David A.J. Neal, * Alexander E.S. Gimson, * Paul Gibbs, and Graeme J.M. Alexander * Methods. Patients

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1 Beneficial Effects of Converting Liver Transplant Recipients From Cyclosporine to Tacrolimus on Blood Pressure, Serum Lipids, and Weight David A.J. Neal, * Alexander E.S. Gimson, * Paul Gibbs, and Graeme J.M. Alexander * Hypertension and hyperlipidemia are more prevalent after liver transplantation with cyclosporine as the primary immunosuppressive agent compared with tacrolimus. To determine whether blood pressure, serum lipid level, or weight improves when patients switch immunosuppression therapy, we retrospectively studied 26 liver transplant recipients with stable graft function who had been converted from cyclosporine to tacrolimus therapy with a median follow-up of 8 months. One of the 26 patients developed pruritus necessitating withdrawal of tacrolimus. The results therefore concern the remaining 25 patients. With the exception of a small decrease in bilirubin level (P <.05), there was no difference in graft or renal function after conversion. Mean systolic blood pressure decreased from to mm Hg over a mean of 8 3 months after conversion to tacrolimus (P.015), whereas mean serum cholesterol level decreased from to mmol/l (P.01). Sixty-eight percent of the patients lost weight, from a mean of to kg, in the 11 months after switching to tacrolimus therapy (P.024). Serum triglyceride and blood glucose levels did not change, and no patient developed diabetes mellitus after conversion. These results indicate that switching from cyclosporine to tacrolimus can reduce blood pressure, serum cholesterol level, and weight after liver transplantation. (Liver Transpl 2001;7: ) Trials of orthotopic liver transplantation have shown small but clear differences between cyclosporine and tacrolimus therapy with respect to the frequency of acute cellular rejection, refractory rejection, and chronic rejection. 1-3 It also has been suggested that grafts with chronic rejection can be rescued by switching from cyclosporine to tacrolimus therapy. 4 There is growing interest in factors that may affect long-term survival after liver transplantation, including the presence or absence of markers of cardiovascular disease. Hypertension, hyperlipidemia, and obesity are encountered frequently in the transplant recipient and may contribute to overall cardiovascular risk. Several studies suggest that cardiovascular risk profiles are more favorable in patients administered tacrolimus than cyclosporine. Thus, the reported rates of hypertension 2,3,5-9 and hypercholesterolemia 5,6,8,10 after transplantation are lower with tacrolimus therapy. The development of moderate or severe obesity after transplantation has been described in more than 34% of patients with a normal body mass index (BMI) before surgery. 11 A trend toward reduced weight gain after transplantation using tacrolimus instead of cyclosporine therapy has been described. 5,6,12 Despite these reported differences between cyclosporine and tacrolimus, there are few data on the effects of conversion from cyclosporine to tacrolimus therapy with respect to blood pressure, serum lipid level, and weight after liver transplantation. One study of 20 cyclosporine-treated liver transplant recipients showed a reduced requirement for antihypertensive medication after tacrolimus was substituted. 13 In another study of 31 patients converted to tacrolimus therapy, serum lipid levels decreased significantly after 3 months. 14 To our knowledge, the effect of changing from cyclosporine to tacrolimus on weight has not been assessed. We reviewed the effects of converting 26 patients with and without cardiovascular risk factors from cyclosporine to tacrolimus therapy on blood pressure, serum lipid level, blood glucose level, and weight. Methods Patients Outpatient case records of the 29 liver transplant recipients who had been converted from cyclosporine to tacrolimus therapy within a 24-month period post liver transplantation were evaluated. Three patients converted to tacrolimus therapy because of chronic allograft rejection were excluded from the study on the basis that resulting changes in cardiovascular parameters on conversion to tacrolimus therapy could be at- From the *Department of Medicine and University Department of Surgery, University of Cambridge, School of Clinical Medicine, Addenbrooke s NHS Trust, Cambridge, England. Address reprint requests to Graeme J.M. Alexander, MD, University Department of Medicine, Box 157, Addenbrooke s NHS Trust, Hills Rd, Cambridge, CB2 2QQ, England. Telephone: ; FAX: ; gja1000@cam.ac.uk Copyright 2001 by the American Association for the Study of Liver Diseases /01/ $35.00/0 doi: /jlts Liver Transplantation, Vol 7, No 6 (June), 2001: pp

