Abu-Elmagd, K

Bronsther, O

Fung, JJ

Ramos, H

Starzl, TE

Takaya, S

Todo, S

D-Scholarship@Pitt

Use of Prostaglandin E1 in Crossmatch-Negative Liver Transplant Recipients Treated With FK 506 S. Takaya, O. Bronsther, K. Abu-Elmagd, H. Ramos, J.J. Fung, S. Todo, and T.E. Starzl ALTHOUGH the overall strategy for the use ofFK 506 remains the same as when this T-cell-directed drug was introduced clinically in 1989,1,2 there have been mod-ifications. As with cyclosporine (CyA), the nephrotoxicity of FK 506 imposes a dose ceiling, necessitating its use in drug cocktails that include adrenal corticosteroids. We recently reported that liver transplant recipients with the immunological disadvantage of a positive cytotoxic cross-match with their donors3 could have their prognosis con-verted to that in crossmatch-negative cases when FK 506 was combined with high induction doses of prednisone. 4 A subgroup of these patients who also were treated periop-eratively with prostaglandin EI (PGE!) had superior renal function, suggesting an amelioration of nephrotoxicity by PGEI without a loss of immunosuppression, or conceiv-ably with a gain. In the trial reported here, PGE] was evaluated in crossmatch-negative liver recipients. METHODS Case Material Primary adult liver recipients (> 16 years of age) from three consecutive periods beginning June 10, 1990, were entered into the study, with exclusion only if there was a positive cytotoxic crossmatch or if the patient had renal failure pre transplantation. Renal failure was defined by dialysis dependence or by multiple preoperative serum creatinines of at least 2 mgldL. Patients in all three study groups (Table I) were started postoperatively on 20 mgld prednisone after being given a single log bolus of methyl-prednisolone intraoperatively. The variables were in FK 506 (high vs low induction dose) and in PGE] (inclusion or not). FK 506 dosing was controlled throughout by measurement of plasma levels.s Trough levels over 1 nglmL were considered to reflect a potential toxicity at all times after the first week. The starting daily intravenous FK 506 doses of 0.1 mg/kgld in group I and half this amount in groups 2 and 3 were given by 24-hour continuous infusion. When the conversion to oral FK 506 was made (Fig I), dosing as close to 0.3 mglkgld was attempted. However, it usually was not possible to give this much of the drug without driving up the plasma trough levels beyond the desired I to 2 nglmL range. The heavy initial FK 506 dosing as a policy in group 1 was reflected in significantly higher plasma levels than in either group 2 or 3 for each of the first 4 weeks and the total month. There were no significant FK 506 dosage or plasma level differences between groups 2 and 3 (Fig I). Patients in group 3 were given intravenous PGE] (Prostin VR) beginning during the operation or after its completion. The starting dose was 0.2 J.£g/kg/h which was increased to 0.6 J.£glkglh and maintained there for the next 5 to 7 days unless hypotension or cardiovascular instability interdicted the increase. When the patients resumed diet, they were switched to the oral PGE] analog misoprostol (Cytotec) at doses of 400 to 800 J.