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John J. Fung, M.D., Ph.D. Cleveland Clinic Foundation Transplant Center

Organ Preservation with Histidine-Tryptophan-Ketoglutarate (HTK) Solution with an Emphasis on Non-Heart Beating Donors (NHBD). John J. Fung, M.D., Ph.D. Cleveland Clinic Foundation Transplant Center. Organ Preservation.

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John J. Fung, M.D., Ph.D. Cleveland Clinic Foundation Transplant Center

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  1. Organ Preservation with Histidine-Tryptophan-Ketoglutarate (HTK) Solution with an Emphasis on Non-Heart Beating Donors (NHBD) John J. Fung, M.D., Ph.D. Cleveland Clinic Foundation Transplant Center

  2. Organ Preservation Preservation solutions are used to maintain the organ in optimal condition from the time of explantation until transplantation

  3. Ischemia • Decreased mitochondrial function • Anaerobic conditions - depletion of ATP • Alterations in ion permeability • Accumulation of lactate • Accumulation of hypoxanthine • Cell swelling • Cytosolic calcium accumulation

  4. Reperfusion • Generation of reactive oxygen species • Increased oxidative stress • Lipid peroxidation of cellular membranes • Free radical formation leads to cellular destruction • Results in macrophage/Kupffer cell activation • Increased serum tumor necrosis factor (TNF) • Damage can lead to prolonged hypoxia after reperfusion

  5. Principles of Liver Preservation • Exsanguination to reduce intravascular thrombosis • Hypothermia to reduce cellular metabolism • Maintain cell membrane integrity to avoid cellular swelling • Susceptibility to cold ischemic injury: vascular endothelium > hepatocytes

  6. History of Organ Preservation • Simple cooling with cold solution • Continuous hypothermic perfusion • Collins (1967) • Euro-Collins (1980) • University of Wisconsin - ViaSpan (1986) • HTK - Custidiol (1980’s) • Celsior - 1994

  7. Component Eurocollins UW HTK Celsior Sodium (mmol/L) 10 40 15 100 Potassium (mmol/L) 107 120 10 15 Magnesium( mmol/L) - 5 4 13 Calcium (mmol/L) - - 0.015 0.25 Sulfate (mmol/L) - 5 - - Lactobionate (mmol/L) - 100 - 80 Phosphate (mmol/L) 57 25 - - Raffinose (mmol/L) - 30 - - Adenosine (mmol/L) - 5 - - Glutathione (mmol/L) - 3 - 3 Allopurinol (mmol/L) - 1 - - Ketoglutarate/Glutamic Acid (mmol/L) - - 1 20 Histidine (mmol/L) - - 198 30 Starch (gm/L) - 50 - - Mannitol (mmol/L) - - 30 60 Glucose (mmol/L) 194 - - - Tryptophan (mmol/L) - - 2 - Osmolalrity (mOsm/L) 355 320 310

  8. Euro-Collins Solution High potassium, glucose, and phosphate-based solution Designed to mimic composition of intracellular fluid Low cost Poor preservation quality Short preservation times achievable

  9. UW Solution • Use of impermeant molecules, lactobionate and raffinose, in preventing cell swelling • First developed for and applied in preservation of canine pancreas • Hydroxyethyl starch to minimize interstitial edema during machine perfusion, not necessary during cold storage • High [K+], low [Na+]

  10. Southard and Belzer

  11. UW Solution: Disadvantages • Glutathione is oxidized during storage: addition of fresh GSH immediately before use; other additives • High viscosity • Solution cannot be released into circulation (high K content) • Huge particles ~ 100 µm in diameter contained in original solution: must use in-line filtration with 40 µm pore size.Particles caught in capillary bed of perfused organ, resulting in vascular constriction, impeded reperfusion, and reduction of functional recovery

  12. Crystals in UW solution stored at sub-zero temperatures (a) perfused livers (b) pancreas (c) kidneys (d) Tullius et al: AJT2:627

  13. M.M. Gebhard, H.J. Kirlum, C. Schlegel. Organ preservation with the solution HTK

  14. HTK Solution (Custodiol) • Developed as cardioplegia • Low potassium, high sodium • No colloid - viscosity equal to that of pure water from 1 to 350C, with mean flow rate 3X that of UW solution at equal perfusion pressure - organs exsanguinate and cool down to lower temperatures more rapidly than with UW

  15. Status of Clinical Use of HTKSolution (Custodiol)

  16. Kidney Transplantation • de Boer et al: Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-collins. Transplant Int, 1999, 12:447 • UW (168) vs EC (155) vs HTK (336), • DGF: 33% UW vs 43% EC* vs 31% HTK • 3-year Graft survival: UW (68%), HTK (73%), EC (67%) • Conclusions: HTK is comparable to UW in its preservative capabilities in cadaveric renal transplantation Factors influencing DGF: Donor age, cause of death, CIT