2 534 Neal et al Table 1. Indication for Conversion to Tacrolimus Therapy No. of Patients Weight gain 8 Late acute cellular rejection 6 Pancytopenia 1 Neurological symptoms 2 Lethargy 2 Nephrotoxicity 2 Itching 1 Hypertension 2 Hirsutism 1 Gum hypertrophy 1 tributed to improvement in graft function rather than the drug alone. This left 26 patients converted from cyclosporine to tacrolimus therapy who had stable graft function during the months preceding conversion. The reasons for switching to tacrolimus are listed in Table 1. Six patients who were started on tacrolimus therapy with the onset of late acute cellular rejection were included because graft function during the months before the episode of rejection had been stable. These patients all responded to 3 days treatment with intravenous methylprednisolone. Data for blood pressure, total serum cholesterol and triglyceride levels, weight, random blood glucose levels, and liver graft and renal functions are collected routinely at each outpatient attendance. Seated blood pressure is measured after a period of rest in the outpatient clinic. Systolic blood pressure greater than 140 mm Hg is an accepted definition of hypertension. 15,16 Serum lipid and blood glucose levels were determined by an automated chemistry analyzer (Dimension RXL; Dade Behring, Irvine, CA). These parameters were evaluated on 3 outpatient visits before changing immunosuppression therapy. After conversion to tacrolimus and when patients had been established on this therapy for 2 months, these same measurements were evaluated for the next 3 outpatient visits. The time span during which the 3 sets of measurements were collected varied among patients according to the frequency of outpatient visits, itself a reflection of graft function and time from transplantation. This time varied from a mean of 7 3 months while patients were administered cyclosporine to a mean of 8 3 months after patients were converted to tacrolimus therapy. Immunosuppression Protocol All patients were administered cyclosporine to maintain whole-blood trough levels between 100 and 150 g/l. The day after cessation of cyclosporine therapy, tacrolimus, 0.1 mg/kg, was administered in 2 divided doses. The dose was subsequently adjusted to maintain plasma trough levels between 5 and 15 g/l. Three patients also were administered azathioprine, 75 mg/d. Two patients were on maintenance hydrocortisone therapy for adrenal dysfunction, 1 of whom was also administered azathioprine. Two patients were administered prednisolone, 10 mg/d, before immunosuppression conversion, and in 1 of these patients, prednisolone dose was reduced to 5 mg/d 4 months after commencing tacrolimus therapy. The remainder of the patients had discontinued steroid therapy before the study period in accordance with our protocol, which includes an initial dose of prednisolone, 20 mg/d, with reductions at intervals and subsequent discontinuation of steroids within 3 months. Statistical Analysis Results are expressed as mean SD, except for serum triglyceride level, expressed as median and range. Comparisons between patients before and after conversion to tacrolimus therapy were performed using Student s t-test or McNemar s test, as appropriate. P less than.05 is considered statistically significant. Results Patient characteristics are listed in Table 2. One patient developed intense pruritus within weeks of commencing tacrolimus therapy, which had to be discontinued. Cyclosporine was restarted, and this patient was excluded from further statistical analysis. There was a small reduction of no clinical relevance in serum bilirubin level after conversion from 14.1 to 10.6 mmol/l (P.05). Otherwise, conversion to tacrolimus therapy had no effect on hepatic or renal function. Thus, there were no significant differences in serum alanine aminotransferase, albumin, prothrombin time, or serum creatinine values after conversion to tacrolimus therapy (Table 3). No cardiovascular events occurred during the follow-up period. Changes in cardiovascular risk factors are listed in Table 4. Table 2. Patient Characteristics Age (yr) 48 3 Sex (M/F) 7/18 Time from transplantation to conversion (mo) Median (range) 29 (6-54) Indication for liver transplantation Primary biliary cirrhosis 6 Alcoholic cirrhosis 5 Fulminant hepatic failure 4 Primary sclerosing cholangitis 3 Hepatitis C cirrhosis 1 Other 6 NOTE. N 25.

