Hypertension frequently occurs early after liver

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1 Late Hypertension After Liver Transplantation: A Comparison of Cyclosporine and Tacrolimus (FK 506) Vincent J. Canzanello,* Stephen C. Textor,* Sandra J. Taler,* Lora L. Schwartz,* Michael K. Porayko,* Russell H. Wiesner,* and Ruud A.F. Krom Hypertension frequently develops early after liver transplantation when cyclosporine-based immunosuppression is used. However, initial experience with tacrolimus has suggested that its use leads to a lower early incidence of hypertension. In this study, the blood pressure status of patients treated with cyclosporine (n 131) and those treated with tacrolimus (n 28) was compared 24 months after liver transplantation. At this time interval, the prevalence of hypertension in the cyclosporine and tacrolimus groups were 82% and 64%, respectively (P F.05). For those patients who were hypertensive by 24 months, onset was delayed in the tacrolimus group compared with the cyclosporine group: 40% versus 71% and 73% versus 93% at 1 and 12 months, respectively (P F.05). Within the cyclosporine group, patients with hypertension were heavier than those with normal blood pressure, versus kg, respectively (P F.05). Within the tacrolimus group, hypertensive patients had lower glomerular filtration rates and higher renal vascular resistances compared with normotensive patients, versus 47 6 ml/min and 15,711 2,445 versus 28,830 4,310 dyne/s/cm 5 / m 2, respectively (P F.05). There were no withingroup differences for age, gender, pretransplant history of hypertension, family history of hypertension, graft function, or daily doses of prednisone, cyclosporine, or tacrolimus. These results indicate that, compared with cyclosporine, the onset of hypertension after liver transplantation is delayed and less prevalent with tacrolimus. Additionally, hypertension is associated with increased body weight in cyclosporine-treated patients and with more severe renal dysfunction in patients receiving tacrolimus. The relationships of these findings to the development of posttransplant hypertension requires further study. Copyright 1998 by the American Association for the Study of Liver Diseases Hypertension frequently occurs early after liver transplantation when immunosuppression with cyclosporine plus prednisone is used, amounting to a prevalence of 75% to 85% by 24 months. 1-3 Several reports have suggested that the incidence of hypertension in patients treated with tacrolimus (also called FK 506) is lower than that in patients treated with cyclosporine within the first year or two after kidney transplantation, 4-6 up to 3 years after heart transplantation, 7-9 and during the first year after liver transplantation We have observed, however, that the prevalence of hypertension in tacrolimus-treated patients increases in the second year after liver transplantation and may From the Departments of *Medicine and Transplantation Surgery, Mayo Clinic, Rochester, MN. Address reprint requests to Vincent J. Canzanello, MD, Division of Hypertension and Internal Medicine, Mayo Clinic, 200 First St, Rochester, MN Copyright 1998 by the American Association for the Study of Liver Diseases /98/ $3.00/0 approach that observed in patients treated with cyclosporine. 3 We examined the development of hypertension in patients treated with cyclosporine or tacrolimus and followed up for 24 months after liver transplantation. The goals of this study were to assess the prevalence of hypertension in these two patient groups and to compare clinical and laboratory characteristics that might be associated with the development of posttransplant hypertension. Patients and Methods We reviewed clinical and laboratory data on all patients having undergone a primary orthotopic liver transplantation at the Mayo Clinic between 1989 and 1993 and who had been followed up for 24 months. During the years 1990 to 1992, all of the tacrolimus-treated patients and an equivalent number of cyclosporine-treated patients were participants in the US Multicenter FK 506 Liver Study. 13 All patients were followed up in the Transplant Hypertension Clinic and had visits before transplantation and at 1, 12, and 24 months postoperatively as previously described. 14 Hypertension was defined as a mean arterial pressure 328 Liver Transplantation and Surgery, Vol 4, No 4 ( July), 1998: pp