  17. J. De Boer, et al. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK, UW and Euro-Collins (Transplant Int, 1999)

  18. J. De Boer, et al. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK, UW and Euro-Collins (Transplant Int, 1999)

  19. J. De Boer, et al. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK, UW and Euro-Collins (Transplant Int, 1999)

  20. J. De Boer, et al. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK, UW and Euro-Collins (Transplant Int, 1999)

  21. Liver Transplantation • Hatano et al: Hepatic preservation with histidine-tryptophan-ketoglutarate solution in living-related and cadaveric liver transplantation. Clinical Science (1997), 93:81 • LRD liver: HTK (15) vs UW (49) • CAD liver: HTK (30) vs UW (18) • Lower transaminases • Improved bile flow • No difference in survival or rejection rates

  22. E. Hatano, et al. Tissue oxygenation in living related liver transplantation (Clinical Science, 1997) LRLT Intraoperative changes in mean value of oxygen saturation of Hb at 10 points in liver graft After reflow of operation

  23. E. Hatano, et al. Tissue oxygenation in living related liver transplantation (Clinical Science, 1997) Cadaveric Intraoperative changes in mean value of hepatic tissue oxygen saturation of Hb at 10 points in liver graft

  24. E. Hatano, et al. Tissue oxygenation in living related liver transplantation (Clinical Science, 1997) LRLT CV of oxygen saturation of Hb at 10 points in liver graft, indicating heterogeneity of tissue oxygenation After reflow of operation

  25. E. Hatano, et al. Tissue oxygenation in living related liver transplantation (Clinical Science, 1997)

  26. Liver Transplant Patient Survival Hannover (1988 - 2000) % HTK (n = 400) UW (n =4 92) P < 0.0331 (LogRank) years

  27. Liver Transplants Graft Survival Hannover (1988 - 2000) % HTK (n = 461) UW (n = 607) P < 0.0029 (LogRank) years

  28. HTK and UW for Liver PreservationHannover (1988 - 2000) n = 1068 • < 5 days after transplantation HTK UW • n 461 607 • PF 439 578 • INF 22 29 • INF % 4.8 % 4.8 % • p = 1.00

  29. HTK and UW for Liver PreservationHannover (1988 - 1998) n = 836 • Biliary Tract Complications HTK UW • n 305 531 • BTC 39 65 • BTC % 12.8 12.2

  30. HTK and UW for Liver PreservationHannover (1988 - 2000) n = 1068 • CIT >15 hours HTK UW • n 36 154 • PF 34 143 • INF 2 11 • INF % 5.6 7.1 • p = 1.000

  31. HTK vs. UWPatients and Methods Patients 123 120 Adults, 3 Children; Age 1 - 70 years Transplantations: Total 134 Cadaveric:123 primary, 10 secondary, 1 tertiary 114 standard orthotopic, 5 split, 4 partial Living donation : 11 (right lobe) Combined:6 kidney transplantation 1 bone marrow transplantation 1 heart and kidney transplantation Preservation solution:63 HTK und 71 UW

  32. HTK vs. UWInitial Liver Function HTK UW OLT total 63 71 Initial function (IF) 45 (71.5%) 43 (60.5%) Initial dysfunction (IDF) 13 (20.6%) 26 (36.6%) Initial nonfunction (INF) 5 (7.9%) 2 (2.8%)

  33. HTK vs. UWBiliary Complications HTK UW Bile duct necrosis 3 (16, 17, 485 d) 3 (44, 10, 8, 46 d) Localized strictures 2 (72, 150 d) 2 (210, 305 d) Diffuse strictures (ITBL) - 3 (610, 210, 365 d) Total 5 8 ITBL = ischemic type biliary lesion

  34. HTK vs. UW Biochemical Parameters HTK UW AST max(U/l) 1320 + 1254 1389 + 1214 “ pod 7 (U/l) 26.7 + 17.5 24.3 + 18.4 AP pod 7 (U/l) 159.7 + 94.6 214.8 + 109.2 GGT pod 7 (U/l) 81 + 52.9 84.6 + 59.5 Bilirubin pod 14 (mg/dL) 9.5 + 9.7 13.8 + 12.6

  35. Pittsburgh Protocol • Trial of HTK in 100 consecutive standard multiorgan donors - comparison group was historic (UW) age matched controls (2:1) for age, CIT, organs removed and transplanted using CORE donor database. Outcomes to include: • Patient and graft survival • Initial function vs. DGF vs. PNF • HTK was used on all NHBD and liver alone donors

  36. Patients HTK UW Donors 84 169 Gender 49 M, 35 F 98 M, 71 F Age 2 Wks - 75Y 3Y - 75Y (47) (46) (43.3 + 19) (43.7 + 18.8) Recipients Gender 62 M, 22 F 101 M, 68 F Age 2Y - 71Y 1Y - 73Y (50) (52) (49.7 + 13) (50.3 + 12.3)