3 Converting From Cyclosporine to Tacrolimus 535 Table 3. Graft and Renal Function Before and After Conversion to Tacrolimus Therapy Cyclosporine Tacrolimus P Prothrombin time (sec) NS ALT (IU/L) NS Bilirubin (mmol/l) Albumin (g/dl) NS Creatinine ( mol/l) NS Abbreviations: NS, not significant; ALT, alanine aminotransferase. Blood Pressure One patient was excluded from the blood pressure analysis because atenolol had been prescribed for hypertension 1 week before starting tacrolimus therapy. Ten of the remaining 24 patients already were administered antihypertensive drugs: 5 patients, a -blocker; 2 patients, an -blocker; 1 patient, a calcium channel blocker; and 2 patients, 3 antihypertensive agents. Mean systolic blood pressure decreased from to mm Hg when patients were converted to tacrolimus therapy (P.015) (Table 4). Nineteen patients (79%) were hypertensive on cyclosporine therapy, whereas 15 patients (63%) remained hypertensive on tacrolimus therapy (P.063). There were no new prescriptions or increases in drug dosages during the period of follow-up after conversion to tacrolimus therapy, even in those patients administered antihypertensive medication. Systolic blood pressure in the 2 patients who were converted because of hypertension decreased by 44 and 18 mm Hg in each case. Serum Lipid Levels A cholesterol-reducing drug was started inadvertently in 1 patient shortly after conversion to tacrolimus therapy, and this patient was excluded from statistical analysis; therefore, cholesterol measurements were available for 24 of 25 patients. Mean serum cholesterol level decreased from to mmol/l after conversion to tacrolimus therapy (P.01) (Table 4). Hypercholesterolemia was defined as a serum cholesterol level of 5.2 mmol/l (200 mg/dl) or greater. Twelve of the 24 patients (50%) had hypercholesterolemia when administered cyclosporine; 7 patients (29%) remained hypercholesterolemic on tacrolimus therapy (P.063). Serial data for triglyceride levels were available for 22 of 25 patients. Hypertriglyceridemia was defined as a serum triglyceride level of 1.9 mmol/l (167 mg/dl) or greater. Five patients (23%) had hypertriglyceridemia on cyclosporine therapy compared with 3 patients (14%) on tacrolimus therapy, a change that was not significant. The median serum triglyceride level did not change after conversion: 1.2 mmol/l (range, 0.7 to 5.2 mmol/l) on cyclosporine therapy compared with 1.2 mmol/l (range, 0.7 to 4.0 mmol/l) on tacrolimus therapy. Weight Sixty-eight percent of patients lost weight on tacrolimus therapy. Mean patient weight was kg at the time of conversion and kg a median of 11 months after commencing tacrolimus therapy (P.024). Mean BMI before conversion was kg/m 2 compared with kg/m 2 11 months after commencing tacrolimus therapy (P.02) (Table 4). Sixteen patients had a BMI greater than 25 kg/m 2 before conversion compared with 13 patients afterward. In the subgroup of 8 patients converted to tacrolimus therapy solely because of weight gain after transplantation, 6 patients lost weight, with mean weight decreasing from kg at the time of conversion to kg 11 months later. BMI in this group decreased from to kg/m 2. Of those patients who lost weight after conversion, 65% also had a reduction in blood pressure and 76% had a reduction in serum cholesterol level. However, there was no correlation between weight loss and reductions in blood pressure and/or serum cholesterol level (P.55 and P.85, respectively). In the subgroup converted because of weight gain, there was a weak correlation between weight loss and cholesterol level reduction (Pearson s correlation coefficient 0.708; P.049), but no correlation between weight loss and blood pressure reduction. Table 4. Cardiovascular Risk Factors After Conversion to Tacrolimus Therapy Cyclosporine Tacrolimus P Systolic BP (mm Hg) Cholesterol (mmol/l) Triglyceride (mmol/l) 1.2 ( ) 1.2 ( ) NS Weight (kg) Glucose (mmol/l) NS NOTE. Values expressed as mean SD or median (range). Abbreviations: NS, not significant; BP, blood pressure.

