cyclosporine-treated patients, 50 were complete for analysis. Forty-one cyclosporine treated patients died within 3 years after their transplant. Eight (20%) of these died of cardiovascular events. The remaining 42 of the 133 patients reviewed treated with cyclosporine had incomplete
J.M. Rabkin et al. / The American Journal of Surgery 183 (2002) 595–599 Table 1 Patient characteristics
Average age (years) Male/female Caucasian/non-Caucasian Diagnoses Alcoholic liver disease/hepatitis C Hepatitis C Alcoholic liver disease Primary biliary cirrhosis Primary sclerosing cholangitis Hepatitis B Cryptogenic Automimmune Others
Cyclosporine (n ⫽ 50)
Tacrolimus (n ⫽ 37)
48 32/18 46/4
45 22/15 35/2
12 11 6 3 3 2 5 2 6
12 8 2 3 3 3 2 1 3
records for analysis. Thirty-seven tacrolimus-treated patients were available for analysis. Twelve of the tacrolimustreated patients died within 3 years of transplant, none of these deaths were from cardiovascular disease. Four tacrolimus-treated patients were excluded owing to incomplete follow-up. Overall, 87 patients were available for complete analysis. The demographics of the two groups of patients were similar (Table 1). The average age of the cyclosporinetreated patients was higher than the tacrolimus-treated patients (48 versus 45 years, P ⬍ 0.05. Although not statistically significant, male sex was overrepresented in the cyclosporine group (M/F: 32/18 versus 22/15). Indications for transplantation were similar. All but 4 of the cyclosporine-treated patients were Caucasian and none were African American; 2 of the 37 tacrolimus-treated patients were African American with the remainder Caucasian. Hypertension was noted in 52% of patients (45/87) at 3 years posttransplantation (Table 2). The incidence of hypertension was significantly greater in the cyclosporine treated group (62% versus 38%, P ⬍ 0.05). The distribution of the severity of the hypertension as represented by the number of
Table 2 Results
Hypertension Hyperlipidemia Diabetes mellitus Nephrotoxicty (mg/dL) Baseline Three years posttransplant Cardiovascular disease Rejection Obesity * P ⬍ 0.05. † P ⬍ 0.001.
Cyclosporine (n ⫽ 50)
Tacrolimus (n ⫽ 37)
31 (62%) 7 (14%) 23 (46%)
14 (38%)* 2 (5%) 12 (32%)
1.1 1.6 9 (18%) 20 (40)% 7 (14%)
1.2 1.3 0† 7 (19%)* 6 (16%)
597
medications required to achieve acceptable hemodynamics was similar between the two groups. Of the patients in the cyclosporine group, 18 (58%) required a single antihypertensive agent, 9 (29%) required two agents, 3 (10%) required three drugs, and a single (3%) patient needed four antihypertensive medications to control the blood pressure. In the tacrolimus-treated group, 8 (57%) required one antihypertensive agent, 4 (28%) required two agents, 1 (7%) required three drugs, and 1 (7%) patient again needed four antihypertensive medications. Hyperlipidemia was noted in 9 (10%) of the patients at 3 years posttransplantation. Seven (14%) of the cyclosporinetreated patients required HMG coenzyme reductase cholesterol lowering medications as part of their pharmacologic regimen while only 2 (5%) patients in the tacrolimus group required these medications to lower their serum cholesterol (P ⫽ 0.08). Posttransplantation new onset diabetes at 3 years posttransplantation was noted in 35 (40%) patients: 23 (46%) of the cyclosporine-treated patients and 12 (32%) of the tacrolimus-treated patients (P ⫽ NS). Of these 14 (16%) patients required insulin and 21 (24%) patients required an oral hypoglycemic agent. The cyclosporine-treated patients included 16 (32%) with a serum creatinine between 1.5 and 2.0 mg/Dl and 6 (12%) with a serum creatinine ⬎2.0 mg/Dl. In contrast, 5 (13%) patients in the tacrolimus-treated group had a serum creatinine between 1.5 and 2.0 mg/Dl and a single (3%) patient had a serum creatinine ⬎2.0 mg/Dl. The cyclosporine-treated group suffered an increase in serum creatinine from an average baseline of 1.1 mg/dL to 1.6 mg/dL compared with the tacrolimus-treated group increase from a baseline of 1.2 mg/dL to 1.3 mg/dL (P ⬍ 0.05). Obesity was noted in 14% of the cyclosporine-treated patients and 16% of the tacrolimus-treated group at 3 years posttransplantation (P ⫽ NS). Finally, rejection was noted in 20 (41%) of the cyclosporine-treated patients and 7 (19%) of the tacrolimus-treated patients (P ⬍ 0.05). In addition, 1 patient in the cyclosporine-treated group experienced steroid-resistant rejection requiring antilymphocyte therapy (OKT3). No allograft was lost due to chronic rejection. Nine (18%) of the cyclosporine treated patients sustained 12 (24%) cardiovascular events leading to a diagnosis of new posttransplant cardiovascular disease during the 3-year follow-up period: 2 patients required cardiac revascularization, 2 sustained a myocardial infarction, 2 had unstable angina, 2 had a cardiac dysrhythmia, 1 had congestive heart failure, 1 had significant carotid stenosis, and 2 sustained strokes. No patients in the tacrolimus-treated group had a cardiovascular event or newly diagnosed cardiovascular disease.