£gld in four divided doses. Two of the 41 patients in group 3 could not complete the PGE] therapy, Table 1. Patient Profile and Outcome Group 1 Group 2 Group 3 Number 124 38 41 Date began 6/10/90 8/27/91 11/1/91 FK 506 (mg/kg/d) 0.1 0.05 0.05 Prednisone (mg/d) 20 20 20 PGE, No No Yes Age 44.9 ± 1.4 51.9 ± 1.7 50.4 ± 1.6 Malelfemale 76/48 27/11 24/17 Liver disease Idiopathic 16 3 6 Alcoholic 25 6 13 Viral 24 19 11 Cholestasis 29 5 4 Malignancy 17 5 4 Fulminant hepatic failure 5 0 1 Miscellaneous 8 0 2 Retransplantation within 1 12 3 5 month Death in 1 month 4 1 2 (Patients died after (1 ) (0) (2) retransplant) Graft survival at 1 month 109 (87.9%) 34 (89.5%) 36 (87.8%) Patient survival at 1 month 120 (96.8%) 37 (97.4%) 39 (95.1%) Cause of graft failure Preservation injury 3 3 2 Technical 8 3 Infection 4 0 0 one because of poor graft function, norepinephrine dependence, and the need for retransplantation after 7 days. Therapy was foreshortened in the other because of a fatal myocardial infarction 3 days posttransplantation. These two patients were included in survival calculations but excluded from the analyses of renal function. Diagnosis and Treatment of Rejection A positive biopsy was a condition for the diagnosis of liver allograft rejection. The histopathological grading system of rejec-From the Pittsburgh Transplant Institute, and the Department of Surgery, University of Pittsburgh Health Science Center, Pitts-burgh, Pennsylvania. Supported by Project Grant No. DK 29961 from the National Institutes of Health. Address reprint requests to Thomas E. Starzl, MD, PhD, De-partment of Surgery, 3601 Fifth Avenue, 5C Falk Clinic, University of Pittsburgh, Pittsburgh, PA 15213. © 1993 by Appleton & Lange 0041-1345/93/$3.00/ + 0 Transplantation Proceedings, Vol 25, No 3 (June), 1993: pp 2381-2385 2381 2382 TAKAYA, BRONSTHER, ABU-ELMAGD ET AL GROUP 1 GROUP 2 GROUP 3 ,. 0.3 D . ORAL DOSE OF FK 506 0.3 0.3,----------, .., .2' • IV DOSE OF FK 506 Q E i if u. 0 W (/) 0 0 10 20 30 -' w > w -'-:z:E 4 OJ .. ::J c 0- 3 a:'" f-~ ..:>< 2 ~uK ..: -,u. 0-0 10 20 30 ~ 2.0 .. 1.8 E W 1.6 z Z 1.4 j::: ..: 1.2 w a: 0 1.0 :E 0.8 ::J a: 0.6 w (/) 0.4 Fig 1. Dose of intravenous and oral FK 506, plasma trough lev-els, and serum creatinine levels in patients surviving 30 days (ex-cluding hemodialysis patients). The mean dose of group 1 was significantly higher than those of group 2 or group 3 (P < .001). The mean FK 506 plasma level of group 1 for the first 30 days was significantly higher than those of group 2 or group 3 (P < .001). No statistically significant difference was observed in the dosage of intravenous and oral FK 506 regimens or plasma FK 506 trough levels between group 2 and group 3. The mean values of serum creatinine in group 3 were significantly lower than those of group 1 patients at the second (P = .22), third (P = .0046), and fourth postoperative weeks (P = .0004). Values are expressed as means ± SE. , " , , 6 8 10121416 18 202224 26 28 30 TIME IN DAYS tion, as developed by Demetris et al,6 was: grade I (early or consistent with rejection), grade 2 (mild), grade 3 (moderate), and grade 4 (severe). In addition to the biopsy, a Doppler ultrasound also was required with intact liver vascularization and no dilata-tion of intrahepatic bile ducts. A cholangiogram and an arterio-gram were performed if the ultrasound findings were equivocal. One gram of intravenous methylprednisolone was given for biop-sy-proven rejection, followed, if necessary, by an additional5-day "burst" of methylprednisolone, beginning with 200 mg the first day, followed by a daily decrease of 40 mg until 20 mg/d was reached on the sixth day. If rejection persisted, a 3- to 5-day course of 5 to 10 mg/d of OKT3 was given. 0.2 0.2 0.1 0.1 10 20 30 O~ 10 20 30 10 20 30 2.0 2.0 1.8 1.8 1.6 ~ 1.6 1.4 1.4 ~ 1.2 1.2 . . 1.0 1.0 0.8 0.8 0.6 O.B 0.4 0.4 ., 0 , . , 8101210(1618202224252830 ·'0 , .. 