4 536 Neal et al Glucose Metabolism One patient had diabetes mellitus before conversion that predated liver transplantation. No changes in insulin requirements were necessary for this patient, and there was no difference in glycosylated hemoglobin concentration (hemoglobin A 1c ) after conversion to tacrolimus therapy. There was no difference in mean blood glucose levels for the remaining patients between cyclosporine and tacrolimus therapy (Table 4), and no new cases of diabetes mellitus developed after conversion. Changes in systolic blood pressure, serum cholesterol level, weight, and blood glucose level are shown in Table 4. Discussion We have shown that conversion to tacrolimus was well tolerated and resulted in significant improvement in a number of cardiovascular risk factors. It has long been recognized that cyclosporine is associated with posttransplantation hypertension. 17,18 More recently, it has emerged that tacrolimus-based immunosuppressive regimens are associated with hypertension less frequently than cyclosporine. 1-3,5-7,9 Canzanello et al 6 reported a prevalence of hypertension at 12 months post liver transplantation of 81% in cyclosporine-treated and 30% in tacrolimus-treated patients. The same group reported 2-year prevalence rates of hypertension of 82% with cyclosporine and 64% with tacrolimus. 9 Forty-eight percent of cyclosporine-treated patients were hypertensive at 1 year compared with 33% of the tacrolimus group in a series by Fung et al. 3 Guckelberger et al 5 reported that hypertension occurred in 57% of long-term survivors after liver transplantation treated with cyclosporine compared with 33% of tacrolimus-treated patients. The mechanisms of posttransplantation hypertension and reasons for differences between tacrolimus and cyclosporine are not fully understood. Both drugs cause systemic vasoconstriction, although tacrolimus induces less vasoconstriction than cyclosporine. 19 Cyclosporine and tacrolimus may interfere with local regulation of vascular tone. Increased plasma levels of the potent vasoconstrictor endothelin-1 have been reported early after liver transplantation. 20 Administration of cyclosporine and tacrolimus may be associated with transient increases in endothelin-1 levels. 21,22 However, it remains to be determined whether endothelin-1 contributes to posttransplantation hypertension. Cyclosporine may also inhibit endothelial nitric oxide synthesis, which would favor vasoconstriction, 19 and it also alters endothelium-mediated vasodilatation in hypertensive transplant recipients. 23 Altered endothelial function may be important in transplant hypertension and could account for some of the difference in frequency of hypertension between patients treated with cyclosporine and tacrolimus. 19 The importance of the renin-angiotensin system in the development of transplant hypertension is unclear, with some studies reporting suppressed plasma renin activity, 20,24 and others, elevated plasma renin activity after liver transplantation. 25 Glucocorticoids have a role in posttransplantation hypertension. Taler et al 26 showed that steroid dose is important in the development of hypertension during the first few months after transplantation with both tacrolimus and cyclosporine therapy. However, hypertension occurs in the absence of glucocorticoid administration, 1,27 and Guckelberger et al 5 found no relationship in the incidence of hypertension and cumulative prednisolone dose in patients treated with cyclosporine or tacrolimus. Abnormalities in lipid profiles with elevated serum cholesterol and triglyceride levels after liver transplantation are well documented The cause of posttransplantation dyslipidemia is multifactorial and includes genetic predisposition, posttransplantation diabetes mellitus, and chronic renal dysfunction, as well as the effects of corticosteroids and immunosuppressant drugs. 30 Cyclosporine binds to the low-density lipoprotein cholesterol receptor and may interfere with feedback control of cholesterol synthesis. 31 It may also limit cholesterol degradation by reducing bile acid synthesis. 32 As with hypertension, hypercholesterolemia and hypertriglyceridemia are observed more frequently with cyclosporine than tacrolimus therapy. In the long-term follow-up report of the US Multicenter FK506 Liver Study Group, there were significance increases in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels in patients treated with cyclosporine compared with tacrolimus. 33 Similar findings are described at 6 and 12 months posttransplantation by Jindal et al. 10 Guckelberger et al 5 showed that patients administered cyclosporine had a significantly greater prevalence of hypercholesterolemia than patients treated with tacrolimus (76.4% v 53.3%), although there was no significant difference in the prevalence of hypertriglyceridemia. Finally, in a report from the Mayo Clinic, both total cholesterol and triglyceride levels were significantly lower at 4 and 12 months in patients treated with tacrolimus compared with cyclosporine. 6 The choice of immunosuppression may influence the degree of weight gain after liver transplantation.

