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ORIGINAL ARTICLE

Preserving Renal Function in Liver TransplantRecipients with Rabbit Anti-Thymocyte Globulinand Delayed Initiation of Calcineurin InhibitorsIman Bajjoka, Lama Hsaiky, Kimberly Brown, and Marwan AbouljoudTransplant Institute, Henry Ford Hospital, Detroit, MI

Early renal dysfunction following liver transplantation is associated with increased morbidity and mortality. To evaluate the

impact of delayed initiation of calcineurin inhibitor on renal function, we conducted a retrospective study comparing 118 liver

transplant recipients who received rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitor with 80 liver

transplant recipients who received no antibody and early initiation of calcineurin inhibitor (control group). All patients received

mycophenolate mofetil and steroids. Delayed calcineurin inhibitor initiation with anti-thymocyte globulin was associated with

significant improvement in renal function throughout the first year post-transplant. At 12 months post-transplant, patients

treated with this regimen experienced lower serum creatinine (1.4 Ϯ 0.5 versus 1.7 Ϯ 0.5 mg/dL, P Ͻ 0.001), a higher

estimated glomerular filtration rate (57.4 Ϯ 20.5 versus 43.7 Ϯ 14.4 mL/min/1.73 m2, P Ͻ 0.001), and less dependence on

dialysis (0.8% versus 13%, P Ͻ 0.001) in comparison with no antibody and early calcineurin inhibitor initiation. Patient survival

and graft survival were similar between groups; however, there was a trend of a lower incidence of early biopsy-proven acute

rejection with anti-thymocyte globulin. Overall infection and cytomegalovirus infection were significantly lower in anti-thymocyte

globulin–treated patients, and there was no increased incidence of hepatitis C recurrence in comparison with controls. In

conclusion, delayed initiation of calcineurin inhibitor with anti-thymocyte globulin in liver transplant recipients is safe and is

associated with improvements in renal function and a lower incidence of early acute rejection in comparison with no antibody

and early initiation of calcineurin inhibitor. Liver Transpl 14:66-72, 2008. © 2007 AASLD.

Received October 16, 2006; accepted August 2, 2007.

Renal dysfunction is a common postoperative compli-cation following orthotopic liver transplantation andhas been reported to occur in 12% to 67% of liver trans-plant recipients.1-3 Early renal dysfunction is a risk factor for chronic renal failure and is associated withsignificant morbidity and mortality in liver transplant recipients.2,4-7

Many risk factors such as preexisting renal impair-ment, hepatorenal syndrome, diabetes mellitus, liver allograft dysfunction, significant intraoperative bloodloss, infection, and exposure to nephrotoxic calcineurin

inhibitors (CNIs) have been reported to be associated with early renal dysfunction and acute renal failureafter liver transplantation.1,2,8-11 Various strategies

have been investigated to minimize the risk of acuterenal failure after orthotopic liver transplantation, suchas optimization of hemodynamic conditions in the op-erative and perioperative periods, but these strategieshave not been successful.12-15

Delaying the initiation of the nephrotoxic CNIs cyclo-sporine and tacrolimus until renal function recoversappears to be a logical approach to minimize early renaldysfunction in liver transplantation. Results from re-cent clinical studies have demonstrated the safety andefficacy of this strategy;16-21 however, there is concern

that delaying the initiation of CNI may place patients at risk for early acute rejection.17

Building on the premise that anti-thymocyte globulin

Abbreviations: CMV, cytomegalovirus; CNI, calcineurin inhibitor; GFR, glomerular filtration rate; HCV, hepatitis C virus; IL-2R,interleukin-2 receptor; MELD, Model for End-Stage Liver Disease; NS, not significant; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; WBC, white blood cell.Supported in part by Genzyme Corp.Potential conflict of interest: Iman Bajjoka has participated in Genzyme Advisory Boards.Address reprint requests to Iman Bajjoka, Pharm.D., B.C.P.S., Director of Transplant Research, Transplant Institute, Henry Ford Hospital, 2799West Grand Boulevard, CFP 219, Detroit, MI 48202. Telephone: 313-916-3709; FAX: 313-916-3433; E-mail: [email protected]