2 Hypertension After Liver Transplantation 329 (MAP) greater than or equal to 107 mmhg ( 140/90 mmhg) and/or the administration of antihypertensive medication. Based on this definition at the 24-month visit, patients were classified into either the hypertensive (HBP) or normotensive (NBP) group. The members of the NBP had never been hypertensive at any clinic visit after liver transplantation, whereas those patients who were hypertensive at 24 months were included regardless of their blood pressure status at the 1- and 12-month posttransplant visits. Because most, if not all, patients had normal or low systemic blood pressures at the time of transplantation, a pretransplant history of hypertension was based on either review of medical records or patient self-reporting of blood pressure status before the development of end-stage liver disease. The family history was considered to be positive for hypertension if the patient reported untreated or treated hypertension in any first-degree relative. The procedures and protocol for this study were reviewed by the institutional review board of the Mayo Clinic. Informed written consent was obtained from all study participants. Immunosuppression Protocols Cyclosporine Group (n 131). Cyclosporine 2 to 3 mg/kg/d was administered intravenously on day 2, followed by oral dosing after establishment of internalized bile flow to maintain whole-blood trough levels by high-pressure liquid chromatography 15 at 250 to 400 ng/ml until month 4 and 100 to 200 ng/ml thereafter. Prednisone was begun at 200 mg/d then tapered to 15 mg/d by month 2 and 10 mg/d by month 6. Azathioprine was administered at a dose of 2 mg/kg/d. Tacrolimus Group (n 28). Tacrolimus was initiated intravenously at a dosage of 0.05 to mg/kg/12 hours with subsequent conversion to an oral dose of 0.15 mg/kg/12 hours to maintain plasma trough levels by enzyme-linked immunoassay 16 at 0.2 to 5.0 ng/ml. Prednisone was begun at a dosage of 100 mg/d with tapering to 7.5 mg/d by month 2 and to 5.0 mg/d by month 3. Renal Hemodynamic Measurements. Glomerular filtration rate and effective renal plasma flow (ERPF) were measured by using 125-iothalamate and para-aminohippurate, respectively. 17 Renal blood flow (RBF) was calculated as ERPF/1-hematocrit (where hematocrit is expressed in its fractional form). Renal vascular resistance was calculated as MAP/RBF 80. Statistical Analyses. Results are expressed as mean standard error unless otherwise specified. Multiple comparisons between subject groups were performed by using analysis of variance followed by the Newman Keuls test. Individual comparisons were then made using parametric or nonparametric methods as appropriate. A P value of less than.05 was considered to represent statistical significance. Results One hundred thirty-one cyclosporine-treated patients and 28 tacrolimus-treated patients had completed a clinical assessment at 24 months posttransplantation. The tacrolimus group was smaller because of the relatively recent introduction of this agent into liver transplantation. There were no significant differences in baseline patient characteristics (Table 1). The prevalence of hypertension in the cyclosporine-treated group versus the tacrolimus group was 71% (93/131) versus 40% (11/28) at 1 month, 93% (122/131) versus 73% (20/28) at 12 months, and 82% (108/131) versus 64% (18/28) at 24 months after transplantation (all P.05) (Fig. 1). At 24 months, treated blood pressures in the hypertensive cyclosporine and tacrolimus groups were similar, at 133/80 and 133/84 mmhg, respectively, although the number of patients requiring more than one antihypertensive drug for blood pressure control was higher in the cyclosporine group compared with the tacrolimus group: 54 of 108 (50%) versus 3 of 18 (17%), respectively. The distribution of antihypertensive medications between the cyclosporine and tacrolimus groups were Table 1. Baseline Patient Characteristics NBP (n 23) HBP (n 108) NBP (n 10) HBP (n 18) Age (y) Sex (M:F) 8:15 52:56 6:4 8:10 Pre-LT history of HBP (% yes) Family history of HBP (% yes) Diagnoses, n (%) PSC 9 (39) 31 (29) 3 (30) 8 (44) PBC 7 (30) 23 (21) 2 (20) 3 (17) CAH 2 (9) 15 (14) 2 (20) 3 (17) ETOH 2 (9) 13 (12) 1 (10) 2 (11) Other 3 (13) 26 (24) 2 (20) 2 (11) NOTE. Data are means SE unless otherwise specified. There were no significant baseline differences between the groups. Abbreviations: LT, liver transplantation; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; CAH, chronic active hepatitis; ETOH, alcoholic cirrhosis.