5 Converting From Cyclosporine to Tacrolimus 537 Canzanello et al 6 reported a significant increase in BMI at 12 months with both cyclosporine and tacrolimus therapy compared with pretransplantation BMI. The relative increase in BMI was slightly greater in patients treated with cyclosporine, although not significantly different from tacrolimus. The studies of Canzanello et al 6 and Guckelberger et al 5 both showed an increased prevalence of obesity in patients treated with cyclosporine versus tacrolimus, although in neither study was the difference between immunosuppression statistically significant. It is not clear why tacrolimus may result in less weight gain than cyclosporine. Although evidence favors tacrolimus to have a more favorable cardiovascular profile than cyclosporine, the impact of changing immunosuppression from cyclosporine to tacrolimus on cardiovascular risk factors in patients with stable graft function has received little attention. Fung et al 13 studied 20 patients converted to tacrolimus from cyclosporine therapy because of (1) complications relating to cyclosporine, including renal failure and hypertension secondary to cyclosporine toxicity, and/or (2) uncontrolled liver allograft rejection. Those patients who were hypertensive on cyclosporine therapy were able to discontinue or reduce their antihypertensive medication. Similarly, Pratschke et al 14 reported that 6 of 9 patients converted from cyclosporine therapy because of hypertension were able to reduce or discontinue antihypertensive drugs in the 3 months after conversion to tacrolimus. Conversely, it was reported recently that conversion from cyclosporine to tacrolimus therapy did not improve blood pressure in 16 liver transplant recipients with hypertension. 34 In the present study, documented measurements for each patient were not collected at the same times before and after conversion because of the variation in clinic follow-up. In many cases, this variation reflects the time elapsed since liver transplantation. We found that systolic blood pressure decreased significantly after conversion to tacrolimus therapy. This change occurred in the absence of additional antihypertensive therapy and in those patients still administered corticosteroids with no significant change in cumulative steroid doses. Furthermore, improvement in blood pressure occurred independently of an effect on serum creatinine level, which did not change after conversion. For those patients with hypertension, the reduction in blood pressure after substituting tacrolimus for cyclosporine could have clinical importance in reducing the need to initiate antihypertensive drugs or increase the existing treatment. The mean decrease in systolic blood pressure of 10 mm Hg may appear small, but it is the same as that achieved by the introduction of an antihypertensive agent in clinical trials of such therapy. Pratschke et al 14 studied serum lipid levels in 31 patients with stable graft function who were converted from cyclosporine to tacrolimus therapy because of cyclosporine-related side effects. Three months after conversion, mean cholesterol and triglyceride levels had decreased significantly. Malekkiani et al 34 noted normalization of serum cholesterol and triglyceride levels after 6 months in 2 patients with hyperlipidemia converted from cyclosporine to tacrolimus therapy. We observed a significant reduction in serum total cholesterol levels, but there was no effect on triglyceride levels. Reduction in serum cholesterol levels may be influenced in part by associated weight loss, shown by a weak correlation between the 2 parameters in patients converted because of weight gain. Of particular interest in the present study is the effect switching to tacrolimus therapy had on weight. BMI decreased significantly over a median of 11 months of tacrolimus treatment. Six of 8 patients converted to tacrolimus therapy solely because of recent weight gain showed a mean weight decrease from to 92.9 kg. Although this difference was not significant, the number of patients is small. In 2 patients, weight loss was dramatic. A man who underwent transplantation 2 years previously whose weight had increased by 30 kg since transplantation lost 22 kg in the 12 months after starting tacrolimus therapy. The second patient was a woman who underwent transplantation 