61012U1!518202224262630 TIME IN DAYS TIME IN DAYS Statistical Analysis Biochemical parameters were followed for 30 days and included hepatic and renal function, and dosage and plasma trough levels of FK 506. Statistical analysis was performed by Mann-Whitney U test or chi-square testing with Yates correction. Results were expressed as means ± SEM. RESULTS Patient and Graft Survival Patient survival was essentially the same in all groups (95.1 % to 97.4%), as were the graft survival rates (87.5% to Table 2. Episodes of Acute Cellular Rejection and Supplemental Immunosuppression in Grafts Surviving 30 Days Group 1 Group 2 Group 3 PValue Number of primary grafts 109 34 36 Number of grafts with rejection in month 1 58 (53.2%) 21 (61.8%) 16 (44.4%) NS Onset of first episode (day)' 9.4 ± 0.8 8.8 ± 0.9 10.7 ± 2.1 NS Number of rejection episodes 1 32 (29.4%) 12 (35.3%) 11 (30.6%) NS 2 19 (17.4%) 8 (23.5%) 3 (8.3%) NS 2:3 7 (6.4%) 1 (2.9%) 2(5.6%) NS Supplemental immunosuppression 1 g methylprednisolone 0.55 :+:: 0.07t 0.97 ± 0.15 0.86 ± 0.13 .012 Steroid cycling 16 (14.7%)* 11 (32.4%) 8 (22.2%) .024 OKT3 4 (3.7%) 2 (5.9%) 0(0%) NS T. Bilirubin at first month (mg/dL) 1.85 ± 0.29 1.26 ± 0.14 1.23±0.17 NS >Biopsy verified, mean ± SE. t P = .012 vs group 2, P = .044 vs group 3. *p = .024 vs group 2. PGE1 IN LIVER TRANSPLANTS WITH FK 506 Table 3. Evaluation of Biopsy Specimens in Grafts Surviving 30 Days Group 1 Group 2 Group 3 Number of primary grafts 109 34 36 Total number of biopsy 179 53 52 specimens* Biopsy specimens per graft 1.64 1.56 1.44 No ACRt 88 (49.2%) 20 (37.7%) 27 (51.9%) Consistent with or early 15 (8.4%) 9 (17.0%) 7 (13.5%) ACR (grade 1) Mild ACR (grade 2) 59 (33.0%) 19 (35.8%) 13 (25.0%) Moderate ACR (grade 3) 14 (7.8%) 5 (9.4%) 5 (9.6%) Severe ACR (grade 4) 3 (1.7%) 0 0 "During the first 30 days. t AeR, Acute cellular rejection. 89.5%) and the need for retransplantation (Table 1). Liver grafts were lost to various causes (Table 1). Primary nonfunction leading to retransplantation was observed in three patients in group 1 (2.4%), three patients in group 2 (7.9%), and two patients in group 3 (4.8%). Sepsis caused four deaths in group 1 but was not responsible for any mortality in groups 2 and 3 (Table 1). Incidence and Treatment of Rejection Although no grafts were lost to acute rejection in any ofthe groups (Table 1), rejection was diagnosed within 1 month in 53%, 62%, and 44% of the recipients in groups 1 through 3, respectively. The time of onset, frequency, and his-topathological severity of these episodes were also similar in the three groups (Tables 2 and 3). However, the mean number of steroid boluses given per patient during the first 30 days was 0.55 for group 1, significantly lower than 0.97 for group 2, and 0.86 for the group 3. In addition, the high induction dose of FK 506 (group 1) significantly reduced the need for steroid recycling vs group 2 (P = .024) but not group 3 (P = .27). Differences in OKT3 usage among the groups were not statistically significant; actually no patient in group 3 required OKT3 in the first 30 days (Table 2). 2383 Renal Function Hemodialysis was required in 13.8% of the group 1 pa-tients, 14.7% of the group 2 patients, and in only one (2.8%) of the 41 patients in group 3 (Table 4). The exceptional patient in group 3 had two treatments for volume overload on the second and third postoperative days with slow continuous ultrafiltration with Dianeal (Table 4). By the end of the first month, 9.2%, 11.8%, and 0% of the patients in groups 1 through 3, respectively, were still on hemodialysis (Table 4). Even excluding those patients on dialysis, the mean serum creatinine during the first 30 days was elevated in all groups. These levels decreased slowly after the second postoperative week in group 3 (Fig 1), but they remained significantly higher in groups 1 and 2 relative to group 3 (Table 4). The beneficial kidney-protective