DOI 10.1002/lt.21309Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 14:66-72, 2008

© 2007 American Association for the Study of Liver Diseases.



allows for delayed initiation of CNI without an increased

risk of acute rejection in kidney transplant recipi-

ents,22,23 and because it has been used safely in liver

transplant recipients,18,21-24 we postulate that delayingthe initiation of CNI with anti-thymocyte globulin may

be safe and effective in preserving renal function in liver

transplant recipients with renal dysfunction. We there-

fore conducted a retrospective study comparing theoutcomes of liver transplant recipients with renal dys-function who received either anti-thymocyte globulin

and delayed initiation of CNI (anti-thymocyte globulin

group) or no antibody and early initiation of CNI (con-

trol group).

PATIENTS AND METHODS

Study Design and Patient Selection

This study was approved by the local institutional re-

view board. This retrospective cohort study compared

outcomes of 118 consecutive liver transplant recipients with renal dysfunction who received anti-thymocyteglobulin and delayed initiation of CNI (anti-thymocyte

globulin group) with 80 consecutive liver transplant

recipients with renal dysfunction who received no anti-

body and early CNI initiation (control group). Renal

dysfunction was defined as a baseline pretransplant serum creatinine Ն 1.5 mg/dL or the need for dialysis

at the time of transplantation.

Immunosuppression

Anti-Thymocyte Globulin Group

All 118 liver transplant patients with renal dysfunction

that underwent transplantation between July 2001 and

September 2006 received rabbit anti-thymocyte globu-

lin (Thymoglobulin, Genzyme Corp., Cambridge, MA) at a dose of 0.5-1.0 mg/kg/day intravenously, starting on

posttransplant day 1, and this continued daily until

either the serum creatinine level had declined to Յ1.2

mg/dL or the patient had received a total of 5 doses.

Anti-thymocyte globulin was infused over 4 hours for

the first and all subsequent doses, with premedicationgiven 30 to 60 minutes prior to infusion (either 40 mg of

dexamethasone or 250 mg of methylprednisolone, 50

mg of intravenous or oral diphenhydramine, and 650

mg of oral acetaminophen). Tacrolimus (Prograf, Astel-

las Pharma US, Inc.) or cyclosporine (modified) wasinitiated either 1 day prior to the last of the 5 target

doses of anti-thymocyte globulin or when the serum

creatinine level declined to Յ1.2 mg/dL. Five hundred

milligrams of mycophenolate mofetil (CellCept, Roche

Pharmaceuticals) orally twice daily was initiated in all

patients on posttransplant day 1 and continued for 6months. Intraoperatively, all patients received cortico-

steroids either as methylprednisolone (500 mg) intrave-

nously or as dexamethasone (100 mg) intravenously.

The dose of corticosteroids was tapered and discontin-ued by 3 months post-transplant.

Control Group

Eighty consecutive liver transplant recipients with re-nal dysfunction transplanted prior to July 2001 re-ceived CNI early post-transplant and did not receiveany antibody therapy. In this historical control group,tacrolimus or cyclosporine was initiated within 48

hours post-transplant. Five hundred milligrams of my-cophenolate mofetil orally twice daily was initiated in allpatients on posttransplant day 1 and continued for 6months. Patients received 500 mg of methylpred-nisolone intravenously intraoperatively. The dose of corticosteroids was tapered and discontinued by 3months post-transplant.

Prophylaxis

All patients received the same prophylactic regimensconsisting of postoperative bacterial and fungal pro-phylactic regimens with piperacillin/tazobactam every 8 hours for 24 hours and clotrimazole troches 5 times

daily for 4 weeks, respectively. Oral ganciclovir wasadministered for 3 months following transplantation,regardless of donor and recipient cytomegalovirus se-rology. Sulfamethoxazole/trimethoprim was adminis-tered 3 times weekly for prophylaxis against Pneumo-

cystis carinii .

