Comparison of histidine-tryptophan-ketoglutarate solution (HTK) and University of Wisconsin solution (UW) in adult liver transplantation

Abstract

Histidine-tryptophan-ketoglutarate solution (HTK) and University of Wisconsin solution (UW) have been shown to have similar outcomes in cadaveric kidney, pancreas, and liver transplantation. Our institution changed from UW to HTK as the primary preservation solution for liver, kidney and pancreas transplantation. This study compares the perioperative and first year outcomes of liver transplantation using UW or HTK. Primary use of HTK began on May 1, 2003. We reviewed the records of all adult liver transplant recipients from July 1, 2002 to December 31, 2004. Recipients were compared based on organ preservation solution (UW n=204, HTK n=174). Outcomes included 1-, 6- and 12-month graft and patient survival and 1-, 7-, 14-, and 30-day liver function and serum creatinine. During the entire study period, the two groups were managed similarly in operative technique, immunosuppressive regimens, and donor liver criteria. Over 30 months, 378 adult patients underwent liver transplantation. There were no significant differences between UW and HTK in 1-, 6-, or 12-month graft or patient survival. The HTK group had a higher day 1 median AST, ALT, and total bilirubin, but the two groups were similar thereafter. An anticipated difference in infused volume between UW and HTK was demonstrated. In conclusion, to our knowledge, this is the first reported large case series from North America comparing HTK and UW in liver transplantation with 2- to 12-month follow-up. There were no significant differences between HTK and UW in this population when comparing 1 month graft function and first-year graft and patient survival. Liver Transpl 12:226–230, 2006. © 2006 AASLD.

University of Wisconsin solution (UW) is the standard preservation solution in cadaveric liver, kidney, pancreas, and small bowel transplantation. The effectiveness of this solution has been demonstrated and has revolutionized the field of transplant surgery. Several competing preservation solutions have been developed, and studies comparing these solutions to UW are ongoing. Histidine-tryptophan-ketoglutarate preservation solution (HTK) was developed in the 1970s as a cardioplegia solution and has recently been used routinely by many centers in kidney, liver, and pancreas preservation.1–8 The composition of these solutions has been described in detail previously.9

UW was developed by Folkert O. Belzer and is based upon three philosophies: 1) osmotic concentration maintained by metabolically inert substrates, 2) additional administration of the colloid carrier hydroxyethylstarch (HES), and 3) addition of oxygen radical scavengers. UW provides organ tolerance to long cold ischemia times in a predictable manner. HTK was developed by H.J. Brettschneider as a cardioplegia solution. This solution is based upon a philosophy of a potent buffer system (Histidine), with two substrates (Tryptophan and Ketoglutarate). This very low viscosity solution was described as being infused at a low flow rate with a large total volume to achieve equilibrium.

UW was first compared to HTK in a randomized fashion in liver transplantation over a decade ago.4 In 60 patients, the two solutions were found to have similar outcomes, which included initial non-function, initial liver function tests, ICU stay, FFP use, and 30-month patient survival. There have been few follow-up studies directly comparing the two solutions. Additionally, there have been no North American studies in which UW and HTK are directly compared.

On May 1, 2003, our abdominal solid organ transplant center adopted HTK for use in all abdominal organ procurements within our organ procurement area, with the exception of small bowel and combined multi-visceral graft procurements. We compared the outcomes for UW and HTK preserved organs from July 1, 2002 until December 31, 2004. These dates provided a sufficient time period before and after the adoption of HTK to allow for comparison of a similar number of recipients. Our outcomes include 1-, 6-, and 12-month patient and graft survival and 1-, 7-, 14-, and 30-day liver function and serum creatinine and incidence of primary non-function. Overall costs per donor for each solution are also compared and a cost effectiveness analysis is presented.

HTK, Histidine-tryptophan-ketoglutarate solution; UW, University of Wisconsin solution.

MATERIALS AND METHODS

Data for all adult liver transplants over a 30-month period were reviewed (n=378). During this period, UW was the primary preservation solution used by our center between July 1, 2002 and May 1, 2003. Thereafter, HTK was the primary preservation solution. However, we frequently received livers procured by out-of-area surgeons in which either UW or HTK had been used (95/378 procured by outside surgeon). Additionally, our center frequently procures organs in outside regions and we occasionally use the preservation solution made available by the local organ procurement organization. Our local organ procurement organization records the preservation solution for all organs either procured locally or imported from other regions. Information regarding preservation solution utilized was not routinely requested at the time of donor liver offer and had no bearing on the use or non-use of a donor liver. The database also includes total volume of infused solution. Procurement technique consisted of an en-block technique with initial aortic flush followed by back table portal vein flush. We obtained total cold ischemia time for each organ from the UNOS database. Recipient immunosuppression included thymoglobulin induction and maintenance with either tacrolimus monotherapy or combined therapy with mycophenolate mofetil. Intra-operative pre-reperfusion flush was done routinely, for both UW and HTK, with 3 L of a mixed colloid solution (normal saline and albumin). Although not required by the manufacturers, all livers were routinely flushed with this solution in order to standardize the procedure at our center.

