An increasing number of organ procurement organizations

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1 Comparison of Histidine-Tryptophan-Ketoglutarate Solution and University of Wisconsin Solution in Intestinal and Multivisceral Transplantation Richard S. Mangus, A. Joe Tector, Jonathan A. Fridell, Marwan Kazimi, Edward Hollinger, and Rodrigo M. Vianna Background. Previous studies have failed to demonstrate a clinical difference between histidine-tryptophanketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions in clinical transplant outcomes for liver, pancreas, and kidney transplantation. This study compares HTK and UW in bowel transplantation with primary outcomes being graft and patient survival, early graft function, and episodes of rejection. Methods. Data were extracted using a retrospective chart and medical record review of all bowel transplants between 2003 and 2007, and included both pediatric and adult grafts. Transplanted organs included isolated small bowel, modified multivisceral (bowel, pancreas, and stomach) and multivisceral (bowel, pancreas, stomach, and liver). Immunosuppression included induction with a steroid taper and antithymocyte globulin and anti-cd20 monoclonal antibody (rituximab), followed by maintenance with prograf monotherapy. Bowel surveillance was performed with twice weekly zoom endoscopy and biopsy. Results. There were 54 patients transplanted with 57 grafts, 22 preserved in UW, and 37 in HTK. No differences were noted between the two solutions in initial graft function, appearance of bowel on initial endoscopy, and number of rejection episodes. There were no episodes of pancreatitis in the 44 multivisceral grafts which included a transplant pancreas (14 UW and 30 HTK). Kaplan-Meier survival analysis did not demonstrate a significant difference in graft or patient survival at 30- or 90-days posttransplant. Conclusions. Intestinal grafts preserved in UW and HTK demonstrate no difference in graft and patient survival at 30- and 90-days posttransplant. There were no differences noted in initial function, endoscopic appearance, rejection episodes, or transplant pancreatitis. Keywords: University of Wisconsin solution, Histidine-tryptophan-ketoglutarate solution, Intestinal transplantation, Organ preservation solutions, Organ procurement. (Transplantation 2008;86: ) An increasing number of organ procurement organizations (OPO) and transplant centers have adopted histidine-tryptophan-ketoglutarate (HTK) preservation solution as their primary solid organ preservation solution. Histidine-tryptophan-ketoglutarate has been shown to have equivalent clinical outcomes compared with University of Wisconsin solution (UW) while providing a significant cost savings (1). Specifically, previously published papers have demonstrated that HTK and UW have similar immediate graft function and graft and patient survival in kidney (2 4), pancreas (5 8), and liver transplantation (9, 10). Our group has also demonstrated equivalence in graft and patient survival in extended criteria liver donors, though there is some suggestion that, overall, livers preserved in HTK may have a lower incidence of biliary complications (11). No previously published study has compared HTK and UW for use in intestinal transplantation (ITx). Presented at the Xth International Small Bowel Transplantation Symposium held in Los Angeles, CA on September 6th 8th, Department of Surgery, Transplantation Section, Indiana University School of Medicine, Indianapolis, IN. Address correspondence to: Richard S. Mangus, M.D., M.S., Transplant Division, Department of Surgery, Indiana University School of Medicine, 550 N University Blvd, Room 4258, Indianapolis, IN rmangus@iupui.edu Received 30 November Accepted 22 April Copyright 2008 by Lippincott Williams & Wilkins ISSN /08/ DOI: /TP.0b013e31817ef074 The composition of HTK and UW preservation solutions, and the history behind their development, have been published previously (12). Briefly, HTK is a low viscosity solution that is based on a buffer system (histidine) with two additional substrates (tryptophan and ketoglutarate). The histidine component is felt to increase the buffering capacity of transplanted organs which slows the decrease in ph during cold ischemia time. The low viscosity of HTK may provide for easier diffusion and a faster cooling