3 330 Canzanello et al Figure 1. Prevalence of hypertension after liver transplantation in patients treated with either cyclosporine (n 131) or FK 506 g (n 28). (*) P F.05 versus cyclosporine group. as follows: dihydropyridine calcium channel blockers, 68% versus 44%; beta blockers, 42% versus 50%; and diuretics, 40% versus 22%. Clinical data at 24 months after transplantation are shown in Table 2. Within the cyclosporine group, the hypertensive patients were heavier than those who remained normotensive: versus kg, respectively (P.05). However, the absolute weight gain between posttransplant months 1 and 24 was not different within the cyclosporine or tacrolimus groups. Of note, at 1 month, mean body weight was not significantly different between the hypertensive and normotensive cyclosporine-treated patients. Daily mean prednisone doses were, by protocol design, significantly lower in the tacrolimus groups; however, there were no differences between normotensive and hypertensive patients within the cyclosporine and tacrolimus groups. Although mean daily cyclosporine doses were similar between the normotensive and hypertensive groups, mean blood levels of cyclosporine were slightly, but significantly, lower in the latter group. Complete renal hemodynamic data were available in 100 of 131 cyclosporine-treated (76%) and 18 of 28 tacrolimus-treated patients (64%) (Table 3, Fig. 2). By 1 month, the tacrolimus-treated patients with hypertension had a lower mean glomerular filtration rate and higher systemic vascular resistance compared with the normotensive group, although these differences were only significant at 24 months. Table 2. Body Weight, Graft Function, and Immunosuppressive Medications 24 Months After Liver Transplantation NBP (n 23) HBP (n 108) NBP (n 10) HBP (n 18) Weight (kg) * Weight change between months 1 and 24 (kg) ALT (U/L) Prednisone dose (mg/d) Cyclosporine dose (mg/d) Cyclosporine blood level (ng/ml) * FK 506 dose (mg/d) FK 506 blood level (ng/ml) NOTE. Data are means SE. Abbreviation: ALT, alanine aminotransferase (reference range, 10 to 45). *P.05 v cyclosporine NBP group. P.05 v cyclosporine NBP and HBP groups.

4 Hypertension After Liver Transplantation 331 Figure 2. Comparison of glomerular filtration rates after liver transplantation in (left) cyclosporine- or (right) FK 506-treated patients. (*) P F.05 versus normotensive group. To investigate the potential impact of the treatment of graft rejection on any observed differences between patient groups, the cumulative dose of methylprednisolone received by those patients with a presumed rejection episode was reviewed. As shown in Table 4, there were no significant differences between the four patient groups with regard to cumulative methylprednisolone administered for graft rejection during the 24-month interval after liver transplantation. Discussion The results of this study demonstrate several differences between cyclosporine and tacrolimus with respect to hypertension. During the first 24 months after liver transplantation, cyclosporine is associated with a higher prevalence of hypertension compared with tacrolimus. This difference in prevalence is present by the first posttransplant month and persists through month 24. Hypertension was associated with increased body weight in the cyclosporine-treated group and a significantly reduced glomerular filtration rate in the tacrolimus group. Factors such as age, gender, cause of liver failure, pretransplant or family history of hypertension, or differences in immunosuppressive medication doses were not different between the normotensive and hypertensive patients within either the cyclosporine- or tacrolimus-treated group. In addition, the cumulative amount of methylprednisolone administered for graft rejection did not differ significantly between any of the patient groups. Hypertension is common after liver transplantation using either cyclosporine- or tacrolimus-based immunosuppression regimens. 1-3,10-12,18 Earlier re- Table 3. Renal Function and Hemodynamic Measurements After Liver Transplantation Scr (mg/d) 1.1 GFR (ml/min/ 1.73M 2 ) RBF (ml/min/ 1.73 M 2 ) RVR (dyne/ s/cm 5 / 1.73 M 2 ) NBP (n 16) HBP (n 84) NBP (n 7) HBP (n 11) 1 mo 12 mo 24 mo 1 mo 12 mo 24 mo 1 mo 12 mo 24 mo 1 mo 12 mo 24 mo ,553 2, ,531 2, ,860 2, ,002 1, ,620 1, ,638 1, ,496 1, ,693 4, ,712 2, ,674 4, ,023 5,288 NOTE. Data are means SE. Abbreviations: Scr, serum creatinine; GFR, glomerular filtration rate; RBF, renal blood flow; RVR, renal vascular resistance. *P.05 v FK 506 NBP group at 24 months * ,830 4,311*