effect of PGE I in the group 3 patients vs those in group 2 was most pronounced in those recipients who were given <15 units of packed red blood cells vs those with a blood transfusion requirement greater than this (P = .0087) (Fig 2). DISCUSSION The pathogenesis of FK 506 nephrotoxicity and other side effects has been thought from the outset to be similar to that of CyA.2,7-9 With both drugs, a decrease in effective renal plasma flow and glomerular filtration rate and an increase in renal vascular resistance may be associated with the secretion of endothelin-l JO or thromboxane A211 and other products of arachidonic acid metabolism. Be-cause prostaglandins of series 12, Eu and E2 are potent vasodilators and modulators of tone in the pre- and post-glomerular arterials, they were evaluated for the pharma-cological interdiction of these undesirable effects ofCyA in the studies by Makowka et al12 and Ryffel et al. 13 In Makowka's original study, CyA blood levels were not obtained. In the present investigation, in which this supporting data ofFK 506 were available, the dose and plasma levels were essentially the same in groups 2 and 3, making it possible in these two groups to make a discriminative Table 4. Hemodialysis and Renal Function in Primary Grafts Surviving More Than 30 Days Group 1 Group 2 Number of patients 109 34 Hemodialysis for first month 15 (13.8%) 5 (14.7%) Hemodialysis at first month 10 (9.2%) 4 (11.8%) Preoperative creatinine (mg/dL) 0.72 ± 0.04 1.03 ± 0.06 Creatinine at 1 week' 1.41 ± 0.09 1.57 ± 0.16 Creatinine at 2 weeks 1.57 ± 0.08 1.50 ± 0.13 Creatinine at 3 weeks 1.63 ± 0.08 1.48 ± 0.11 Creatinine at 4 weeks 1,68 ± 0.07 1,53 ± 0.12 Creatinine 2:2.0 mg/dL at first month 18 (19.1%) 3 (10.3%) 'Patients required two times of slow continuous ultrafiltration with Dianeal. b, c, d; Group 1 vs group 3. tGroup 1 vs group 2, group 1 vs group 3. 'Excludes the hemodialysis patients, mean ± SE. §Group 1 vs group 3. Group 3 PValue 36 1 (2.8%)* NS 0(0%) NS 1.06 ± 0,06t <.001 1.42 ± 0.12 NS 1.24 ± 0.08§ .022 1.25 ± 0.08§ .0046 1.31 ± 0.09§ .0004 3(8.6%) NS 2384 TAKAYA, BRONSTHER, ABU-ELMAGD ET AL <15 units of PRBC >15 units of PRBC 2.0 -,-------------, 2.0 1.8 1.8 1.6 1.6 -~ o 1.4 C) ....,t 1111tfhrffff~ "KK~ , ,-1.4 E 1.2 1.2 -CI) C 1.0 ""DK-Kgi~-C ! 1.0 _ 0.8 0.8 co CI) ... 0.6 0.6 o Fig 2. Division of blood usage during liver transplantation in group 2 (n = 23) and group 3 (n = 19) with low transfusion group [<15 units of packed red blood cells (PRBC)] and high transfu-sion group (215 units of PRBC) (n = 6 in group 2, n = 16 in group 3, excluding hemodialysis pa-tients). In the lower transfusion group, the mean creatinine in group 3 was significantly lower than that of group 2 for the first 30 days (1.48 ± 0.08 mg/dL vs 1.20 ± 0.05 mg/dL, P = .0087). Values are expressed as mean ± SE. 0.4 ."".o.u0e-uo_ Group 2 0.4 1IIIIIU"I1£1 __ Group 2 Group 3 • Group 3 0.2 0.2 0.0 . ·20 2 4 681012141618202224262830 ·20 2 4 6 8 1012141618202224262830 Time in Days Time In Days assessment of the kidney-sparing effect of PGE,. The PGE, appeared to have substantially reduced the FK 506 nephrotoxicity. This was particularly evident in patients with the least troublesome perioperative courses, as re-flected by their minimum needs for blood transfusion. In contrast, the value of PGE, was obscured in patients who required more than I5-unit transfusions. The reduced nephrotoxicity in the PGE,-treated group 3 was reflected not only in the better average postoperative renal function, but also by the nearly complete elimination of the need for posttransplant dialysis. Only a single patient of the 36 in group 3 required such support, and