Comments With the steady improvement in early posttransplant allograft and patient survival experienced over these past 2
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decades, more pharmacologically immunosurpressed patients are facing nonallograft-related morbidity and potential mortality. Mandatory immunosuppression, which has contributed immensely to this remarkable early posttransplant success, now is increasingly implicated in poor longterm outcomes. With limited preexisting information in liver transplantation, this study characterizes the incidence of known cardiovascular disease risk factors and significant posttransplant cardiac disease under the two primary immunosuppessive treatment regimens currently employed. Despite previous studies highlighting the superiority of tacrolimus over cyclosporine in short-term patient and allograft survival as well as incidence of rejection, skepticism remains with respect to a potential long-term adverse impact of tacrolimus on cardiovascular risk factors and disease [2,9]. This study confirms a diminished risk of rejection and suggests improved long-term results with tacrolimus indicated by a significantly lower incidence of cardiovascular risk factors and events. Despite the high prevalence of many of these risk factors under both immunosuppressive regimens, modification of the immunosuppression employed may improve long-term survival and quality of life. Calcineurin inhibitors (cyclosporine and tacrolimus) are well known to cause posttransplant hypertension [7,16]. Several overlapping hormonal and neuronal compensatory systems have been linked to increased blood pressure including release of endothelin, decreased responsiveness of blood vessels to nitric oxide, and activation of sympathemimetic nerves [17,18]. Canzanello et al [19] found that cyclosporine treated patients had a significantly higher incidence of posttransplant hypertension compared to tacrolimus treated patients (82% versus 64%, P ⬍ 0.05) [19]. This study also found that the onset was delayed in the tacrolimus-treated group. We found increased hypertension in the cyclosporine treated patients but without a proportionate increase in the need for more aggressive use of multiple anti-hypertensive agents. Tacrolimus causes less of a rise in mean blood pressure as it has less of an effect on hormonal and neuronal auto regulation. Solid organ transplant patients are at increased risk for developing hyperlipidemia for a variety of reasons [20 –22]. Immunosuppressive agents, notably cyclosporine and corticosteroids, markedly alter the lipid profile and may induce or augment hyperlipidemia [23]. There are changes not only in the concentration of lipoproteins but also changes in the quality of these lipoproteins [24]. This quality change may be more significant than the increased concentration [20]. In cardiac and renal transplant recipients, hyperlipidemia has been found in up to 90% and 70% of recipients, respectively [2,13]. Interestingly, liver transplant recipients appear to be at diminished overall risk: this study found that only 9 (10%) patients required lipid-lowering agents 3 years posttransplantation. Chronic liver disease is associated with significantly impaired cholesterol synthesis. Most patients, therefore, have depressed serum lipids at the time of transplantation. This may mitigate the long-term impact of the
immunosuppressive agents on hyperlipidemia post liver transplantation [4,5,25,26]. Nevertheless, although not statistically significant, cyclosporine-treated patients appeared to have a greater incidence of hyperlipidemia when compared with tacrolimus-treated patients. Calcineurin inhibitors are potent vasoconstrictors of renal afferent arterioles [27]. This results in decreased renal blood flow and a diminished glomerular filtration rate. Although cyclosporine and tacrolimus both have associated nephrotoxicity, tacrolimus effects significantly less expression of transforming growth factor beta-1 (TGF beta-1), a key cytokine associated with renal interstitial fibrosis [28]. This study confirmed a significant increase in average serum creatinine for the cyclosporine treated group but not for the tacrolimus treated patients (P ⬍ 0.05), and found that significantly more cyclosporine treated patients had elevated serum creatinines either between 1.5 and 2.0 mg/dL or greater than 2.0 mg/dL (32% versus 12% and 13% versus 3%, respectively). Importantly, in this cohort of patients, no recipients were either dialysis dependent