BACKGROUND.: Calcineurin inhibitor nephrotoxicity in nonrenal allograft recipients can lead to end-stage renal disease and the need for kidney transplantation. We sought to evaluate the role of alemtuzumab induction in this population. PATIENTS AND METHODS.: We evaluated 144 patients undergoing kidney transplantation after nonrenal transplantation between May 18, 1998, and October 8, 2007. Seventy-two patients transplanted between January 15, 2003, and October 8, 2007, received alemtuzumab induction and continued their pretransplant immunosuppression. Seventy-two patients transplanted between May 18, 1998, and July 21, 2007, did not receive alemtuzumab induction, but received additional steroids and maintenance immunosuppression. Donor and recipient demographics were comparable. RESULTS.: Overall, 1-and 3-year patient survival and renal function were comparable between the two groups. One-and 3-year graft survival was 93.0% and 75.3% in the alemtuzumab group and 83.3% and 68.7% in the no alemtuzumab group, respectively (P=0.051). The incidence of acute rejection was lower in the alemtuzumab group, 15.3%, than in the no alemtuzumab group, 41.7% (P=0.0001). The incidence of delayed graft function was lower in the alemtuzumab group, 9.7%, than in the no alemtuzumab group, 25.0% (P=0.003). The incidence of viral complications was comparable. CONCLUSION.: Alemtuzumab induction with simple resumption of baseline immunosuppression in patients undergoing kidney transplantation after nonrenal transplantation represents a reasonable immunosuppressive strategy. Copyright © 2009 by Lippincott Williams & Wilkins