time. Histidine-tryptophanketoglutarate has a low potassium content which allows direct release into the patients circulatory system. Initial descriptions of HTK usage involved flushing of the donor organs with 10 to 15 L of the solution, though our group has shown that infusion with 3 to 4 L results in equivalent clinical outcomes at a lower cost (6, 9). University of Wisconsin solution is a much more viscous solution which flushes at a slower rate and with a lower total fluid volume. Preservation of solid organs in UW is based on three principles: (1) osmotic concentration maintained by metabolically inert substrates, (2) additional administration of the colloid carrier hydroxyethylstarch, and (3) addition of oxygen radical scavengers. University of Wisconsin solution is felt to provide organ tolerance to long cold ischemia times in a predictable manner. The compositions of UW and HTK are compared in Table 1. Between July 1, 2004 and May 30, 2007, our center performed 57 intestinal transplants in 54 adult and pediatric patients. This study compares HTK and UW for immediate and long-term transplant outcomes in this population. Our pri- 298 Transplantation Volume 86, Number 2, July 27, 2008

2 2008 Lippincott Williams & Wilkins Mangus et al. 299 TABLE 1. Description of components of UW and HTK organ preservation solutions Component UW HTK Osmolarity (mosm/l) Sodium (mmol/l) Potassium (mmol/l) Magnesium (mmol/l) 5 4 Calcium (mmol/l) Sulfate (mmol/l) 5 Lactobionate (mmol/l) 100 Phosphate (mmol/l) 25 Raffinose (mmol/l) 30 Adenosine (mmol/l) 5 Glutathione (mmol/l) 3 Allopurinol (mmol/l) 1 Histidine (mmol/l) 198 Tryptophan (mmol/l) 2 Ketoglutarate (mmol/l) 1 Starch (g/l) 50 Mannitol (mmol/l) 30 mary outcomes include perioperative, 30- and 90-day graft loss and patient death, initial intestinal allograft function and endoscopic appearance, transplant pancreatitis, and incidence of intestinal rejection posttransplant. MATERIALS AND METHODS Records for all adult and pediatric intestinal transplants performed over the study period were reviewed. The type of preservation solution and total volume infused for all locally procured and imported organs were obtained from our Organ Procurement Organization records. All of the intestinal transplant allografts in this series were procured by a team from our center. However, the choice of primary preservation solution was reached by consensus among the teams procuring the abdominal organs. Cold and warm ischemia times for each organ were obtained from the United Network for Organ Sharing database. After May 1, 2003, the primary preservation solution for our OPO was changed from UW to HTK. Posttransplant immunosuppression included induction with rabbit antithymocyte globulin (10 mg/kg total) with a rapid steroid taper. Additionally, each patient received a single dose of rituximab (150 mg/m 2 ) as part of the induction protocol. Maintenance immunosuppression was with tacrolimus monotherapy with a steroid taper. Initial goal maintenance level for prograf was (12 15 ng/dl). Overall incidence of acute cellular rejection within 90 days of transplant was 55%. Rejection was treated with one to three doses of intravenous solumedrol (500 mg), depending on initial severity of rejection and clinical response to treatment. There were two events of graft loss because of severe acute cellular rejection. All patients received cytomegalovirus and pneumocystis carinii pneumonia prophylaxis therapy will valganciclovir, cytogam, and septra. Posttransplant intestinal allograft surveillance is performed with serial magnification endoscopy with mucosal biopsy. Intestinal donor demographic and clinical data were obtained from the original donor charts as recorded by the on-site OPO representative. An extensive literature review was undertaken before the data collection phase of this study to determine those donor factors that have been previously cited as potentially impacting intestinal transplant outcome. Graft and patient survival data were collected from the transplant database at our center. Patients are closely followed posttransplant by our center, and no patients were lost to follow-up. All recipients were listed for transplantation according to standard procedures and protocols as established by the United Network for Organ Sharing. Patients included in the analysis received