Primary transplant outcomes included 1, 6 and 12-month graft and patient survival, and 1-, 7-, 14-, and 30-day AST, ALT, total bilirubin, alkaline phosphatase, and serum creatinine. The two solutions were compared for incidence of primary non-function. All patients received a minimum of daily labs while in-patient and twice weekly labs in the first month after hospital discharge. All of these labs were recorded in our transplant database and were extracted for this analysis. All occurrences of graft loss or patient death were included in the final analysis regardless of the etiology. There were no exclusions for intra-operative or perioperative mortality or graft loss or for non-liver related deaths. In patients receiving a second transplant within 30-days of the first transplant, the second transplant was excluded from analysis, though the first transplant remained in the final results. This study was reviewed and approved by the Indiana University School of Medicine institutional review board.

Statistical analysis was conducted using commercially available software (SPSS, SPSS, Inc., Version 13.0, 2004). Graft and patient survival and primary non-function were analyzed at each time point using a chi-square test. Laboratory values were non-normal in their distribution and therefore median values were compared using the Median test. UW and HTK differences were considered significant for a P-value < 0.05.

RESULTS

During the study period, 378 adults underwent cadaveric whole organ liver transplantation. Recipient ages ranged from 18 to 74 (median 54) and did not differ in the UW and HTK groups. These groups were also similar in recipient gender (66% male) and primary diagnosis (41% hepatitis C) (Table 1). There were 204 livers preserved with UW and 174 with HTK. Follow-up time for recipients ranged from 2- to 12-months (n=253 with 12-month follow-up). Donor ages were the following [(UW/HTK (years)]: median 45/46; mean UW, HTK 44.9/46.1; and range 12-69/23-76. Cold ischemia time for the groups were the following [UW/HTK (hours)]: mean 7.7/6.8, median 7/7, and range 3-20/3-13. Twelve donor livers had cold ischemia time greater than 12 hours (UW 9, HTK 3). Steatosis was not routinely recorded as our group infrequently requests biopsy of donor livers in deciding to use an organ.

Table 1. Recipient Demographics Categorized by Preservation Solution Used in Donor

	ALL (%)	UW Solution	HTK Solution
NUMBER	378	204	174
Age
Mean	54	53	54
Median	54	53	54
Range	18 to 74	18 to 72	18 to 74
Gender
Male	249 (66%)	141 (69%)	108 (62%)
Re-transplant	15 (4.0%)	5 (2.5%)	10 (5.7%)
Primary diagnosis
Viral hepatitis	155 (41%)	90 (45%)	65 (37%)
Alcoholic liver disease	39 (10%)	24 (12%)	15 (9%)
NASH	34 (9%)	13 (6%)	21 (12%)
Cryptogenic	36 (10%)	14 (7%)	22 (13%)
Autoimmune	21 (6%)	11 (5%)	10 (6%)
HCC/Cholangiocarcinoma	13 (4%)	8 (4%)	5 (3%)
PSC	35 (9%)	18 (9%)	17 (10%)
PBC	19 (5%)	9 (4%)	10 (6%)
Metabolic/Fulminant/Other	16 (4%)	8 (4%)	8 (5%)
HBV	8 (2%)	7 (4%)	1 (1%)

Graft and patient survival in the first year post-transplant are shown in Table 2. Overall graft and patient survival were 81% and 83%, respectively. The overall incidence of primary non-function was 1%. The UW and HTK groups did not differ significantly at any measured time point for graft or patient survival. The two groups did not differ in the incidence of primary non-function (UW 1.5%, HTK 0.5%).

Table 2. One, 6 and 12-Month Graft and Patient Survival Data for UW and HTK Preservation Solutions for Liver Transplantation

	1-Month	6-Month	12-Month
p = NS for comparison of UW and HTK at all time points. Follow-up numbers: 1-month UW n = 204, HTK n = 174, Total n = 378; 6-months UW n = 195, HTK n = 138, Total n = 333; 12-months UW = 175, HTK = 78, Total n = 253.
Graft survival
UW	91.7%	86.2%	81.7%
HTK	92.0%	85.5%	80.8%
Patient survival
UW	93.1%	87.7%	84.6%
HTK	93.1%	86.2%	82.1%

Analysis of post-transplant laboratory data demonstrated that recipients of UW and HTK preserved grafts differed significantly only on post-transplant day 1 in median serum AST, ALT, total bilirubin, and alkaline phosphatase. The two groups were identical for all time points thereafter. The HTK group did have a persistently higher total bilirubin level at post-operative days 1, 7, and 14, but this was similar to the level in the UW group by day 30. Both groups had a trend of increasing serum creatinine in the first month. Intra-operative use of blood products was not routinely recorded in the transplant database, though no clinical difference was noted between the solutions. Post-operative day 1 INR was equivalent between UW and HTK (mean 1.6/1.5 and median 1.4/1.4) and was not closely followed thereafter.