Amit Basu

Calne

Claire Morgan

Deanna Blisard

Demetrius Ellis

Eghtesad

Geoffrey Kurland

George Mazariegos

Henkie P. Tan

Igor Dvorchik

J Wallis Marsh

Jerry McCauley

Kareem Abu-Elmagd

Kenneth R. McCurry

Kirk

Knechtle

Parmjeet S. Randhawa

Ron Shapiro

Shapiro

Steven Webber

Stuart

Thomas E. Starzl

Vivek Sharma

Waldmann

English

PubMed

Crossref

Kidney After Nonrenal Transplantation—The Impact of Alemtuzumab Induction

Shapiro, R

Basu, A

Tan, HP

Morgan, C

Sharma, V

Blisard, D

Randhawa, PS

Dvorchik, I

McCauley, J

Ellis, D

Marsh, JW

Webber, S

Kurland, G

McCurry, K

Abu-Emlagd, K

Mazariegos, G

Starzl, TE

Name not available

Kidney after nonrenal transplantation-the impact of alemtuzumab induction

McCurry, KR

Abu-Elmagd, K

D-Scholarship@Pitt

Kidney after Non-renal Transplantation-The Impact of Alemtuzumab Induction Ron Shapiroa, Amit Basu a, Henkie P. Tan a, Claire Morgan a, Vivek Sharma a, Deanna Blisard a, Parmjeet S. Randhawab, Igor Dvorchik a, Jerry McCauley a, Demetrius Ellis c, 1. Wallis Marsh a, Steven Webber d, Geoffrey Kurland e, Kenneth R. McCurry f, Kareem Abu-Elmagd a, George Mazariegos a, and Thomas E. Starzl a a University of Pittsburgh, Thomas E. Starzl Transplantation Institute, Department of Surgery, Division of Transplantation, Pittsburgh, PA b University of Pittsburgh, Thomas E. Starzl Transplantation Institute, Department of Pathology, Pittsburgh, PA C Children's Hospital of Pittsburgh, Division of Nephrology, Pittsburgh, PA d Children's Hospital of Pittsburgh, Division of Cardiology, Pittsburgh, PA e Children's Hospital of Pittsburgh, Division of Pulmonology, Pittsburgh, P A f University of Pittsburgh, Division of Cardiothoracic Transplantation, Pittsburgh, PA Keywords: kidney; non-renal; Alemtuzumab Abstract word count: 214 Body word count: 1091 Corresponding Author: Ron Shapiro, MD Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center Montefiore 7 South 3459 Fifth A venue Pittsburgh, PA 15213 Email: shapiror@upmc.edu Phone: 412-647-5730 Fax: 412-647-5736 In patients undergoing non-renal transplantation, the favorable outcomes associated with calcineurin inhibitors (CNI) have been tempered by the negative impact of CNI nephrotoxicity (1). This well described phenomenon has led to the development of end stage renal disease (ESRD) as an important complication of non-renal transplantation, and some of these patients have gone on to kidney transplantation. A number of centers have reported on the efficacy of alemtuzumab induction or preconditioning in patients undergoing kidney transplantation alone (2 - 10). However, there are no publications describing the utility of alemtuzumab in patients undergoing kidney after non-renal transplantation. In this report, we discuss our single center, retrospective experience with alemtuzumab induction, and compare it to a previous cohort not receiving alemtuzumab. Patients and Methods Between May 18, 1998 and October 8, 2007, 144 patients underwent kidney after non-renal transplantation (Table 1). 72 patients received alemtuzumab induction (1 dose of 30 mg IV or 0.4 - 0.5 mg/kg in pediatric patients), with 2 peri operative doses of steroids, and simple resumption of the pre-kidney transplantation immunosuppressive regimen. 72 patients did not receive alemtuzumab; they routinely received additional induction and maintenance steroids, higher doses of CNIs, and the addition of an antiproliferative agent (MMF) if they had not been on one previously; in addition 3 patients received thymoglobulin and 10 received daclizumab induction. There were 133 (92.4%) adults and 11 (7.6%) children. 35 (24.3%) had undergone previous heart, 16 (11.1%) lung, 87 (60.4%) liver, and 6 (4.2%) multivisceral transplantation. There were 100 (69.4%) deceased donor transplants, with a mean CIT of 24.7 ± 7.9 hours, and 44 (30.6%) living donor cases; although there was a slightly higher percentage of living donors in the alemtuzumab group compared to the no alemtuzumab group, this was not statistically different. Alemtuzumab began to be used in our institution in late 2002, so that the follow-up for the alemtuzumab patients was shorter, 23.3 ± 15.0 months, than for the no alemtuzumab patients, 48.1 ± 36.9 months. Once alemtuzumab began to be utilized, almost all patients undergoing kidney after non-renal transplantation received it, except for 1 patient who received thymoglobulin and 6 patients who received daclizumab. The overall mean follow-up was 35.7 ± 30.7 months. Statistics Continuous variables were compared using the t-test with Levene's test employed for verifying the assumption of equality of variance. The chi-square test was used to compare categorical variables. Institutional Oversight The data analysis was performed on de-identified data by one of the honest brokers in our division, Joseph Donaldson, under the guidelines