3 years previously. In the 12 months before starting tacrolimus therapy, her weight had increased from 134 to 146 kg. In the 11 months after conversion, her weight decreased from 146 kg to her current weight of 136 kg. Reasons for the observed weight reduction with tacrolimus are not clear. By the time immunosuppression therapy was changed, patients had already been assessed by a dietician and appropriate weight-reducing measures had been attempted. Only after such measures were undertaken was cyclosporine changed to tacrolimus therapy. To our knowledge, no weight-reducing measures or formal dietary manipulation were undertaken by any patient during this study period. Only 4 of the 25 patients were administered corticosteroids (at a maximum dose of 10 mg of prednisolone), and dose reduction occurred in only 1 patient after conversion, 4 months after commencing tacrolimus therapy. The daily dose of corticosteroids in the other 3 patients did not differ between the periods of cyclosporine and tacrolimus treatment. Differences in steroid exposure with cyclosporine and tacrolimus do not account for the observed weight reduction. No patients reported

6 538 Neal et al new gastrointestinal symptoms such as anorexia that could account for weight loss. Although it is not clear why such marked weight loss occurs in certain patients, we have shown that for patients administered cyclosporine whose weight increased excessively after transplantation, switching to tacrolimus is a useful therapeutic maneuver to achieve weight reduction. Recent studies have not reported a difference in the rates of new-onset diabetes between cyclosporine- and tacrolimus-treated liver transplant recipients. 6,9,11 There were no new cases of diabetes mellitus in the patients studied here and no difference in blood glucose levels when patients were converted to tacrolimus therapy. These findings are in agreement with those previously reported 14 and suggest that converting patients to tacrolimus therapy does not have diabetogenic effects. In summary, we have shown that switching immunosuppression was well tolerated, with no significant changes in allograft or renal function. Only 1 patient did not tolerate tacrolimus. There was an overall benefit in cardiovascular risk profiles when patients were converted from cyclosporine to tacrolimus therapy. In particular, significant benefits were realized in reductions of blood pressure, serum cholesterol level, and weight. Conversion to tacrolimus may eliminate the need for additional drug treatment of hypertension or hypercholesterolemia or may allow discontinuation of existing medication. In patients whose weight is increasing, we have shown that stopping cyclosporine and starting tacrolimus therapy can achieve impressive weight loss. References 1. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994;331: European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus and cyclsporin in prevention of liver allograft rejection. Lancet 1994;344: Fung J, Abu-Elmagd K, Jain A, Gordon R, Tzakis A, Todo S, et al. A randomised trial of primary liver transplantation under immunosuppression with FK506 vs cyclosporin. N Engl J Med 1991;23: Sher LS, Cosenza CA, Michel J, Makowka L, Miller CM, Schwartz ME, et al. Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation. Transplantation 1997;64: Guckelberger O, Bechstein WO, Neuhaus R, Luesebrink R, Lemmens HP, Kratschmer B, et al. Cardiovascular risk factors in long-term follow-up after orthotopic liver transplantation. Clin Transplant 1997;11: Canzanello VJ, Schwartz L, Taler SJ, Textor SC, Wiesner RH, Porayko MK, et al. Evolution of cardiovascular risk factors after liver transplantation: A comparison of cyclosporine A and tacrolimus (FK506). Liver Transpl Surg 1997;3: Jain A, Reyes J, Kashyap R, Rohal S, Abu-Elmagd K, Starzl T, et al. What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg 230;3: Charco R, Cantarell C, Vargas V, Capdevila L, Lazaro JL, Hidalgo E, et al. Serum cholesterol changes in long-term survivors of liver transplantation: A comparison between cyclosporine and tacrolimus therapy. Liver Transpl Surg 1999;5: Canzanello VJ, Textor SC, Taler SJ, Schwartz LL, Porayko MK, Wiesner RH, et al. Late hypertension after liver transplantation: A comparison of cyclosporine and tacrolimus (FK506). Liver Transpl Surg 