Histidine-Tryptophan-Ketoglutarate (HTK) Is Associated With Reduced Graft Survival in Pancreas Transplantation
Stewart ZA, Cameron AM, Singer AL, Dagher NN, Montgomery RA, Segev DL
Am J Transplant. 2009;9:217-221
Increased Pancreatitis in Allografts Flushed With Histidine-Tryptophan-Ketoglutarate Solution: A Cautionary Tale
Alonso D, Dunn TB, Rigley T, et al
Am J Transplant. 2008;8:1942-1945
Histidine-Tryptophan-Ketoglutarate (HTK) Is Associated With Reduced Graft Survival of Deceased Donor Kidney Transplants
Stewart ZA, Lonze BE, Warren DS, et al
Am J Transplant. 2009;9:1048-1054. Epub 2009 Mar 3
Increased Primary Non-Function in Transplanted Deceased-Donor Kidneys Flushed With Histidine-Tryptophan-Ketoglutarate Solution
Stevens RB, Skorupa JY, Rigley TH, et al
Am J Transplant. 2009;9:1055-1062
Histidine-Tryptophan-Ketoglutarate (HTK) Is Associated With Reduced Graft Survival in Deceased Donor Livers, Especially Those Donated After Cardiac Death
Stewart ZA, Cameron AM, Singer AL, Montgomery RA, Segev DL
Am J Transplant. 2009;9:286-293
Summary
The 3 above studies by Stewart and colleagues are retrospective analyses using the United Network for Organ Sharing database for deceased-donor kidney, liver, and pancreas transplants performed from July 2004 through February 2008. In each of these analyses, after adjusting for other donor, recipient, graft, and transplant factors, preservation with histidine-tryptophan-ketoglutarate (HTK) solution was directly compared with organs preserved with University of Wisconsin (UW) solution.
In kidney transplantation, HTK preservation had no effect on delayed graft function (odds ratio [OR] 0.99) but was associated with an increased risk for death-censored graft loss (hazard ratio [HR] 1.20, P = .008), particularly late (> 1 year) graft loss (HR 1.43, P = .007). The detrimental effect of HTK preservation was much stronger in black recipients (HR 1.55, P = .024) compared with white recipients (HR 1.18, P = .5).
In liver transplantation, HTK preservation was associated with an increased risk for graft loss (HR 1.14, P = .002), especially in donation after cardiac death allografts (HR 1.44, P = .025) and in transplants with cold ischemia times over 8 hours (HR 1.16, P = .009). HTK preservation was also associated with a higher incidence of early (< 30 days) graft loss (OR 1.20, P = .012) with a more pronounced effect on liver allografts with cold ischemia times over 8 hours (OR 1.31, P = .007), donation after cardiac death allografts (OR 1.63, P = .09), and donors over 70 years of age (OR 1.67, P = .081).
In pancreas transplantation, HTK preservation was independently associated with an increased risk for pancreas graft loss (HR 1.30, P = .014), especially with cold ischemia times beyond 12 hours (HR 1.42, P = .017). Moreover, HTK preservation was associated with a higher risk for early (< 30 days) pancreas graft loss (OR 1.54, P = .008).
The other 2 single-center studies reported a preliminary retrospective experience chronicling an increased incidence of allograft pancreatitis, thrombosis, and postoperative complications in pancreas transplantation and an increased risk for primary nonfunction and early graft loss in kidney transplantation, especially with marginal donors or prolonged preservation times, in organs preserved with HTK solution.
Viewpoint
The above studies suggested that the use of HTK solution for abdominal organ preservation is associated with reduced kidney, pancreas, and liver graft survival, especially with longer preservation times and/or marginal donors. Unfortunately, in each of these studies, the volume of in situ aortic flush, which may be an important confounding factor, was either not analyzed or controlled.
HTK solution was introduced by Bretschneider as a cardioplegic solution in the 1980s and has been used as an organ preservation solution in Europe since this time and in North America since 2002. Advantages of HTK solution compared with UW solution are lower viscosity, which may permit more complete exsanguination and rapid cooling; lower potassium concentration; and lower cost per liter. The cost differential, however, is offset by the manufacturer recommendation of using a high-volume flush (8-10 L), or alternatively, at least 10 minutes of flushing at the time of organ procurement in order to optimize electrolyte equilibration across the cell membrane and ensure that the extracellular fluid compartment is completely replaced with HTK solution. Clinical experience has demonstrated that this high-volume flush may not be necessary and in fact may be detrimental, particularly for pancreas preservation. Limiting the flush volume until the venous effluent is clear may be a more practical, cost-effective, and safe strategy.
Previous randomized and single-center retrospective cohort studies have demonstrated the safety and efficacy of HTK compared with UW solution; therefore, the results reported in the above studies are unexpected and alarming. It is important to acknowledge limitations inherent to the above 3 observational studies using retrospective data from a large registry database, including possible selection bias, missing data, reporting error, and no data on confounding factors. Moreover, the remaining 2 additional studies cited above are from the same center, report small retrospective experiences, and may represent the "learning curve" for introducing and optimizing the use of a "new" preservation solution in clinical transplantation. Until new randomized studies are available that control for volume of flush, preservation time, and donor factors, one must question the safety and efficacy of using HTK solution in the setting of marginal donors, donation after cardiac death donors, and extended cold storage preservation times.
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