at 3 years posttransplantation or had undergone renal transplantation. Previous studies have noted increased new onset diabetes mellitus associated with tacrolimus use [29]. In this study, no significant difference in the incidence of persistent posttransplant (new onset) diabetes mellitus was found between the two patient populations examined. Similarly, no specific difference in the subjective diagnosis of obesity was found. However, there was a pronounced decrease in the incidence of allograft rejection in the tacrolimus-treated patients. Consequently, the increased use of steroids to treat rejection in the cyclosporine-treated group may have mitigated tacrolimus’ effect on diabetes mellitus (and possibly obesity) in the comparison between the two groups of patients. Corticosteroids are also associated with the development of cardiovascular risk factors and disease [29]. The most important finding in this study was the absence of cardiovascular events in the tacrolimus-treated patients. One-fifth of the cyclosporine-treated patients had significant cardiovascular disease diagnosed during the 3 year study period following transplantation. This potentially will increase the long-term mortality from cardiovascular disease in this patient population. Early posttransplant mortality (⬍3 years) from cardiovascular disease was also marked in the cyclosporine-treated patients (20% of overall mortality) and absent in the tacrolimus-treated group. These findings all point to the importance of cardiovascular risk factors and disease in the liver transplant patient population. Most importantly, the refinement of the immunosuppressive regimen needs to embrace long-term outcome issues beyond disease recurrence, to date the major focus of long-term studies in this patient population. Remarkably good early patient and allograft survivals allow this refocused effort, which, in time, will hopefully lead to new approaches diminishing the toxicities associated with the immunosuppressive medications. Immunologic tolerance posttransplantation, a condition that would obviate the
J.M. Rabkin et al. / The American Journal of Surgery 183 (2002) 595–599
need for pharmacologic immunosuppression and, therefore, eliminate all of these associated toxicities, remains an illusive goal. Conclusion Risk factors for the development of cardiovascular disease are common 3 years after liver transplantation. Cardiovascular disease events are also frequent in the liver transplant patients. Pharmacologic immunosuppression, particularly the choice of the calcineurin inhibitor used, appears to affect the prevalence of these risk factors as well as the development of cardiovascular disease. This study suggests tacrolimus is superior to cyclosporine in liver transplantation because of diminished rejection as well as for avoidance of long-term cardiovascular disease. Additional studies are warranted to further refine immunosuppressive protocols to diminish these long-term adverse side effects without foregoing the remarkable curtailment of rejection permitting the gratifying early survival currently enjoyed. References [1] American Heart Association data 2001. Available at: http://www. americanheart.org / downloadable / heart / 4838_HSSTATS2001_1.0.pdf. Accessed October 15, 2001. [2] Ritz E, Schwenger V, Wiesel M, Zeier M. Atherosclerotic complications after renal transplantation. Transplant Int 2000;13(suppl 1): S14 –19. [3] Wheeler DC, Steiger J. Evolution and etiology of cardiovascular diseases in renal transplant recipients. Transplantation 2000;70: SS41–5. [4] Plotkin JS, Johnson LB, Rustgi V, Kuo PC. Coronary artery disease and liver transplantation: the state of the art. Liver Transplant 2000; 6:S53– 6. [5] Romero M, Parera A, Salcedo M, et al. Cardiovascular risk factors and late cardiovascular disease in liver transplantation. Transplant Proc 1999;31:2364 –5. [6] Rabkin JM, delaMelana LM, Orloff SL, et al. Late mortality after orthotopic liver transplantation. Am J Surg 2001;181:475–9. [7] Wong KS. Posttransplant hypertension. Transplant Proc 2000;32: 1495– 6. [8] Goldsmith DJ, Covic A. Coronary artery disease in patients with renal failure. Int J Clin Pract 2001;55:196 –210. [9] Stewart G, Jardine AG, Briggs JD. Ischaemic heart disease following renal transplantation. Nephrol Dialy Transplant 2000;15:269 –77. [10] Massy ZA. Cardiovascular risk factors in kidney transplantation. Curr Opin Urol 2001;11:139 – 42. [11] Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2000;20:176 – 87.