Within the group of HTK-preserved livers, survival outcomes did not vary by recipient age, gender, or primary diagnosis. For HTK-preserved livers, there was one case of primary non-function and four cases of peri-operative vascular thrombosis. Twelve patients in the HTK group died within 1 month of transplantation (7%) compared to 14 in the UW group (7%). The HTK group deaths were attributed to sepsis (8), myocardial infarction (2), primary non-function (1) and hyperacute rejection (1), while the UW group deaths were attributed to: sepsis (5), myocardial infarction (3), primary non-function (2), hemorrhage (2), hepatic artery thrombosis (1), and stroke (1).

Mean infused volumes of each preservation solution were the following: UW 3,200 ± 1,400 ml and HTK 3,800 ± 1,000 ml and include back table flush, where applicable. According to current charges reported by our organ procurement organization (HTK $150/liter and UW $310/liter), these flush volumes correspond to a cost-savings of $422 per donor when using HTK solution.

DISCUSSION

HTK has been adopted by many transplant centers for routine use in procurement of liver, kidney, and pancreas. This study is the first large scale report comparing UW and HTK in general use for liver transplantation. The two solutions appear indistinguishable in clinical outcomes including 1-year graft and patient survival, primary non-function, and 1-month initial function. A significant difference was noted in post-operative day 1 AST and ALT, though these values were equivalent by post-operative day 7, and the difference did not appear to have any clinical relevance. This study did not find any evidence of adverse event specifically related to HTK usage after 174 liver transplants.

Clinical evaluation of HTK has been relatively sparse, in spite of its excellent safety record and potential cost savings over UW. Gubernatis and colleagues published their first clinical experiences in Germany with HTK in liver transplantation in 1990.2 The subsequent German randomized, controlled trial found no differences in primary non-function and 30-month patient survival in 60 patients.4 In 1997, Hatano and colleagues reported a comparison of UW and HTK in 64 patients (HTK 15 vs. UW 49) undergoing living-related liver transplantation at Kyoto University Hospital in Japan. There were no incidences of primary non-function in this group and peak post-operative amino transferases were lower in the HTK group. Long-term graft and patient survival were not reported. This same paper reports on 48 cadaveric liver transplants at the Mediinische Hochshule Hannover (Germany) in which 30 livers were preserved with HTK and 18 with UW. The 1-month mortality was HTK 20% and UW 26%. Both of these groups had improved hepatic oxygenation (measured intraoperatively from hepatic vein) in the HTK-preserved livers.3) Lange and colleagues published the results of 70 liver transplants over 30-months time, 51 preserved with UW and 19 with HTK solution. There were no occurrences of primary non-function in HTK-preserved livers and four in UW-preserved livers (0% vs. 7.8%). There was 1 HTK-preserved liver with delayed function compared to four UW-preserved livers (5.3% vs. 7.8%). Long-term outcomes were not reported..10 Canelo and colleagues reported on 123 liver transplants in which 63 were preserved with HTK and 71 with UW. They report no significant difference between HTK and UW in patient and graft survival ICU stay and initial liver function values. Both groups, though, had high rates of graft dysfunction and nonfunction (HTK 28.5% and UW 39.4%).11) Most recently, a prospective, observational, multi-center European study reported on 214 patients receiving HTK preserved liver grafts. Primary dysfunction rate in this group was 8.8% with primary non-function 2.3%. One-year graft and patient survival were 83% and 80%, respectively.12 Two groups have presented data on UW and HTK in living-related liver transplantation. Chan and colleagues found no difference between HTK and UW in 60 right lobe liver transplants when comparing liver function tests, use of blood products, complications, length of stay, and graft and patient survival.13 Testa and colleagues prospectively followed right lobe liver transplants and reported no difference in post-operative biochemistries, complications, or patient and graft survival.14

The earliest studies of HTK preservation in clinical liver transplantation reported use of large volume flush (10 to 20 L). In the German studies, a volume of 10 to 20 L of HTK was used compared to 4 L UW solution.2–4 In our case series, the HTK-preserved livers received an average of only 600 cc more preservation solution than the UW-preserved livers (HTK 3,800 cc vs. UW 3,200 cc). These results suggest that large volume infusion of HTK solution is unnecessary to achieve safe organ preservation. This finding, then, translates into a significant cost savings for use of HTK solution over UW solution as HTK solution is significantly less expensive per unit of volume. The cost for HTK as quoted by our local organ procurement organization is $150 per liter, while UW is $310 per liter. For the volumes reported in this analysis, these costs result in a total cost of $570 per donor for HTK and for UW $992. This is a cost savings of $422 per donor. Our organ procurement organization has an annual volume of 160 donors. HTK, therefore, represents of local cost savings of $67,520 yearly for equivalent outcomes for liver transplantation.

In conclusion, this study is the first published report of successful routine use of HTK in liver transplantation in a large, North American transplant center. Results of this analysis suggest that graft function and patient and graft survival is equivalent between UW and HTK-preserved livers. Our total infused volume of HTK during procurement suggests that much lower flush volumes than previously described can be safely utilized without adverse consequences. Use of HTK may provide significant cost savings to organ procurement organizations. 1, 2

Figure 1. Serum transaminase and alkaline phosphatase.

Figure 2. Serum total bilirubin and creatinine.