Abu-Elmagd, KM

Alessiani, M

Bryant, J

Day, R

Fung, JJ

Jain, AB

Starzl, TE

Takaya, S

Todo, S

Tzakis, A

Venkataramanan, R

English

PubMed

Name not available

Correlation of rejection episodes with FK 506 dosage, FK 506 level, and steroids following primary orthotopic liver transplant

D-Scholarship@Pitt

/~Tt/ Correlation of Rejection Episodes With FK 506 Dosage, FK 506 Level, and Steroids Following Primary Orthotopic Liver Transplant A.B. Jain. S. Todo. J.J. Fung, A. Venkataramanan. A. Day. J. Bryant. K.M. Abu-Elmagd, M. Alessiani. S. Takaya. A. Tzakis. and T.E. Slarzl L ESS frequent and less severe rejection following orthotopic liver transplants IOL T) under FK S06 has been reported earlier from our institution. 1.2 In the present study. the frequency of episodes of rejection were corre-lated with: (I) IV FK S06 dosage. (2) oral FK S06 dosage. (3) trough FK 506 plasma concentrations. and (4) use of steroids following primary OLT in a group of patients who experienced rejection episodes. and to compare them with a group who did not experience any rejection episodes. MATERIAL AND METHODS One hundred ten adults (mean ~ SO: 46.2 ± 12.4 yean: 58 male. 52 female I Wllh pnmary OlT were selected. Fint. a 9O-day posllransplant penod was chosen for study purposes. since the majority of rejection (approximately 90%) generaUy occurs in this time period. Six patients who underwent retransplants III - 5) or died (II = I) within 10 days after transplant were excluded from the analysis. FK506 Protocol. All patients were commenced on LV FK 506 (0.15 mgtkg per dav) in two divided doses. This dose was hiller than the current fK 506 dose (which is 0.1 m8lk8 per day). and was given over 24-hour continuous infusion. Subsequent adjustments in doses were made depending on the trough levels. hepatic func· tlon. renal function. Side effects from the drug. historY of rejec· tlon. or presence of infection. Steroids Hif(h PrnphyltUis SltrOld Group. Of the 104 pauents available for analysis. 53 patients received 1 g of methyl prednisone after perfusion of the liver. then 200 mg In four divided doses was given on the first postoperative day. The dose was reduced by 40 mg every day until a 20 m8ld baseline maanlenance dose was reached. :OK' ProphvltUlS Sitroid Group. The reltWning S I patients received only 20 m8ld of methylpredrusone. Subsequent adjust-Table 1. Amoum of 01111 FK 501. FK SOIlAwIa. and ......... Steroid Do .. It .he TIme of Refection In .... PeIIenIs Over eo P ....... Who Old Not Retect et .. Same TIme FK !I08o.-{fTI9/IIO per ch!fMU~ day!. (19ftII.I. I'!wcNane IMIIM ....... E~"""D4pM1 Rejedaon 0.207 1.05 14.10 (7.8' (II. 4<4, Nor.ntecoon 0.199 0.90 18.07 (10.n (11·60) P.,.. NS NS NS FlC 11'0 DOS.I OV1l" TlMI (MGllCG) .. -o .•• • DAYI ~ 1. Graphical representatlon of ePISOdes of rejectIOn (.) With oral FK 506 dose over time. pumU1~ line toins the median covanate of oral FK 506 dose over bme for nonrelector. ment in baseline steroid dose was made on an individual basis In relation to the clinical coune of the pallent. Rejection The diagnOSIS of rejecuon was made by nses In serum bilirubin and hepatic enzymes an the absence of biliary compllcauons. From Itte 08I)atIIMnt of Sutgery. Uniwnllty of Plttsbutgh School of Medicine Ind PhatrNlCV. and Itte Veterans AIIII,. Medical Center. Pittsburgh. mUfK~K Supported by reseettn grants trcm Itte Veterans AdmanlS1ratlOn and Proj8cI Grant No. OK 29981 from 1tI8 National Instnutea of Healltl. Beth88da. Maryland. Addresa retn1l requea 10 Thoma E. StarzS. MD. PhD. De-p.II1m8nI Of Surgery. 3601 F"ifttI Avenue. Faile ClIniC SC. Pittsburgh. PA 15213. C 1991 by ~ , Lange 004 1-134H11S3.Q01+ 0 3024 FICa TIIOUGH PLAIIIA UVlL NQ/IIL OVEII T-. • • ... ~ '" ... ~ .. ~ • :I: " ::I 0 • " l-loC • • lAo • • •• • DAYI Fig 2. Graphic representalJOn of ePISOdes of relectlOn (.) with FK 506 trough plasma level (nglmL) over time (days). Supenmposed line lOins the median covanate of FK 506 level over time lor nonrelector. ischemic damage. or development of hepatitis (hepatitis B. non-A. non·B. or cvtometlalovlrus (CMVjl. In addition. all the patients had protocol biopsies at 10 to 1-1 da\'s posttransplant. and subse· quenth' If clinlcallv indicated. Statistical Methodology For each patient. daily doses of IV FK S06. oral FK 506. FK S06 trough levels. and daily dose of steroids were recorded. A format test of the relationship of the following four vanables to organ rejection was carned out: (1l1V FK 506.12l. oral FK 506. Ol FK 506 troutlh plasma levels. and (4) baseline steroids: a proponlonal hazards model wnh time·varylng covanates was used. Time-Independent covanate of inillal prophylaXIS stcrOid uose and I V FK 