1998;4: Jindal R, Popescu I, Emre S, Schwartz ME, Boccagni P, Meneses P, et al. Serum lipid changes in liver transplant recipients in a prospective trial of cyclosporine versus FK506. Transplantation 1994;57: Sheiner PA, Magliocca JF, Bodian CA, Kim-Schluger L, Altaca G, Guarrera JV, et al. Long-term medical complications in patients surviving 5 years after liver transplant. Transplantation 2000;69: Mor E, Facklam D, Hasse J, Sheiner P, Emre S, Schwartz M, et al. Weight gain and lipid profile changes in liver transplant recipients: Long-term results of the American FK506 Multicenter Study. Transplant Proc 1995;27: Fung JJ, Todo S, Jain A, McCauley J, Alessiani M, Scotti C, et al. Conversion from cyclosporin to FK506 in liver allograft recipients with cyclosporin-related complications. Transplant Proc 1990;22: Pratschke J, Neuhaus R, Tullius SG, Haller GW, Jonas S, Steinmuller T, et al. Treatment of cyclosporine-related adverse effects by conversion to tacrolimus after liver transplantation. Transplantation 1997;64: Kannel WB. Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 2000;85: Cushman WC. The clinical significance of systolic hypertension. Am J Hypertens 1998;11:S182-S Eid A, Steffen R, Porayko MK, Beers TR, Kaese DE, Wiesner RH, et al. Beyond 1 year after liver transplantation. Mayo Clin Proc 1989;64: Porter GA, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. Arch Intern Med 1990;150: Textor SC, Wiesner R, Wilson DJ, Porayko M, Romero JC, Burnett JC Jr, et al. Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. Transplantation 1993;55: Textor SC, Wilson DJ, Lerman A, Romero JC, Burnett JC Jr, Wiesner R, et al. Renal hemodynamics, urinary eicosanoids, and endothelin after liver transplantation. Transplantation 1992;54: Grieff M, Loertscher R, Shohaib SA, Stewart DJ. Cyclsporineinduced elevation in circulating endothelin-1 in patients with solid-organ transplants. Transplantation 1993;56: Min DI, Chen HY, Lee MK, Ashton K, Martin MF. Timedependent disposition of tacrolimus and its effect on endothelin-1 in liver allograft recipients. Pharmacotherapy 1997;17: Albillos A, Cacho G, Barrios C, Alvarez-Mon M, Rossi I, Gomez-Arnau J, et al. Selective impairment of endothelium-mediated vasodilation in liver transplant recipients with cyclosporin A-induced hnypertension. Hepatology 1998;27: Navasa M, Feu F, Garcia-Pagan JC, Jimenez W, Llach J, Rimola A, et al. Hemodynamic and humoral changes after liver trans-

7 Converting From Cyclosporine to Tacrolimus 539 plantation in patients with cirrhosis. Hepatology 1993;17: Julien J, Farge D, Kreft-Jais C, Guyene TT, Plouin PF, Houssin D, et al. Cyclsporine-induced stimulationof the renin-angiotensin system after liver and heart transplantation. Transplantation 1993;56: Taler SJ, Textor SC, Canzanello VJ, Schwartz L, Porayko M, Wiesner RH, et al. Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine. Transplantation 1996;62: Gisbert C, Prieto M, Berenguer M, Breto M, Carrasco D, de Juan M, et al. Hyperlipidaemia in liver transplant recipients: Prevalence and risk factors. Liver Transpl Surg 1997;3: Munoz SJ, Deems RO, Moritz MJ, Martin P, Jarrell BE, Maddrey WC. Hyperlipidaemia and obesity after orthotopic liver transplantation. Transplant Proc 1991;23: Stegall M, Everson G, Schroter G, Bilir B, Karrer F, Kam I. Metabolic complications after liver transplantation. Transplantation 1995;60: Munoz S. Hyperlipidaemia and other coronary risk factors after orthotopic liver transplantation: Pathogenesis, diagnosis, and management. Liver Transpl Surg 1995;1(suppl 1): S29-S DeGroen P. Cyclosporine, low density lipoprotein, and cholesterol. Mayo Clinic Proc 1988;63: Princen HMG, Meijer P, Hofstee B, Havekes LM, Kuipers F, Vonk RJ. Effects of cyclosporine A on LDL receptor activity and bile acid synthesis in hepatocyte monolayer cultures and in vivo in the rat [abstract]. Hepatology 1987;7: Abouljoud MS, Levy MF, Klintmalm GB, and the US Multicenter Study Group. Hyperlipidaemia after liver transplantation: Long-term results of the FK506/Cyclosporine A US Multicenter Trial. Transplant Proc 1995;27: Malekkiani N, Durand F, Bernuau JR, Heneghan MA, Tutelle- Newhall JE, Belghiti J, et al. Conversion from cyclosporin to FK506 in adult liver transplantation: Results from a North American and European series [abstract]. Hepatology 2000;32: 741.