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[12] Coresh J, Longenecker JC, Miller ER, et al. Epidemiology of cardiovascular risk factors in chronic renal disease. J Am Soc Nephrol 1998;9:S24 –30. [13] Young JB. Heart disease in non-heart transplant recipients. In: Norman D, Turka L, editors. Primer on transplantation. 2nd ed. AST, 2001:201–212. [14] Neal DA, Gimson AE, Gibbs P, Alexander GJ. Beneficial effects of converting liver transplant recipients from cyclosporine to tacrolimus on blood pressure, serum lipids, and weight. Liver Transplant 2001; 7:533–9. [15] Manzarbeitia C, Reich DJ, Rothstein KD, et al. Tacrolimus conversion improves hyperlipidemic states in stable liver transplant recipients. Liver Transplant 2001;7:93–9. [16] Olyaei AJ, deMattos AM, Bennett WM. A practical guide to the management of hypertension in renal transplant recipients. Drugs 1999;58:1011–27. [17] Textor SC, Taler SJ, Canzanello VJ, et al. Posttransplantation hypertension related to calcineurin inhibitors. Liver Transplant 2000;6: 521–30. [18] Taler SJ, Textor SC, Canzanello VJ, et al. Cyclosporin-induced hypertension: incidence, pathogenesis and management. Drug Safety 1999;20:437– 49. [19] Canzanello VJ, Textor SC, Taler SJ, et al. Late hypertension after liver transplantation: a comparison of cyclosporine and tacrolimus (FK 506). Liver Transplant Surg 1998;4:328 –34. [20] Charco R, Cantarell C, Vargas V, et al. Serum cholesterol changes in long-term survivors of liver transplantation: a comparison between cyclosporine and tacrolimus therapy. Liver Transplant Surg 1999;5: 204 – 8. [21] Reich D, Rothstein K, Manzarbeitia C, et al. Common medical diseases after liver transplantation. Semin Gastrointest Dis 1998;9: 110 –25. [22] Atillasoy E, Gurkan A, Mor E, et al. Cholesterol levels long-term after liver transplant. Transplant Proc 1998;30:2049 –50. [23] Guckelberger O, Langrehr JM, et al. Does the choice of primary immunosuppression influence the prevalence of cardiovascular risk factors after liver transplantation? Transplant Proc 1996;28:3173– 4. [24] Smith SL. Risk factors for premature coronary heart disease after successful liver transplantation in adults. J Transplant Coor 1996;6: 178 – 85. [25] Prifti E, Maccherini M, Capannini G, et al. Coronary revascularization after liver transplantation. Eur J Cardio-Thorac Surg 1998;14: 643– 4. [26] Plotkin JS, Benitez RM, Kuo PC, et al. Dobutamine stress echocardiography for preoperative cardiac risk stratification in patients undergoing orthotopic liver transplantation. Liver Transplant Surg 1998;4:253–7. [27] Olyaei AJ, de Mattos AM, Bennett WM. Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. Drug Safety 1999;21:471– 88. [28] Vieira JMJ, Noronha IL, Malheiros DM, et al. Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow. Transplantation 1999;68:1746 –53. [29] Otto G, Bleyl J, Neuhaus P, et al. Corticosteroids and concomitant medication in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation. Transplant Int 1994;7(suppl 1):S7–10.
Scientific paper
Immunosuppression impact on long-term cardiovascular complications after liver transplantation John M. Rabkin M.D.a,*, Christopher L. Corless, M.D., Ph.D.b, Hugo R. Rosen, M.D.c, Ali J. Olyaei, Pharm.D.a a
Department of Surgery, Division of Abdominal Organ Transplantation, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, 3181 SW Sam Jackson Park Rd. L590, Portland, Oregon 97201-3098, USA b Department of Pathology Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, OR, USA c Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, OR, USA Manuscript received December 14, 2001; revised manuscript January 17, 2002 Presented at the 88th Annual Meeting of the North Pacific Surgical Association, Victoria, British Columbia, November 8 –11, 2001
Abstract Background: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. Objective: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. Methods: Eighty-seven sequential patients (CSA: n ⫽ 50, mean age 48 years, M/F 32/18; and FK-506: n ⫽ 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were ⱖ18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. Results: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P ⬍ 0.05), HTN (62% versus 38%, P ⬍ 0.05), HLIP (14% versus 5%, P ⫽ 0.08), and cardiovascular disease (18% versus 0%, P ⬍ 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. Conclusion: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease. © 2002 Excerpta Medica, Inc. All rights reserved. Keywords: Liver transplantation; Cardiovascular complications; Nephrotoxicity
Cardiovascular disease is the major cause of mortality in the United States. It accounts for crude an annual death rate of 200 per 100,000 population and $91 billion dollars of annual health care expenditures [1]. Cardiovascular complications also account for a majority of the morbidity and mortality posttransplantation [2–5]. The incidence of cardiovascular disease is much higher in transplant recipients * Corresponding author. Tel.: ⫹1-503-494-7810; fax: ⫹1503-4945292. E-mail address: [email protected]
than in the general population. For example, the annual cardiovascular mortality rate is increased from 0.28% for the general population to 0.54% in renal transplant recipients where it accounts for 55% of the overall mortality [1]. Up to 10% of the late mortality in the liver transplant patient population has been ascribed to cardiovascular disease [6]. Furthermore, the overall rate for cardiovascular disease may be underestimated as a result of incomplete or indeterminate death reports. Despite the prevalence of cardiovascular disease in transplant patients, most of the focus posttransplantation has been on rejection or early postoperative compli-