isolated ITx, modified multivisceral transplant (stomach, pancreaticoduodenal complex, and small intestine), and multivisceral transplant (modified multivisceral transplant Liver). In addition, six patients also received a renal allograft. For this cohort, there were no ABO mismatches. Transplant outcomes included graft and patient survival, initial intestinal allograft function, and incidence of rejection of the intestine. All patients received a minimum of twice weekly magnification endoscopy with biopsy in the first 4-weeks posttransplant. All occurrences of graft loss or patient death were included in the final analysis regardless of the causative factors. There were no exclusions for intraoperative or perioperative mortality or graft loss or for nontransplant related deaths. Minimum follow-up time was 3 months, with median follow-up time of 17.5 months. This study was reviewed and approved by the Indiana University School of Medicine institutional review board. Statistical analysis was conducted using commercially available software (Statistical Package for the Social Sciences, SPSS Inc., Version 15.0, 2006). Graft and patient survival outcomes were analyzed using the 2 test and the Fisher s exact test, as indicated. Kaplan-Meier survival curves with log rank testing were used to compare HTK and UW for graft survival. Differences in outcomes for UW and HTK within the study groups were considered significant for a P value RESULTS During the study period, 54 patients underwent 57 intestinal transplants (Table 2). There were 37 allografts preserved in HTK and 22 in UW. Patients were found to belong to two age groups, ages three and under (Pediatric, n 15), and ages 14 to 66 (Adult, n 42). Recipient and donor demographics, and warm and cold ischemia times, were similar when comparing the UW and HTK study groups. Median flush volume during procurement varied according to donor size, but did not differ based on solution used. Perioperative and early transplant results are listed in Table 3. The HTK and UW groups did not differ in the incidence of intraoperative death or perioperative graft loss. The two groups did not differ in 30- and 90-day graft and patient survival. Initial allograft appearance and function, including surgical complications and rejection, did not differ between the HTK and UW groups (Table 4). The study groups did not differ with regard to early episodes of rejection or transplant bowel anastomotic leak. Initial appearance of the bowel mu-

3 300 Transplantation Volume 86, Number 2, July 27, 2008 TABLE 2. Donor and recipient demographics, indications, and operative data for intestinal allografts preserved in either HTK or UW HTK UW P value 6 Total n 35 (61) n 22 (39) Recipient gender Male 22/35 (63) 13/22 (59) 0.78 Recipient race White 29/35 (83) 21/22 (96) 0.23 Other 6/35 (17) 1/22 (4) Recipient age (yr) a 3 yr and younger 6/35 (17) 9/22 (41) 0.10 (median 1.4, 0.3 to 3.9) Age 14 and older 29/35 (83) 13/22 (59) 0.50 (median 42, 14 to 66) Allograft transplanted Isolated small intestine 5/35 (14) 8/22 (36) (intestine alone) Modified multivisceral 3/35 (9) 2/22 (9) (stomach, duodenum, intestine, pancreas) Multivisceral (stomach, 27/35 (77) 12/22 (55) duodenum, intestine, pancreas, liver) Indication Pediatric (n 15) 6 9 Necrotizing 4/6 3/9 enterocolitis Gastroschisis/atresia 1/6 1/9 Volvulus 1/6 2/9 Microvillus inclusion 1/9 Pseudoobstruction 1/9 Retransplantation 1/9 Adult (n 42) Portomesenteric 9/29 6/13 thrombosis Short gut syndrome 6/29 3/13 Pseudoobstruction 1/29 3/13 Chron s disease 5/29 1/13 Nonresectable tumor 3/29 Retransplantation 2/29 1/13 Abdominal 3/29 1/13 catastrophe Donor gender Male 24/35 (69) 14/22 (64) 0.70 Donor race White 24/35 (69) 15/22 (68) 0.79 Other 11/35 (31) 7/22 (32) Donor age (yrs) Age 3 and younger 6/35 (17) 9/22 (41) 0.14 Age 4 to 18 18/35 (51) 8/22 (36) Age 19 and above 11/35 (31) 5/22 (23) TABLE 2. Continued HTK UW P value Cause of death Stroke 4/35 (11) 4/22 (18) 0.73 Trauma 21/35 (60) 13/22 (59) Other 10/35 (29) 5/22 (23) Flush volume b Donor weight 25 kg 1500 ml 1200 ml and less (n 16) Donor weight 36 kg 4000 ml 3000 ml and above (n 41) Total cold ischemia time (hr) Median, range 8, 5 to 14 8, 5 to Total warm ischemia time (min) Median, range 23, 13 to 47 28, 15 to Values in parentheses indicate percentage. a There were no recipients