in this instance the dialysis intervention for correction of volume overload was very brief. It has long been known that the liver recipient is especially vulnerable to renal failure, partly because occult renal dysfunction so often already is present in the preoperative period. '4 Causes of further renal damage perioperativeiy are multifactorial and, in addition to suspect immunosuppressive drugs, include cardiovascular instability, endotoxemia, and neph-rotoxic antibiotics. In spite of the complexity of this background in the liver transplant recipients, our conclu-sion that PGE I protects the kidney from concomitantly administered nephrotoxic drugs was essentially the same as that reached by Moran et ailS in less complicated clinical renal transplant trials. The second and less clearly resolved question in this study was whether PGE, altered the efficacy of FK 506 or was itself inherently immunosuppressive. There was no clear evidence for either possibility. In the low FK 506 dose groups 2 and 3, in which the therapeutic variable was PGE I , the presence or absence of the PGE I did not obviously influence the rate of rejection, the use of sup-plemental steroids or adjuvant immunosuppressive mea-sures, or the doses and plasma levels of FK 506. In both groups 2 and 3, the need for augmented steroids was significantly greater than in the patients of group 1, who were started on high doses of FK 506. Thus, this study, as well as our earlier one of patients who received crossmatch-positive livers,4 has shown that the greatest value of PGE I is amelioration of nephrotoxic-ity. However, we emphasize that previous workers in controlled animal experiments have shown obtundation of cellular'6.'7 or humoral responsiveness, '8 or both. '9-21 We believe that an immunosuppressive effect was too subtle to be detected under the complex circumstances of these liver transplantation cases. REFERENCES 1. Starzl TE, Todo S, Fung J, et al: Lancet 2:1000, 1989 2. Todo S, Fung JJ, Starzl TE, et a1: Ann Surg 212:295, 1990 3. Takaya S, Bronsther 0, Iwaki Y, et al: Transplantation 53:400, 1992 4. Takaya S, Iwaki Y, Starzl TE: Transplantation 54:927,1992 5. Tamura K, Kobayashi M, Hashimoto K, et al: Transplant Proc 19(5uppI6):23, 1987 6. Demetris AI, Qian S, Sun H, et al: Am J Surg Pathol 14:49, 1990 PGE1 IN LIVER TRANSPLANTS WITH FK 506 7. Kusne S, Dummer JS, Singh N, et al: Medicine 67:132,1988 8. Starzl TE, Fung JJ: JAMA 263:2686, 1990 9. Nalesnick M, Lai HS, Murase N, et al: Transplant Proc 22:87, 1990 10. Moutabarrik A, Ishibashi M, Fukunaga, et al: Transplant Proc 23:3133, 1991 11. Rogers TS, Elzinga L, Bennet WM, et al: Transplantation 45:153,1988 12. Makowka L, Lopatin W, Gilas T, et al: Clin Nephrol 25:S89, 1986 13. Ryffel B, Donatsch P, Hiestand P, et al: Clin Nephrol 25:S95, 1986 2385 14. Klintmalm GBG, Klingensmith WC III, Iwatsuki S, et al: Radiology 142:199, 1982 15. Moran M, Mozes MF, Maddux MS, et al: N Eng! J Med 322: 1183, 1990 16. Chonaib S, RobbRJ, Welte K, etal: J Clin Invest 80:333, 1987 17. Makoul GT, Robinson DR, Bhalla AK, et al: J Immunol 134:2645, 1985 18. Makowka L, Miller C, Chapchap P, et al: Ann Surg 206:482, 1987 19. Rappaport RS, Dodge GR: J Exp Med 155:943, 1982 20. Snyder DS, Beller 01, Unanue ER: Nature 299:163, 1982 21. Weir MR, Wang Li X, Gomolka D, et al: Transplantation 52:1053, 1991 

Use of prostaglandin E<inf>1</inf> in crossmatch-negative liver transplant recipients treated with FK 506

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Use of prostaglandin E<inf>1</inf> in crossmatch-negative liver transplant recipients treated with FK 506

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