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cations such as infections or metabolic abnormalities with little attention paid to long-term cardiovascular complications. Established risk factors for cardiovascular disease include hypertension, hyperlipidemia, diabetes mellitus, renal insufficiency, obesity, family history of cardiovascular disease, advanced age, African-American race, male gender and tobacco abuse [7–9]. In renal transplantation hypertension, diabetes mellitus, age, family history, tobacco use and total serum cholesterol ⬎200 mg/dL or HDL ⬍35 mg/dL have been established as independent risk factors for cardiovascular disease [3,10,11]. The relationship between the required immunosuppressive medications, particularly the calcinerin inhibitors, these risk factors, and cardiovascular disease, has been outlined in renal transplant patients [12, 13]. Several investigators have sought to characterize the relationship of immunosuppressive medications to cardiovascular risk factors in liver transplantation. For example, Neal et al [14] have shown that liver transplant recipients receiving tacrolimus have improved lipid profiles compared with those receiving cyclosporine based immunosuppression. Manzarbetia et al [15] have also demonstrated that cyclosporine has been associated with significantly higher triglyceride levels while tacrolimus has been associated with a moderate reduction in cholesterol and low density lipoprotein but has had no affect on triglycerides and high density lipoprotein. The significance of this lower incidence of hyperlipidemia on long-term cardiovascular complications and the possible impact of appropriate pharmacologic modifications has yet to be studied in liver transplantation. Therefore, this study is designed to evaluate the effect of two different immunosuppressive regimens, cyclosporine or tacrolimus, on the incidence of cardiovascular risk factors and disease in liver transplant patients.
Methods Records of liver transplant recipients from the Oregon Health Sciences University, Portland Veterans Affairs Medical Center Liver Transplant Program were retrospectively reviewed. Outpatient charts, hospitalization records, and physician communication notes were reviewed along with the liver transplant database. Pretransplant recipient information including age at transplant, gender, race, diagnosis for transplant, and renal function was collected. The preexisting diagnosis of hypertension, hyperlipidemia, diabetes mellitus or cardiovascular disease was also screened for. No patients with a pretransplant diagnosis of hypertension or hyperlipidemia were identified. Included were sequential adult (⬎18 years) patients beginning in 1994 treated with a cyclosporine-based immunosuppressive regimen who survived 3 years and had complete follow-up during that time frame. One hundred and 33 cyclosporine treated patients were reviewed to obtain 50 analyzable cases (41 deaths, 42
incomplete). An additional 53 patient records of recipients transplanted beginning in 1997 after a change in baseline immunosuppression from cyclosporine to tacrolimus were reviewed to obtain 37 analyzable cases (12 deaths/4 incomplete). All patients over age 50, with a history of alcoholic cirrhosis or prior history of cardiovascular disease or cardiac events underwent a complete cardiac consultation including an echocardiogram with additional cardiac evaluation as indicated; no patients with significant abnormal findings or prior cardiac history were included in the study. Data at 3 years posttransplantation reflective of diagnoses of hypertension, hyperlipidemia, diabetes mellitus, renal function, obesity, and cumulative cardiac events was collected. In addition, patients succumbing during the 3 year study period and their cause of death were recorded. Hypertension was defined as a diastolic blood pressure ⬎90 mm/Hg, a systolic blood pressure ⬎160 mm/Hg or the initiation of new antihypertensive agents posttransplantation continued at 3 years posttransplantation. Hyperlipidemia was defined as a total serum cholesterol ⬎250 mg/dL or the initiation of a cholesterol-lowering agent posttransplantation. New onset diabetes mellitus was defined as an untreated fasting glucose ⬎200 mg/dL, new use of an oral hypoglycemic agent, or new insulin dependence at 3 years posttransplantation. Obesity was based on an indicated diagnosis; no accompanying body mass index was calculated. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dL or more when the baseline was less than 1.5 mg/dL or 1.0 mg/dL increase or more when the baseline value was greater than 1.5 mg/dL. Graft rejection was documented by allograft biopsy. Cardiovascular disease was defined as the need for cardiac revascularization or a cardiovascular or cerebrovascular event including myocardial infarction, unstable angina, cardiac dysrhythmia, congestive heart failure, carotid stenosis and/or stroke during the three year study period. Congestive heart failure was defined as evidence of cardiogenic pulmonary edema, inability to perform significant physical activity or documented presence of American Heart Association heart failure classification criteria. Stroke was defined as a sudden nonconvulsive focal neurologic deficit including thrombosis, embolism, or hemorrhage. Statistical analyses were performed using SPSS statistical software. A reported standard deviation including an alpha error of 0.05 and a beta error of 0.2 was used.