between ages 4 and 13. b There were no donors with weight between 25 and 36 kg. c Categorical variables compared using 2 test. Continuous variables compared using Mann-Whitney U test. TABLE 3. Comparison of intestinal transplant recipient outcomes for donor organs preserved in HTK or UW HTK UW P value Intraoperative death 0/35 (0) 0/22 (0) 1.0 Graft loss within 0/35 (0) 0/22 (0) d of transplant 30-d survival (n 57) Pediatric 6/6 (100) 7/9 (78) 0.49 Adult 23/29 (79) 13/13 (100) d survival (n 57) Pediatric 5/6 (83) 5/9 (56) 0.58 Adult 19/25 (76) 13/13 (100) 0.08 HTK and UW are compared within each subgroup using the 2 or Fisher s exact test, as appropriate. None of the statistical tests resulted in a P value 0.05 for comparison of HTK and UW. Values in parentheses indicate percentage. cosa on magnification endoscopy was equivalent. There were no episodes of transplant pancreatitis in the 44 patients (77%) receiving a pancreas with their intestinal transplant (UW 14, HTK 30). A Kaplan-Meier analysis of graft survival demonstrates no difference between HTK and UW up to 90- days posttransplant (Fig. 1). DISCUSSION Histidine-tryptophan-ketoglutarate has been adopted worldwide by many transplant centers for routine use in procurement of liver, kidney, and pancreas allografts. We have previously reported results from our center comparing HTK and UW as the primary preservation solution in liver (9, 11),

4 2008 Lippincott Williams & Wilkins Mangus et al. 301 TABLE 4. Overall summary of postintestinal transplant complications and endoscopy results for UW and HTK solutions Overall HTK UW P value Overall (61) 22 (39) Rejection Rejection within 24/53 15/31 (48) 9/22 (41) d of transplant Bowel leak 1/57 1/35 (3) 0/22 (0) 1.0 Values in parentheses indicate percentage. kidney (2, 3), and pancreas (5, 6) transplantation. This study is the only report comparing UW and HTK in ITx. From the small case series data presented in this analysis, the two solutions do not differ significantly in clinical intestinal transplant outcomes, for both pediatric and adult grafts. Graft survival does not differ in the perioperative period, and at 30- and 90-days posttransplant. Though our results do not reach statistical significance, there is a difference in survival for adult grafts preserved in HTK at 30- and 90-days. These graft losses were clearly related to a more aggressive approach by our newly established center as we gained increasing intestinal transplant experience. Several of the grafts were transplanted into patients critically ill in the intensive care unit, or debilitated patients with poor functional reserve. As evidence of this aggressiveness, our center has had no deaths among adult patients listed for ITx, and our median waitlist time to intestinal transplant is 2 months. Organ preservation solutions are critical to the success of routine organ transplantation. These solutions provide the additional time necessary for transport of organs, tissue matching, preparation of the recipient, and they maintain organ quality during cold ischemia. Various solutions for these purposes have been introduced in the decades since solid organ transplantation was introduced. University of Wisconsin solution has survived as the gold standard solution in many areas of the world. However, as with other areas of medicine, new products are introduced that provide similar outcomes at a significant cost savings. This argument appears to be the case for HTK preservation solution. Our center has studied the use of this product in all abdominal solid organ transplants. We have never been able to identify a difference in early graft function, graft survival rates, or incidence of complications or rejection in kidney, pancreas, or liver transplantation. Intestinal allografts preserved with the two solutions are clinically indistinguishable by initial mucosal appearance on magnification endoscopy and by serial biopsy of the transplant bowel. The Indiana Organ Procurement Organization adopted HTK for routine use in Using HTK, Indiana Organ Procurement Organization realizes a cost savings of $300 to 400 per donor, as our center uses HTK flush volumes essentially equivalent to those used for UW. It should be noted that several U.S. centers still refuse to accept HTK in the initial flush of the donor organs. As multiple teams may be working