Data Collection

Patients were evaluated at baseline, at completion of anti-thymocyte globulin therapy, and at 1, 3, 6, and 12months post-transplant. The primary outcomes of in-terest were patient and graft survival at 12 months,early (30 days) biopsy-proven acute rejection, renal

function, incidence of hepatitis C recurrence, and inci-dence of adverse events. Donor and recipient demo-graphics, etiology of end-stage liver disease, Model for End-Stage Liver Disease (MELD) score, pretransplant hospitalization, and dialysis dependence were also col-lected. Collected laboratory parameters included serumcreatinine levels, CD3 cell counts, white blood cell(WBC) counts, platelet counts, and hemoglobin levels.Creatinine clearance at baseline was measured by 24-hour urine collection. The glomerular filtration rate(GFR) was estimated with the Modification of Diet inRenal Disease equation.

Biopsies were performed in all suspected rejection

episodes. Rejection episodes were graded according toBanff criteria, with the first episode treated with either 500 mg of methylprednisolone per day for 3 days or 100mg of dexamethasone per day for 3 days. Refractory rejection was treated with anti-thymocyte globulin (1.5mg/kg/day) for 7 to 10 days. Recurrence of hepatitis C

was determined either by histological changes on biop-sies or by significant increase in hepatitis C viral load inthe presence of abnormal liver function.

Statistical Analysis

Categorical variables were summarized with countsand percentages and were compared with either the

PRESERVING RENAL FUNCTION IN TRANSPLANT RECIPIENTS 67

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases



chi-square test or Fisher’s exact test when appropriate.Continuous variables were summarized as means andstandard deviations or medians and ranges and werecompared with the Student t test. Comparisons of theserum creatinine levels during the follow-up period

were made by analysis of variance.

RESULTS

Patient Characteristics

Patient demographics and baseline characteristics were similar between groups (Table 1). There were sig-nificantly more hepatitis C virus–positive patients inthe anti-thymocyte globulin group [63/118 (53%)] incomparison with the control group [11/80 (14%); P Ͻ

0.001]. A high percentage of patients in both groups

were hospitalized prior to transplant, and the majority of patients had MELD scores Ն 20 at the time of trans-plant (Table 1). All patients had preexisting renal dys-function as reflected in the elevated serum creatininelevels, low creatinine clearance, reduced GFR, and highnumber of patients on dialysis prior to liver transplant (Table 1). One hundred thirteen patients (95%) in theanti-thymocyte globulin group and all patients in thecontrol group completed 12 months of follow-up.

Immunosuppression

The mean total cumulative dose of anti-thymocyte glob-ulin was 2.1 Ϯ 1.2 mg/kg, given in a mean of 3.3 Ϯ 1.6

doses over 4.7 Ϯ 2.6 days. Infusion-related side effectsrequiring dosing adjustment and interruption occurredin 3 patients. Sixteen patients (13%) required adjust-ment of the anti-thymocyte globulin dose because of thrombocytopenia, leukopenia, or a combination of these reasons.

The mean time to initiation of CNI was 4.6 Ϯ 2.3 daysin anti-thymocyte globulin–treated patients and 1.9 Ϯ2.5 days in control patients (P Ͻ 0.001). Tacrolimus wasthe most common CNI administered in both groups(anti-thymocyte globulin: 90%, control: 80%, P ϭ not significant). There were no differences in tacrolimus or cyclosporine trough levels between the 2 groups duringthe follow-up period (Fig. 1).

Patient Survival, Graft Survival, and Biopsy-Proven Acute Rejection

Actual patient (anti-thymocyte globulin: 90%, control:89%) and graft survival rates (anti-thymocyte globulin:88%, control: 86%) at 12 months post-transplant weresimilar between groups. The causes of death and graft failure were also similar between groups. Five patientsin each group died of infection. Two patients in theanti-thymocyte globulin group and 1 patient in the con-trol group died of a cerebral vascular event. Other causes of death in the anti-thymocyte globulin groupincluded noncentral pontine myelinolysis (n ϭ 1), graft failure (n ϭ 2), hepatic artery thrombosis (n ϭ 1), and