Results A total of 186 patient records were reviewed, 133 patients treated with cyclosporine and 53 treated with tacrolimus. Of the cyclosporine-treated patients, 50 were complete for analysis. Forty-one cyclosporine treated patients died within 3 years after their transplant. Eight (20%) of these died of cardiovascular events. The remaining 42 of the 133 patients reviewed treated with cyclosporine had incomplete
J.M. Rabkin et al. / The American Journal of Surgery 183 (2002) 595–599 Table 1 Patient characteristics
Average age (years) Male/female Caucasian/non-Caucasian Diagnoses Alcoholic liver disease/hepatitis C Hepatitis C Alcoholic liver disease Primary biliary cirrhosis Primary sclerosing cholangitis Hepatitis B Cryptogenic Automimmune Others
Cyclosporine (n ⫽ 50)
Tacrolimus (n ⫽ 37)
48 32/18 46/4
45 22/15 35/2
12 11 6 3 3 2 5 2 6
12 8 2 3 3 3 2 1 3
records for analysis. Thirty-seven tacrolimus-treated patients were available for analysis. Twelve of the tacrolimustreated patients died within 3 years of transplant, none of these deaths were from cardiovascular disease. Four tacrolimus-treated patients were excluded owing to incomplete follow-up. Overall, 87 patients were available for complete analysis. The demographics of the two groups of patients were similar (Table 1). The average age of the cyclosporinetreated patients was higher than the tacrolimus-treated patients (48 versus 45 years, P ⬍ 0.05. Although not statistically significant, male sex was overrepresented in the cyclosporine group (M/F: 32/18 versus 22/15). Indications for transplantation were similar. All but 4 of the cyclosporine-treated patients were Caucasian and none were African American; 2 of the 37 tacrolimus-treated patients were African American with the remainder Caucasian. Hypertension was noted in 52% of patients (45/87) at 3 years posttransplantation (Table 2). The incidence of hypertension was significantly greater in the cyclosporine treated group (62% versus 38%, P ⬍ 0.05). The distribution of the severity of the hypertension as represented by the number of
Table 2 Results
Hypertension Hyperlipidemia Diabetes mellitus Nephrotoxicty (mg/dL) Baseline Three years posttransplant Cardiovascular disease Rejection Obesity * P ⬍ 0.05. † P ⬍ 0.001.
Cyclosporine (n ⫽ 50)
Tacrolimus (n ⫽ 37)
31 (62%) 7 (14%) 23 (46%)
14 (38%)* 2 (5%) 12 (32%)
1.1 1.6 9 (18%) 20 (40)% 7 (14%)
1.2 1.3 0† 7 (19%)* 6 (16%)
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medications required to achieve acceptable hemodynamics was similar between the two groups. Of the patients in the cyclosporine group, 18 (58%) required a single antihypertensive agent, 9 (29%) required two agents, 3 (10%) required three drugs, and a single (3%) patient needed four antihypertensive medications to control the blood pressure. In the tacrolimus-treated group, 8 (57%) required one antihypertensive agent, 4 (28%) required two agents, 1 (7%) required three drugs, and 1 (7%) patient again needed four antihypertensive medications. Hyperlipidemia was noted in 9 (10%) of the patients at 3 years posttransplantation. Seven (14%) of the cyclosporinetreated patients required HMG coenzyme reductase cholesterol lowering medications as part of their pharmacologic regimen while only 2 (5%) patients in the tacrolimus group required these medications to lower their serum cholesterol (P ⫽ 0.08). Posttransplantation new onset diabetes at 3 years posttransplantation was noted in 35 (40%) patients: 23 (46%) of the cyclosporine-treated patients and 12 (32%) of the tacrolimus-treated patients (P ⫽ NS). Of these 14 (16%) patients required insulin and 21 (24%) patients required an oral hypoglycemic agent. The cyclosporine-treated patients included 16 (32%) with a serum creatinine between 1.5 and 2.0 mg/Dl and 6 (12%) with a serum creatinine ⬎2.0 mg/Dl. In contrast, 5 (13%) patients in the tacrolimus-treated group had a serum creatinine between 1.5 and 2.0 mg/Dl and a single (3%) patient had a serum creatinine ⬎2.0 mg/Dl. The cyclosporine-treated group suffered an increase in serum creatinine from an average baseline of 1.1 mg/dL to 1.6 mg/dL compared with the tacrolimus-treated group increase from a baseline of 1.2 mg/dL to 1.3 mg/dL (P ⬍ 0.05). Obesity was noted in 14% of the cyclosporine-treated patients and 16% of the tacrolimus-treated group at 3 years posttransplantation (P ⫽ NS). Finally, rejection was noted in 20 (41%) of the cyclosporine-treated patients and 7 (19%) of the tacrolimus-treated patients (P ⬍ 0.05). In addition, 1 patient in the cyclosporine-treated group experienced steroid-resistant rejection requiring antilymphocyte therapy (OKT3). No allograft was lost due to chronic rejection. Nine (18%) of the cyclosporine treated patients sustained 12 (24%) cardiovascular events leading to a diagnosis of new posttransplant cardiovascular disease during the 3-year follow-up period: 2 patients required cardiac revascularization, 2 sustained a myocardial infarction, 2 had unstable angina, 2 had a cardiac dysrhythmia, 1 had congestive heart failure, 1 had significant carotid stenosis, and 2 sustained strokes. No patients in the tacrolimus-treated group had a cardiovascular event or newly diagnosed cardiovascular disease.