simultaneously to procure the abdominal organs, it is important to establish a consensus regarding an acceptable preservation solution. To this point, because UW is the gold standard solution for abdominal solid organ preservation, if any one participating center is insistent on the use of UW, then all participating centers should accept this option. For our center, initial flush with HTK or UW is acceptable for all abdominal organs. We have had experience with incomplete clearance of grossly visible blood from the vessels of the mesentery of the small intestine with UW. In a select number of cases, we have performed a subsequent back table flush with HTK, after a previous on-table flush with UW, and seen immediate clearance of the residual blood with the less viscous HTK. Mixing of HTK and UW has not been previously reported, and we cannot comment on the consequences of this practice. We have recently published our experience with HTK and UW in extended criteria livers (11). In this analysis of 698 consecutive, adult deceased donor transplants, there was a trend towards less biliary complications in the HTK study group. Thorough flushing of the peribiliary arterial tree may FIGURE 1. Kaplan-Meier graft survival for intestinal allografts preserved in University of Wisconsin (UW, n 22) and histidine-tryptophan-ketoglutarate (HTK, n 35) preservation solutions up to 90-days posttransplant. Log-rank P 0.35.

5 302 Transplantation Volume 86, Number 2, July 27, 2008 be an important step in avoiding postliver transplant biliary complications (13, 14). The low viscosity HTK may provide a better flush of these small vessels when compared with UW. Clinically, we have noted an improvement in the clearance of blood during intestinal procurement for HTK when compared with UW. The arterioles of the small bowel mesentery are easily visible under loupe magnification during procurement. On occasion, we have noted an incomplete flush of blood from these vessels when UW is used for procurement. On several occasions, we have subsequently performed a backtable flush with HTK and had immediate clearance of the residual blood. Rapid exsanguination and uniform achievement of hypothermia are two of the primary principles of organ preservation, and HTK may perform better than UW in achieving these goals because of its low viscosity. Other goals of organ preservation, such as prevention of cellular swelling and the maintenance of cellular integrity and ionic composition, are not assessed by the present study. However histologically, we have not noted a difference between organs preserved in either solution. A concern with the use of UW in multivisceral transplantation is the potassium load maintained within the organs before reperfusion. A multivisceral graft contains a proportionally higher volume of transplant organs to patient size when compared with single organs transplants. This may result in a larger potassium load being released at the time of reperfusion. Histidine-tryptophan-ketoglutarate contains 8% of the amount of potassium contained in UW and potentially ameliorates this effect. It has been suggested that UW performs better in organ preservation for prolonged cold ischemia times. This study cannot address this issue as we strive to minimize cold ischemia time in all patients. The maximum cold ischemia time in this analysis was 14 hr for a multivisceral graft, but the median time in each group was 8 hr. These short times may limit the impact of preservation solution choice on outcome. This may explain, in part, the equivalence seen in the solutions. University of Wisconsin solution may indeed perform better for prolonged cold ischemia time, but this cannot be determined from our data. In conclusion, this study is the only published report comparing HTK and UW in routine use in ITx at a large volume center. Results of this analysis suggest that graft function, and patient and graft survival, compare favorably between UW and HTK-preserved intestinal grafts within short cold and warm ischemia times. University of Wisconsin solution or HTK may be superior in certain clinical situations, such as prolonged cold or warm ischemia time, but further study would be required to delineate the impact of preservation solution on each of these factors individually. 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