TABLE 1. Baseline Characteristics

Anti-Thymocyte Globulin

(n ϭ 118)

Control

(n ϭ 80) P Value

Recipient age (years) 54 Ϯ 9 53 Ϯ10 NSRecipient gender (males) 78 (66%) 48 (60%) NS

Recipient race (Caucasian) 84 (71%) 61 (76%) NSHCV-positive recipients 63 (53%) 11 (14%) Ͻ0.001Etiology of end-stage liver disease

HCV 45 (38%) 9 (11%)HCV and hepatocellular carcinoma 3 (3%) 1 (1%)HCV and alcoholic cirrhosis 15 (13%) 2 (3%) Alcohol cirrhosis 19 (16%) 22 (28%)Cryptogenic cirrhosis 11 (9%) 18 (23%)PBC/PSC 6 (5%) 13 (16%) Autoimmune hepatitis 4 (3%) 4 (5%)Others 15 (13%) 11 (14%)

CMV donor (D)/recipient (R) serology NSCMV Dϩ/R Ϫ 23 (19%) 11 (14%)CMV Dϩ/R ϩ 61 (52%) 45 (56%)CMV DϪ/R ϩ 26 (22%) 18 (23%)

CMV DϪ/R Ϫ 8 (7%) 6 (8%)Retransplants 13 (11%) 9 (11%) NSMELD score 23.4 Ϯ 6.1 22.2 Ϯ5.2 NSHospitalized prior to transplant 63 (53%) 31 (39%) 0.043Dialysis prior to transplant 19 (16%) 10 (13%) NSSerum creatinine (mg/dL) 2.8 Ϯ 1.5 2.2 Ϯ 0.9 0.005Creatinine clearance (mL/min) 39.4 Ϯ 23.9 41.4 Ϯ 16.0 NS

Abbreviations: CMV, cytomegalovirus; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; NS, not significant;PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

68 BAJJOKA ET AL.




pulmonary edema (n ϭ 1). None of the deaths wererelated to anti-thymocyte globulin administration. Inthe control group, 1 patient died of recurrent hepatitisC and 1 patient died of hepatocellular carcinoma. Nine-teen of 118 patients (16%) in the anti-thymocyte glob-ulin group and 21 of 80 patients (26%) in the controlgroup experienced biopsy-proven acute rejection withinthe first 30 days post-transplant (P ϭ 0.08). The major-ity of rejection episodes were considered mild as graded

by the Banff criteria.

Renal Function

Serum creatinine levels significantly decreased from2.7 Ϯ 1.5 mg/dL at baseline to 2.0 Ϯ 1.3 mg/dL at theend of anti-thymocyte globulin treatment (P Ͻ 0.01),and serum creatinine levels continued to decline andremained stable between 1 and 12 months post-trans-plant (Fig. 2). Early improvements in renal function

were also observed in the control group; however, thisimprovement was not sustained as serum creatininelevels increased starting at 3 months post-transplant and remained elevated at 12 months (Fig. 2). Anti-thy-mocyte globulin–treated patients had significantly higher GFR (57.4 Ϯ 20.5 mL/min/1.73 m2) than the

control group (43.7 Ϯ 14.4 mL/min/1.73 m2) at 12months of follow-up (P Ͻ 0.001; Fig. 3). Compared to

baseline, estimated GFR at 12 months had improved by 36.6% in the anti-thymocyte globulin group, whereasestimated GFR increased by only 8.5% in the controlgroup (P Ͻ 0.01).

Of the 19 patients (16%) in the anti-thymocyte glob-ulin group who were dialysis-dependent prior to trans-plant, none of the patients required dialysis at 1 year post-transplant. One patient who was not on dialysisprior to or during anti-thymocyte globulin administra-tion required dialysis at the end of follow-up (0.8%). Incontrast, the proportion of patients in the control grouprequiring dialysis before transplantation (13%) re-mained the same post-transplantation (13%) and wassignificantly higher than that of the anti-thymocyteglobulin group (13% versus 0.8%; P Ͻ 0.001).