Comments With the steady improvement in early posttransplant allograft and patient survival experienced over these past 2
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decades, more pharmacologically immunosurpressed patients are facing nonallograft-related morbidity and potential mortality. Mandatory immunosuppression, which has contributed immensely to this remarkable early posttransplant success, now is increasingly implicated in poor longterm outcomes. With limited preexisting information in liver transplantation, this study characterizes the incidence of known cardiovascular disease risk factors and significant posttransplant cardiac disease under the two primary immunosuppessive treatment regimens currently employed. Despite previous studies highlighting the superiority of tacrolimus over cyclosporine in short-term patient and allograft survival as well as incidence of rejection, skepticism remains with respect to a potential long-term adverse impact of tacrolimus on cardiovascular risk factors and disease [2,9]. This study confirms a diminished risk of rejection and suggests improved long-term results with tacrolimus indicated by a significantly lower incidence of cardiovascular risk factors and events. Despite the high prevalence of many of these risk factors under both immunosuppressive regimens, modification of the immunosuppression employed may improve long-term survival and quality of life. Calcineurin inhibitors (cyclosporine and tacrolimus) are well known to cause posttransplant hypertension [7,16]. Several overlapping hormonal and neuronal compensatory systems have been linked to increased blood pressure including release of endothelin, decreased responsiveness of blood vessels to nitric oxide, and activation of sympathemimetic nerves [17,18]. Canzanello et al [19] found that cyclosporine treated patients had a significantly higher incidence of posttransplant hypertension compared to tacrolimus treated patients (82% versus 64%, P ⬍ 0.05) [19]. This study also found that the onset was delayed in the tacrolimus-treated group. We found increased hypertension in the cyclosporine treated patients but without a proportionate increase in the need for more aggressive use of multiple anti-hypertensive agents. Tacrolimus causes less of a rise in mean blood pressure as it has less of an effect on hormonal and neuronal auto regulation. Solid organ transplant patients are at increased risk for developing hyperlipidemia for a variety of reasons [20 –22]. Immunosuppressive agents, notably cyclosporine and corticosteroids, markedly alter the lipid profile and may induce or augment hyperlipidemia [23]. There are changes not only in the concentration of lipoproteins but also changes in the quality of these lipoproteins [24]. This quality change may be more significant than the increased concentration [20]. In cardiac and renal transplant recipients, hyperlipidemia has been found in up to 90% and 70% of recipients, respectively [2,13]. Interestingly, liver transplant recipients appear to be at diminished overall risk: this study found that only 9 (10%) patients required lipid-lowering agents 3 years posttransplantation. Chronic liver disease is associated with significantly impaired cholesterol synthesis. Most patients, therefore, have depressed serum lipids at the time of transplantation. This may mitigate the long-term impact of the
immunosuppressive agents on hyperlipidemia post liver transplantation [4,5,25,26]. Nevertheless, although not statistically significant, cyclosporine-treated patients appeared to have a greater incidence of hyperlipidemia when compared with tacrolimus-treated patients. Calcineurin inhibitors are potent vasoconstrictors of renal afferent arterioles [27]. This results in decreased renal blood flow and a diminished glomerular filtration rate. Although cyclosporine and tacrolimus both have associated nephrotoxicity, tacrolimus effects significantly less expression of transforming growth factor beta-1 (TGF beta-1), a key cytokine associated with renal interstitial fibrosis [28]. This study confirmed a significant increase in average serum creatinine for the cyclosporine treated group but not for the tacrolimus treated patients (P ⬍ 0.05), and found that significantly more cyclosporine treated patients had elevated