of the IRB protocol number 0505123. (11) Results (Table 2) Overall 1 and 3 year actuarial patient survival was 91.5% and 75.3%, and was 93.0% and 78.9% in the alemtuzumab group and 90.0% and 72.4% in the no alemtuzumab group, respectively (p = ns). Overall 1 and 3 year actuarial graft survival was 88.1 % and 71.4%, and was 93.0% "and 75.3% in the alemtuzumab group and 83.3% and 68.7% in the no alemtuzumab group, respectively (p = 0.051 - Figure 1). The overall mean serum creatinine levels at 1 and 3 years were 1.4 + 0.7 mg/dl and 1.5 + 0.9 mg/dl, respectively, and were not statistically different between the two groups. The incidence of acute rejection was lower in the alemtuzumab group, 15.3%, than in the no alemtuzumab group, 41.7% (p = 0.0001 - Table 3). The incidence of delayed graft function, defined as the need for dialysis during the rust week after transplantation, was lower in the alemt.uzumab group, 9.7%, than in the no alemtuzumab group, 25.0% (p = 0.003 - Table 3). This difference persisted when only the deceased donor cases were considered: The incidence of DGF in the alemtuzumab group was 15.6%, and in the no alemtuzumab group, it was 32.7% (p < 0.05). The incidence of viral complications was not different between the two groups. We performed several subgroup analyses, looking for any other significant factors, including living donation, hepatitis C, diabetes, and the use of extended criteria donor kidneys, which might have explained the differences, but none was associated with any outcome differences (data not shown). There were 19 HCV + patients undergoing kidney after non-renal transplantation; 7 (4 liver, 2 heart & 1 lung) received alemtuzumab and 12 (all liver) did not; 10 received no induction, and 2 received daclizumab. The alemtuzumab cases were transplanted prior to the publication of the paper that showed problematic outcomes associated with alemtuzumab and HCV in liver transplantation (12). The numbers of cases were in any event too small to analyze. The alemtuzumab / no alemtuzumab differences were observed in all non-renal transplant subgroups (i.e. heart, lung, liver, multivisceral- data not shown), although statistical significance was noted only when the groups were combined. Discussion Kidney after non-renal transplantation is an uncommon subject for discussion, and the approach to immunosuppression is not well defined. In our center, it has accounted for 7.1 % of the kidney transplantations that have been performed, with 144/2034 cases in less than 10 years. As the kidney is a third party antigen, and as the level of immunosuppression in non-renal transplant recipients tends to be relatively low by the time a kidney transplantation needs to be performed, some additional immunosuppression needs to be administered to prevent rejection of the kidney. The advantage of alemtuzumab induction in this context is that the baseline immunosuppression does not need to be changed. This simplifies patient management after transplantation and may have the further advantage of being associated with less rejection, less DGF, and slightly better graft survival, without any increase in viral complications. It is important to remember, however, that the no alemtuzumab group was not randomized and was more of an historic control, so that these differences have to be interpreted with caution. There are certain settings in kidney after non-renal transplantation where alemtuzumab may not necessarily be a good idea. These would include patients who are hepatitis C (HCV) positive and have had a previous liver transplant (12), or recently transplanted patients who have received heav-ry immunosuppression for the non-renal organ. In these situations, accounting for 6 cases in our series, we utilized daclizumab induction 1mg/kg at the time of transplantation and every 2 weeks for 4 additional doses, with standard tacrolimus/MMF-based immunosuppression, without additional maintenance steroids. This seemed anecdotally to be a satisfactory approach in tllese 6 patients. This expenence has important and obvious limitations. It is retrospective, and, as mentioned above, not randomized, and the no alemtuzumab group is mostly an historical control. Unfortunately, kidney after non-renal transplantation is not performed very often, and a randomized trial, either single center or multicenter, while desirable, will not be straightforward to perform. In the absence of such a trial, the experience reported here suggests that alemtuzumab induction with resumption of pre-kidney transplantation immunosuppression may possibly represent a simple and effective regimen in patients undergoing kidney after non-renal transplantation. Table 1 Alemtuzumab No Alemtuzumab Overall Group Group 5/18/1998 - 1/15/2003 - 5/18/1998 -Time 10/8/2007 10/8/2007 7/21/2007 N 144 72 72 Recipient Age_(yrs.) 52.1 +- 16.6 54.1 +- 15.5 50.1 +-17.5 Donor Age (yrs.) 38.4 +- 16.5 38.0 +- 15.5 38.9 +- 17.6 Time after Non-renal Tx (yrs.) 8.1 +- 4.7 8.3 +- 5.1 8.0 +- 4.4 Adult 133 (92.4%) 68 (94.4%) 65 (90.3%) Child 11 (7.6%L 4 (5.6%) 7 (9.7%) Previous Heart 35 (24.3%) 26 (36.1%) 9 (12.5%L Lung 16 (11.1 %) 7 (9.7%) 9 (12.5%) Liver 87 (60.4%) 37 (51.4%) 50 (69.4%) Multivisceral 6 (4.2%) 2 (2.8%) 4 (5.6%1 Deceased Donor 100 (69.4%) 45 (62.5%) 55 (76.4%) Cold Ischemia Time 24.7 +- 7.9 hrs 24.2 +- 7.5 rus 25.1 +- 8.4 hrs HCV+ 19 (13%) 7 (10%1 12 (17%)_ Living Donor 44 (30.6%) 27 (37.5%) 17 (23.6%) PRA 3.3 +- 9.6 2.6 +- 9.7 4.0 +- 9.4 Table 2 Alemtuzumab No Alemtuzumab Overall Group Group Patient 1 year Survival % 91.5% 93.0% 90.0% 3 year Survival % 75.3% 78.9% 72.4% Graft 1 vear Survival % 88.1% 93.0% 83.3% 3 vear Survival % 71.4% 75.3%* 68.7% " Mean Serum Creatinine 1 vear 1.4 +- 0.7 mg/dl 1.3 +- 0.5 mg/ dl 1.5 +- 0.8 mg/ dl 3,year 1.5 +- 0.9 mg/dl 1.3 +- 0.7 mg/ dl 1.6 +- 1.0 mg/ dl * p = 0.051 Table 3 Overall Alemtuzumab No Alemtuzumab Group Group Complications Acute Rejection 6 Month 16% 2.8% 29.2%** 1 Year 20.8% 8.3% 33.3%*** Total 28.5% 15.3% 41.7%** Delayed Graft Function 17.4% 9.7% 25.0%*** Living Donor 0% 0% 0% Deceased Donor 25% 15.6% 32.7%**** CMV 0% 0% 0% PTLD 0.7% 0% 1.4% BK Virus 4.2% 4.2% 2.8% ** P = 0.0001 *** P = 0.003 **** P < 0.05 ci~ure 1 - Graft Survival in Kidney after Non-renal Transplantation (alemtuzumab _: no alerntulUmab_ ) 1.0 0.9 0.8 07 0.3 0.::: 0.1 00 - l o 3'30 720 10801440 1800 2160 :::520 2880 3:240 3600 Time After Transplantation (days) ACKNOWLEDGMENTS InductlonCod.,. : 10 1 + O-censored 1-censored The author:; thank Deborah Cood, R.N., BK~KkKI C.C.T.C, C;erri fames, R.N., C.CTC,\ngda Barber, R.N., BK~KI c.Cr.(.,.Ianicc Clidewdl, ltN., BSN, C.C.T.C., \Iitzi Barker, R.N., C.CT.C., Conk :Dv1ch:atcr~I R.N., H.:'.N., C.C.T.c., Kim ylcvl~rI lC\, Stacy .\ccycdo, R.N., ccre., Nancy Egcr, R.N., H.S.N.,\lice Maglione, R.N., .\.D., Mark Paymer, B.S.N., R.N., C.CT.C, i\1aunTn Veka:;y, R.N, CCr.C,\my Singh, R.N., B.S.N., C.c:.TJ:., Lori Prothero, R.N., Diane CEFnnor~I R.N., M.P.II., Tim Donovan, R.N., c.C.U:., Mcli~~a Choma, RN., C.CR.N., Hollie Lambert R.N., \lichcllc Coombs, P .. \.c., Shannon Ross. P .. \ .. C,\shky Myers, P,,\.·c:., and Kris Schonder, )lilaI'm!). , for their pfl'()pcratin' and postopnarivc carl' of the patients, and \!elissa (:onndl for manuscnpt preparation. References 1. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young EW, ArndorferJ, Christensen L, Merion RM. Chronic Renal Failure after Transplantation of a Nonrenal Organ. N EnglJ Med 2003; 349(10):331-40. 2. Waldmann H. A personal history of the CAMPATH-1H antibody. Med Oncol2002; 19(suppl):3. 3. Calne R, Friend P, Moffatt S, et al. Prope tolerance, perioperative Campath 1H, and low-dose cyclosporine Monotherapy in renal allograft recipients. Lancet 1998; 351: 1701. 4. Stuart FP, Leventhal JR, Kaufman DB. Alemtuzumab facilitates prednisone free immunosuppression in kidney transplant recipients with no early rejection. Am J Transplant 2002; 2(suppl):397. 5. Knechtle SJ, PirschJD, H Fechner] ]r, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation results of a pilot study. Am j Transplant 2003; 3:722. 6. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating tl1e humanized CD 52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation 2003; 76:120. 7. Shapiro R, Basu A, Tan HP, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with thymoglobulin or Campath. J Am Coll Surg 2005; 200:505. 8. Shapiro R, Ellis D, Tan HP, et al. Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 2006; 148:813. 9. Tan HP, Kaczorowski D], Basu A, et al. Living donor renal transplantation using alemtuzumab induction and tacrolimus mono therapy. Am J Transp12006; 6:2409. 10. Shapiro R, Zeevi A, Basu A, Tan HP, Kayler L, Blisard D, Thai N, Girnita A, Randhawa P, Gray E, Marcos A, Starzl TE. Alemtuzumab preconditioning with tacrolimus monotherapy-the impact of serial monitoring for donor-specific antibody. Transplantation 2008; 85(8):1125-1132. 11. University of Pittsburgh Institutional Review Board (homepage on the internet) Pittsburgh: University ofPittsburgh;2006 (updated 2006 January 17; cited'2006 February 10). Jurisdiction, Structure, and Responsibilities of the Institutional Review Board. Reference Manual for the Use of Human Subjects in Research. Available online at http://www.irb.pitt.edu/manuallpreface.pdf 12. Eghtesad B, FungJJ, Demetris, AJ, Murase N, Ness R, Bass DC, Gray EA, Shakil 0, Flynn B, Marcos A, and Starzl TE, Immunosuppression for Liver Transplantation in HCV-Infected Patients: Mechanism-Based Principles. Liver Transplantation 2005; 11(11):1343-52. 

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Kidney after nonrenal transplantation-the impact of alemtuzumab induction

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