506 were also examined. The data were 31so examaned graphtcall\' to see whether any obVIOUS panem clustcd. RESULTS Elfects ot FK 506 Dosage (IV ... oral). FK 506 Trough Plasma Levels. and Baseline Steroids Of 104 pallents. ~ expenenced episodes of rejecllon within the 9O-day posttransJ)lant J)eriod. The median FK 506 dose at the time of rejection was 0.207 mglkg per day while. at the same lime. an the nonrejectlon groUJ). it was 0.199 mglkg J)er day. The median FK 506 level J)rior to ,.. c 9 ~ 11/ ~ i Q III II: K~ . ... ~ , .. Z ; Q III II: A. ... ,.. e II JAIN. TOOO. FUNG ET AL STl:JlOID DOSII OVER Tlill • • .. '------DAYI Fig 3. Graphic representation of episode of rejection (.) With prednisone dose {mgld) over time (days). Supenmposed hne Joins the median covanate of prednisone dose over time tor nonrelector. rejection was 1.05 ng/mL comJ)ared with 0.9 ng/mL for the nonrejecting patients. Similarly. baseline mean steroid dose at the time of rejection was 14.8 mg/d (SO = 7.6) for patients who expenenced reJection. and 16.03 mgtd (SO = 10.7) for those who had no rejection episodes m the same time J)eriod (Table I). The proportional hazards models with time.varving co-variates gave no mdicallon of any relationshiJ) between the incidence of rejection and the values of FK 506 dose (IV and orall. FK 506 level. or baseline J)rednisone. for any of the four co variates just pnor to rejection (p = .6): nor was any relationship observed graphically. In Figs 1. 2. and 3. the covanate level of each of the 44 patients expenencmg rejections IS graJ)hed agatnst the lime to rejection (plotted with astensks I. wtlh lines supenmJ)osed joining the medtan covariate values over time for nonreJectors. Effect High-Dose SterOid PrOPhyl8XIs Versus Low-Dose IV FK 506 EXJ)lorallon of the data did reveal fewer episodes of rejection m the grouJ) of pallents who received a high prophylactic dose of steroids on day I to 5 (17 of 53) (Table 2) comJ)ared with low prophylaxis (27 of 51). This differ· ence. by chi·square test of aSSOCiation. is not SignIficant IP = .(8) as reponed beforeK~ However. if a J)roponlonal FK 506 REJECTION EPISODES IN OlT Table 2. High V .... ua Low-OoM Steroid Prophylaxis (Dlys 1 to 5) Did nor Reject (%) AIIjIaon (%1 eigh~ose sterotd 36 (68) 17 (32) prophyt8Xls Low-dose sterOId 24 (47) 27(53) propttyl8XlS Total 60(58) 44 (42) Total 53 51 104 Chi-~ lest Of 8SSOCIIIIon wu nor ~ (P > .051. ~K tile bmH Ideoet Ide! ~ PI'OOOI1IOI1If fIaZIrcIs modIII rW¥MI • IIgI1Ific8ntIy lOwer rISk of r8jedlOn among recIPIents DllndllllIIgh-<IOIe ... ~ tP. OOn. hazards model is fit to the data with (time-independent) covariates of initial steroids (over days I to 5) (Table 2) and IV FK 506. then the initial steroid level is significantly related to rejection (P < .05). while initial IV FK 506 dose is not. DISCUSSION AND CONCLUSIONS One aim was to discover whether lowering the dose of FK 506 increased the risk of rejection. Downward adjustments in FK 506 dose did not correlate significantly with the 3025 frequency of rejection. There were insufficient data points to correlate the results with FK 506 levels. However. the initial 5 days of high-dose of prophylactic steroids had an effect on the 9O-day incidence of rejection. This difference between high- or low-dose steroid induc-tions was not significant by Chi-square test of association. but it was significant with the time-independent propor-tional hazard model. Severity of rejection usually was mild and readily controlled with minor augmentation of main-tenance steroids as reported before.:: Because of this. we currently do not give the 5-day course of prophylactic high-dose steroids to our OL T patients. except in those who have positive lymphocyte crossmatch or higher per-centage of (>40%) panel-reactive antibodies. in whom incidence of rejection episodes are higher.J REFERENCES I. Todo S. Fung JJ. Demetns AJ. el al: Transplant Proc 23:1397.1991 ~K Jain AB. Fung JJ. Todo S. et al: Transplant Proc 23:928. 1991 3. Takaya S. Duquesnoy R. lwaki Y. et al: Transplant Proc 23:396. 1991 

A. B. JAIN

S. TODO

J. J. FUNG

R. VENKATARAMANAN

R. DAY

J. BRYANT

K. M. ABUELMAGD

S. TAKAYA

A. TZAKIS

T. E. STARZL

ALESSIANI, MARIO

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

Correlation of Rejection Episodes With Fk-506 Dosage, Fk-506 Level, and Steroids Following Primary Orthotopic Liver-transplant

http://d-scholarship.pitt.edu/4660/1/31735062118256.pdf

Correlation of rejection episodes with FK 506 dosage, FK 506 level, and steroids following primary orthotopic liver transplant

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Archivio Istituzionale della Ricerca - Università degli Studi di Pavia