Hematology Profile

Following treatment with anti-thymocyte globulin, CD3cell counts declined from 201 Ϯ 275 to 20 Ϯ 23 cells/mm3 (P Ͻ 0.01). There were no statistically significant differences in WBC counts and platelet counts betweenthe 2 groups (Fig. 4A,B). However, hemoglobin levels inthe controls were significantly lower than those of theanti-thymocyte globulin–treated patients at 12 monthspost-transplant (Fig. 4C).

Adverse Events

Of the 63 hepatitis C virus–positive patients in theanti-thymocyte globulin group, hepatitis C disease

recurred in 25 patients (40%) during the 12 months of follow-up and occurred at a median of 133 days(range: 22-362 days) post-transplant. Similarly, re-currence of hepatitis C was observed in 7 of the 11hepatitis C virus–positive patients (64%) in the con-trol group, with a median time to recurrence of 110days (range: 9-201 days) post-transplant. Cytomega-lovirus disease was significantly less common in theanti-thymocyte globulin–treated patients (2.5%) com-pared with control patients (11.3%; P Ͻ 0.01). Overallinfection incidence was also significantly less com-mon in the anti-thymocyte globulin group (38%) com-pared with the control group (51%; P Ͻ 0.05). In bothgroups, the majority of these infections were of bac-

Figure 1. Calcineurin inhibitor levels through 12 monthspost-transplant. Data represent mean values standard de-

viation. At all time points, calcineurin inhibitor levels weresimilar between treatment groups.

Figure 2. Serum creatinine levels at baseline and through 12months post-transplant. Data represent mean values stan-dard deviation.

Figure 3. Glomerular filtration rate (GFR) as estimated by the Modification of Diet in Renal Disease equation at baselineand 12 months post-transplant. Data represent mean values

standard deviation.





terial origin. Seven anti-thymocyte globulin–treatedpatients (5.9%) and 9 control patients (11.3%) expe-rienced systemic fungal infections. One patient in thecontrol group experienced herpes simplex viral infec-

tion. One patient in the anti-thymocyte globulingroup, who had a history of previous liver transplant,developed squamous cell carcinoma of the skin dur-ing the follow-up period. There were no cases of post-transplant lymphoproliferative disorder or other ma-lignancies observed in either group.

DISCUSSION

Early renal dysfunction in liver transplant recipients isassociated with the development of end-stage renal dis-ease and significant morbidity and mortality post-transplant.2-5,7-9 Delaying the initiation of CNI with an-ti-thymocyte globulin in patients at high risk of acute

renal failure was associated with a recovery in renalfunction in the early posttransplant period. Patients onthis regimen also experienced a continual improvement in renal function, with a greater independence fromdialysis, higher estimated GFR, and lower serum creat-inine levels than control patients at 12 months post-transplant. This observation may have significant clin-

ical implication as 12-month serum creatinine Ͼ 1.7mg/dL has been reported to be a significant risk factor for development of end-stage renal disease requiringdialysis and kidney transplantation.8

One surprising observation from our study is that using anti-thymocyte globulin to delay the initiation of CNI by only 4.6 days resulted in significant improve-ment in estimated GFR. GFR increased by 36.6% at 12months post-transplant in comparison with pretrans-plant values. In contrast, the early initiation of CNI andno antibody therapy were not associated with a contin-ual improvement and resulted in only an 8.5% changein GFR at 12 months post-transplant compared to

baseline. Anti-thymocyte globulin was well tolerated in thiscohort of acutely ill patients, with few patients experi-encing any serious adverse events. Leukopenia andthrombocytopenia, which are known side effects of an-ti-thymocyte globulin, were uncommon and were easily managed by dose reduction or interruption. Starting at 1 month post-transplant, there were no differences in