serum creatinines either between 1.5 and 2.0 mg/dL or greater than 2.0 mg/dL (32% versus 12% and 13% versus 3%, respectively). Importantly, in this cohort of patients, no recipients were either dialysis dependent at 3 years posttransplantation or had undergone renal transplantation. Previous studies have noted increased new onset diabetes mellitus associated with tacrolimus use [29]. In this study, no significant difference in the incidence of persistent posttransplant (new onset) diabetes mellitus was found between the two patient populations examined. Similarly, no specific difference in the subjective diagnosis of obesity was found. However, there was a pronounced decrease in the incidence of allograft rejection in the tacrolimus-treated patients. Consequently, the increased use of steroids to treat rejection in the cyclosporine-treated group may have mitigated tacrolimus’ effect on diabetes mellitus (and possibly obesity) in the comparison between the two groups of patients. Corticosteroids are also associated with the development of cardiovascular risk factors and disease [29]. The most important finding in this study was the absence of cardiovascular events in the tacrolimus-treated patients. One-fifth of the cyclosporine-treated patients had significant cardiovascular disease diagnosed during the 3 year study period following transplantation. This potentially will increase the long-term mortality from cardiovascular disease in this patient population. Early posttransplant mortality (⬍3 years) from cardiovascular disease was also marked in the cyclosporine-treated patients (20% of overall mortality) and absent in the tacrolimus-treated group. These findings all point to the importance of cardiovascular risk factors and disease in the liver transplant patient population. Most importantly, the refinement of the immunosuppressive regimen needs to embrace long-term outcome issues beyond disease recurrence, to date the major focus of long-term studies in this patient population. Remarkably good early patient and allograft survivals allow this refocused effort, which, in time, will hopefully lead to new approaches diminishing the toxicities associated with the immunosuppressive medications. Immunologic tolerance posttransplantation, a condition that would obviate the
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need for pharmacologic immunosuppression and, therefore, eliminate all of these associated toxicities, remains an illusive goal. Conclusion Risk factors for the development of cardiovascular disease are common 3 years after liver transplantation. Cardiovascular disease events are also frequent in the liver transplant patients. Pharmacologic immunosuppression, particularly the choice of the calcineurin inhibitor used, appears to affect the prevalence of these risk factors as well as the development of cardiovascular disease. This study suggests tacrolimus is superior to cyclosporine in liver transplantation because of diminished rejection as well as for avoidance of long-term cardiovascular disease. Additional studies are warranted to further refine immunosuppressive protocols to diminish these long-term adverse side effects without foregoing the remarkable curtailment of rejection permitting the gratifying early survival currently enjoyed. References [1] American Heart Association data 2001. Available at: http://www. americanheart.org / downloadable / heart / 4838_HSSTATS2001_1.0.pdf. Accessed October 15, 2001. [2] Ritz E, Schwenger V, Wiesel M, Zeier M. Atherosclerotic complications after renal transplantation. Transplant Int 2000;13(suppl 1): S14 –19. [3] Wheeler DC, Steiger J. Evolution and etiology of cardiovascular diseases in renal transplant recipients. Transplantation 2000;70: SS41–5. [4] Plotkin JS, Johnson LB, Rustgi V, Kuo PC. Coronary artery disease and liver transplantation: the state of the art. Liver Transplant 2000; 6:S53– 6. [5] Romero M, Parera A, Salcedo M, et al. Cardiovascular risk factors and late cardiovascular disease in liver transplantation. Transplant Proc 1999;31:2364 –5. [6] Rabkin JM, delaMelana LM, Orloff SL, et al. Late mortality after orthotopic liver transplantation. Am J Surg 2001;181:475–9. [7] Wong KS. Posttransplant hypertension. Transplant Proc 2000;32: 1495– 6. [8] Goldsmith DJ, Covic A. Coronary artery disease in patients with renal failure. Int J Clin Pract 2001;55:196 –210. [9] Stewart G, Jardine AG, Briggs JD. Ischaemic heart disease following renal transplantation. Nephrol Dialy Transplant 2000;15:269 –77. [10] Massy ZA. Cardiovascular risk factors in kidney transplantation. Curr Opin Urol 2001;11:139 – 42. [11] Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2000;20:176 – 87.
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