5 332 Canzanello et al Table 4. Cumulative Amount Per Patient of Methylprednisolone Administered for Graft Rejection During 24 Months After Liver Transplantation NBP (n 19) HBP (n 84) NBP (n 7) HBP (n 13) Methylpredisolone (mg/patient) 1, , , , NOTE. Data are means SE. There were no significant differences between groups. ports suggested a lower incidence of posttransplant hypertension with tacrolimus, although this may have reflected, in part, a shorter period of observation. 10,11,18 The mechanisms of early posttransplant hypertension appear to differ between cyclosporine and tacrolimus. Both drugs produce similar degrees of renal vasoconstriction, reduction of glomerular filtration rate, and enhancement of proximal renal tubular sodium absorption at a time when cyclosporine is associated with a higher incidence of systemic hypertension, findings suggestive of a disproportionate effect of cyclosporine on vascular endothelial function with subsequent systemic vasoconstriction. 3,17,19,20 Higher glucocorticosteroid doses in cyclosporine-treated patients may also contribute to a increased incidence of hypertension. 18 Glucocorticosteroid dose also plays a role in tacrolimus-associated hypertension. We have observed an increased incidence of hypertension in tacrolimus-treated patients after a protocol change increased the daily dose of prednisone during the first posttransplant month by only 10 mg. 21 The primary goals of this study were to ascertain the prevalence of hypertension between cyclosporine and tacrolimus-treated patients 24 months after transplantation at a time when immunosuppression regimens and graft function are generally stable and to identify those clinical characteristics associated with the development of hypertension within the two groups. We believed that at this time point either a pretransplant history of hypertension or a family history of hypertension might contribute to hypertensive risk, but such was not the case. Additionally, this time point would minimize inclusion of a subset of cyclosporine-treated patients who develop early posttransplant hypertension that resolves spontaneously by 24 to 30 months after transplantation. 22 In the cyclosporine-treated group at 24 months, the hypertensive patients were heavier than normotensive patients by an average of 11.2 kg. Obesity is a well-known risk factor for hypertension, 23 and we have previously shown that cyclosporine is associated with a higher prevalence of posttransplant weight gain and obesity in comparison with tacrolimus. 11 The reason for this discrepancy in degree of weight gain after liver transplantation is not clear. Possible explanations might include higher daily prednisone doses in cyclosporine-treated patients or a greater incidence of gastrointestinal disturbances such as anorexia, diarrhea, and vomiting reported in patients receiving tacrolimus. 12 Surprisingly, we were unable to implicate a role for glucocorticosteroids in the late development of hypertension within the cyclosporine and tacrolimus groups either compared by daily dose or cumulative doses administered for rejection episodes. We did not investigate a direct individual patient-cumulative glucocorticosteroid blood pressure response; therefore, it is possible that an exacerbating effect of this drug could be overlooked. Additionally, it is possible that different daily doses may account, in part, for the different prevalence of hypertension between the two groups. Of interest was the finding of more severe renal dysfunction in hypertensive tacrolimus-treated patients. Renal insufficiency of this degree is often associated with hypertension. 24 On the other hand, the kidney is a target of hypertensive damage, particularly in the setting of renal transplantation. 25,26 Sehgal et al 27 have found hypertension to be an important risk factor for progressive renal insufficiency in cyclosporine-treated heart-transplant recipients. At 24 months posttransplant, blood pressure levels were similar in both hypertensive groups, whereas a greater severity of hypertension in the cyclosporine group was suggested by the larger number of patients receiving more than one antihypertensive drug. Another area of speculation is the potentially renoprotective effect of calcium channel blockers following liver transplantation. Whereas one recent review concluded there was little benefit at least early after liver transplantation, 28 another small study of hypertensive tacro-

6 Hypertension After Liver Transplantation 333 limus liver-transplant recipients reported lower serum creatinine levels at 1 year in patients treated with nifedipine as opposed to other antihypertensive agents. 29 Whether tacrolimus, in the setting of hypertension, results in greater renal dysfunction is not clear. Tacrolimus doses and blood levels were similar between the normotensive and hypertensive groups. Several studies suggest that tacrolimus is no more nephrotoxic than cyclosporine, although follow-up has often been limited to 1 year and the use of serum creatinine measurements (a relatively insensitive marker of renal function) has been common. 