WBC and platelet counts between the 2 groups. In con-trast, hemoglobin levels were significantly higher in theanti-thymocyte globulin–treated patients than the con-trols at 12 months of follow-up. Because anemia is a common manifestation of chronic renal insufficiency,this observation is consistent with the higher serum

creatinine levels observed in the controls. The use of any antibody therapy for induction in liver

transplantation has remained controversial. The liver isconsidered an immunologically privileged organ; thus,the use of antibody to prevent rejection has been per-ceived as unnecessary and may increase the risk of overimmunosuppression. In this study, the use of anti-thymocyte globulin was associated with a numerically lower incidence of early acute rejection, a significantly lower incidence of infection, and no increased risk of malignancy in comparison with controls. Importantly,anti-thymocyte globulin was not associated with an in-creased incidence of hepatitis C recurrence.21,24 This

low incidence of adverse events, especially infection,may be related to the relatively low mean cumulativedose of anti-thymocyte globulin (2.2 mg/kg) used todelay the initiation of CNI in contrast to the conven-tional 1.5 mg/kg/day for 3 to 7 days used in kidney transplantation as induction therapy.25-28 Addition-ally, the control patients required additional immuno-suppression to treat acute rejection, which might leadto increased overall immunosuppression load and anincreased incidence of infection.

Our results are similar to those reported by Tcher- venkov and colleagues18 on their experience with anti-thymocyte globulin induction in 298 consecutive liver transplant recipients. Anti-thymocyte globulin induc-

Figure 4. (A) White blood cell (WBC) counts at baseline and through 12 months post-transplant. (B) Platelet counts at

baseline and through 12 months post-transplant. (C) Hemo-globin levels at baseline and through 12 months post-trans-plant. Data represent mean values standard deviation.

70 BAJJOKA ET AL.




tion was found to be safe and effective in liver trans-plant recipients, and a subgroup analysis of patients

with existing renal dysfunction (n ϭ 59; serum creati-nine Ն1.5 mg/dL) revealed that anti-thymocyte globu-lin induction (n ϭ 47) allowed a significantly delayedinitiation of CNI compared with no induction (n ϭ 12):10.8 versus 2.4 days, respectively. Despite higher base-

line serum creatinine levels, patients receiving anti-thymocyte globulin showed a significant recovery inrenal function. In agreement with our observations, thedelayed initiation of CNI with anti-thymocyte globulin

was not associated with an increased risk of acute rejection in this study.18

Although delaying initiation of CNI with interleukin-2receptor (IL-2R) antagonists basiliximab and dacli-zumab has been associated with acceptable short-termoutcomes, long-term benefits in renal function have not

been observed.16,17,20,29,30 In comparison with our cur-rent study, the lack of apparent long-term renal func-tion benefits from the use of IL-2R antagonists to delay

CNI initiation may be related to the differences in thepatient populations studied and the pharmacology of these antibodies. In previous studies that used IL-2R antagonists to delay initiation of CNI, most patients didnot have preexisting renal dysfunction and were not critically ill.16,19,29 In this study, all patients had pre-existing renal dysfunction (Ն1.5 mg/dL), and most

were critically ill at the time of transplant, as evident by the high MELD score and high percentage of patientshospitalized prior to transplant. Therefore, it is possiblethat patients at high risk for acute renal failure may derive the most benefit from antibody therapy and de-layed initiation of CNI. Furthermore, because subclini-cal renal dysfunction can result from ischemia-reper-

fusion injury, improvements in renal function observed with delaying initiation of CNI with anti-thymocyteglobulin may be related to the effects of anti-thymocyteglobulin in minimizing ischemia-reperfusion inju-ry.31,32 Prospective, randomized, comparative studiesare needed to determine whether there are advantagesto using anti-thymocyte globulin over the IL-2R antag-onists to facilitate delayed initiation of CNI in liver transplantation.

In conclusion, we observed that anti-thymocyte glob-ulin is safe in critically ill liver transplant recipients

with renal dysfunction and allows for delayed initiationof CNI. This strategy was successful in preserving renal

function through 12 months of follow-up. Anti-thymo-cyte globulin and delayed CNI initiation were also asso-ciated with a low incidence of acute rejection and sig-nificantly less infection at 12 months post-transplant incomparison with patients receiving early initiation of CNI and no antibody. Prospective, randomized, controlstudies are warranted to further evaluate the safety andefficacy of this approach in liver transplant recipients at risk for renal dysfunction.

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