15,29-31 The insensitivity of serum creatinine concentration as a marker of glomerular filtration rate in the liver-transplant population is underscored in the present study by the significant differences in iothalamate measurements between the cyclosporine and tacrolimus groups despite similar serum creatinine values. In summary, hypertension in tacrolimus-treated liver-transplant recipients occurs less frequently, has a delayed onset, and is associated with more severe renal dysfunction compared with hypertension in patients treated with cyclosporine. These preliminary findings underscore the need for longterm follow-up from prospective randomized trials of the two immunosuppressive agents and, preferably, the use of sensitive markers of renal function. In addition, our results suggest a role for therapeutic strategies to reverse or ameliorate these adverse changes associated with hypertension. These strategies could include the prevention of obesity after cyclosporine use and perhaps clinical trials with angiotensin-converting enzyme inhibitors or other drugs to minimize progressive renal insufficiency in tacrolimus-treated liver-transplant recipients. References 1. Textor SC. De novo hypertension after liver transplantation. Hypertension 1993;22: Textor SC, Canzanello VJ, Taler SJ, Wilson DJ, Schwartz LL, Augustine JE, et al. Cyclosporine-induced hypertension after transplantation. Mayo Clin Proc 1994;69: Textor SC, Burnett JC Jr, Romero JC, Canzanello VJ, Taler SJ, Wiesner R, et al. Urinary endothelin and renal vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995;47: Ellis D, Shapiro R, Jordan ML, Scantlebury VP, Gilboa N, Hopp L. Comparison of FK-506 and cyclosporine regimens in pediatric renal transplantation. Pediatr Nephrol 1994;8: Kokado Y, Takahara S, Kameoka H, Okuyama A. Hypertension in renal transplant recipients and its effect on long-term renal allograft survival. Transplant Proc 1996; 28: Pirsch JD, Miller J, Deierhol MH, Vincenti F, Filo FS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997;63: Swenson JM, Fricker FJ, Armitage JM. Immunosuppression switch in pediatric heart transplant recipients: Cyclosporine to FK506. J Am Coll Cardiol 1995;25: Pham SM, Kormos RL, Kawai A, Murali S, Hattler BG, Demetris AJ, et al. Tacrolimus (FK506) in clinical cardiac transplantation: A five year experience. Transplant Proc 1996;28: Pham SM, Kormos RL, Hattler BG, Kawai A, Tsamandas AC, Demetris AJ. A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: Intermediateterm results. J Thorac Cardiovasc Surg 1996;111: Todo S, Fung JJ, Demetris AJ, Jain A, Alessiani M, Takaya S, et al. One hundred ten consecutive primary orthotopic liver transplants under FK506 in adults. Transplant Proc 1991;23: Canzanello VJ, Schwartz L, Taler SJ, Textor SC, Wiesner RH, Porayko MK, et al. Evolution of cardiovascular risk after liver transplantation: A comparison of cyclosporine A and tacrolimus (FK506). Liver Transplant Surg 1997;3: Clark W. Tacrolimus: Immunosuppression following liver and kidney transplant. J Clin Pharm Ther 1996;21: The U.S. Multicenter FK 506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994;331: Schwartz L, Raymer J, Canzanello V, Taler S, Textor S. Nurse management of posttransplant hypertension in liver transplant recipients. J Transpl Coord 1996;6: Porayko MK, Textor SC, Krom RAF, Hay JE, Gores GJ, Richards TM, et al. Nephrotoxic effects of primary immunosuppression with FK-506 and cyclosporine regimens after liver transplantation. Mayo Clin Proc 1994;69: Jusko WJ, D Ambrosio R. Monitoring FK506 concentrations in plasma and whole blood. Transplant Proc 1991;23: Canzanello VJ, Textor SC, Taler SJ, Wilson DJ, Schwartz L, Wiesner RH, et al. Renal sodium handling with cyclosporin A and FK506 after orthotopic liver transplantation. J Am Soc Nephrol 1995;5: Monsour HP Jr, Wood RP, Dyer CH, Galati JS, Ozaki CF, Clark JH. 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7 334 Canzanello et al JC, Burnett JC Jr, et al. Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. Transplantation 1993;55: 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: Textor SC, Schwartz L, Canzanello VJ, Wiesner RH, Taler SJ, Porayko M, et al. Resolution of posttransplant hypertension after liver transplantation despite impaired glomerular filtration. J Am Soc Nephrol 1994;5: Schmieder RE, Messerli FH. Obesity hypertension. Med Clin North Am 1987;71: Brazy PC, Stead WW, Fitzwilliam JF. Progression of renal insufficiency: Role of blood pressure. Kidney Int 1989;35: Paul LC, Benediktsson H. Post-transplant hypertension and chronic renal allograft failure. Kidney Int 1995; 48(suppl 52):S34-S Sanders CE Jr, Curtis JJ. Role of hypertension in chronic renal allograft dysfunction. Kidney Int 1995; 48(suppl 52):S43-S Sehgal V, Radhakrishnan J, Appel GB, Valeri A, Cohen DJ. Progressive renal insufficiency following cardiac transplantation: Cyclosporine, lipids, and hypertension. Am J Kidney Dis 1995;26: Klintmalm GB, Gonwa TA: Nephrotoxicity associated with cyclosporine and FK506. Liver Transplant Surg 1995;1: Seifeldin R, Marcos-Alvarez A, Lewis WD, Gordan FD, Jenkins RL: Effect of nifedipine on renal function in liver transplant recipients receiving tacrolimus. Clin Ther 1996;18: Frei U, Wagner K. Renal function in liver transplant patients receiving FK506 or cyclosporin A immunosuppressive therapy. Transplant Proc 1994;26: Bennett WM. The nephrotoxicity of immunosuppressive drugs. Clin Nephrol 1995;43(suppl 1):S3-S7.