  37. Liver Transplantation, CadavericUW / HTK Age D/R 43.7+18.8 (3-75) / 50.3+12.3 (1-73) Age D/R 43.3+19 (1wk-75) / 49.7+13 (2-71) CIT 619+191 CIT 616+193 AST1 1293+2907 Median: (597) (97-31490) AST1 1489.2+2404 (595) (72-15750) ALT1 834.9+1192 (483) (91-6552) ALT1 914.8+1131.3 (450) (85-7016) AST7 99.9+189.2 (51) (17-1969) AST7 72.9+64.4 (55) (12-498) ALT7 189.4+191.2 (137) (40-1408) ALT7 178.9+145.6 (139) (22-568)

  38. Graft Function HTK UW 84 (%) 169 (%) IGF 66 (78.5) 134 (79) DGF 16 (19) 15 (9) PNF 2 (2.2) 20 (11.8) CIT > 14 hours 13 (%) 27 (%) IGF 8 (62) 19 (70) DGF 3 (23) 5 (18.5) PNF 2 (15) 3 (11)

  39. 30-day Survival HTK UW 84 169 Graft 94% 83% Patient 96% 89% Re-OLTX 3 13 in 30 days HAT 2 4

  40. HTK vs. UW in LDLT Chan et. al. Liver Transplantation 2004; 10:1415-1421 (Hong Kong) UWHTK Number of patients 30 30 Age 38.5 35.5 CIT 112 (79 + 334) 111.5 (75 + 222) Biliary stricture* 10 (33%) 6 (20%) Pre-reperfusion flush Yes No Graft loss 0 1 Hospital mortality 0 0 Biochemicals: Same, except PT (higher in HTK) Cost analysis: UW $137.6 higher than HTK/patient * Not significant

  41. HTK vs. UW in LDLTA Prospective Study Testa et. al. Liver Transplantation 2003; 9:822-826 (Chicago and Essen) Donors: Right lobe Age: (33 + 10) 18 M, 12 F Recipients: Age: (49 + 9), 20 M, 10 F, MELD: 13.4 + 7.4 Mean Follow-up 13 + 7 months UWHTK Perfusion 14 16 Artery 1 mL/g 3 mL/g Portal vein 1 mL/g 1.5 mL/g Pre-reperfusion flush Yes No (practical advantage) CIT 147 + 44 144 + 40 Patient survival 79% 88% Graft survival 72% 83% PNF 1 0 HAT 1 1 Liver biochemical values: Similar No intrahepatic biliary stricture Overall: Equally effective. HTK has practical and economical advantage

  42. HTK solution for organ preservation in human liver transplantationA prospective multi-center observation study Pokorny et. al. Transplant International 2004; 17:256-260 (Austria, Germany) 214 patients in 4 European centers (1996-1999) 5 liters of HTK for preservation CIT 444 + 224 All vascular anastomoses completed before reperfusion No pre-reperfusion flush PNF 2.3%, Initial dysfunction 6.5% Graft dysfunction not correlated with CIT 1-year patient and graft survival 83% and 80% (unrelated to CIT) HTK: safe and effective and easy to use. Comparable to UW with less cost.

  43. HTK vs. UW in liver transplantationA meta analysis Feng et.al. Liver Transplant, 2007

  44. HTK vs. UW in liver transplantation A meta analysis P= 0.87 RR 1.01 Patient Survival P= 0.86 RR 1.01 Graft Survival Feng et.al. Liver Transplant, 2007

  45. HTK vs. UW in liver transplantationA meta analysis Feng et.al. Liver Transplant, 2007

  46. HTK vs. UW in liver transplantationA meta analysis • Cost: HTK cheaper than UW • Biliarycomplications: Trend for less biliary strictures with HTK • PNF, PDF, DGF: No difference • Graft survival: No difference • Patient survival: No difference • Biochemical values: No difference Feng et.al. Liver Transplant, 2007

  47. Kidney Transplantation, Cadaveric(HTK) Total of 198 kidneys recovered, 155 used • Immediate function: (53%%) CIT: 22 Hrs • Fair function : (30.6%) • ATN: (16.4%) CIT: 28 Hrs All functioning One kidney thrombosed shortly after transplant (technical) One kidney lost (hyperacute rejection) 39 kidneys were sent out of the OPO area Kidneys from NHBD: 75% primary function (12 transplanted, 4 discarded) 25% ATN with late function

  48. Pancreas Transplantation, Cadaveric(HTK) • 40 pancreata recovered • 20 used • 20 research • 19 used locally • One sent to another center (out of OPO) with kidney for K-P transplant with good function

  49. HTK vs. UW in Pancreas Transplantation Potdar et al. Clinical Transplantation 2004;18:661-665 (University of Pittsburgh)

  50. Kidney Transplantation, Cadaveric(HTK) Total of 198 kidneys recovered, 155 used • Immediate function: (53%%) CIT: 22 Hrs • Fair function : (30.6%) • ATN: (16.4%) CIT: 28 Hrs All functioning One kidney thrombosed shortly after transplant (technical) One kidney lost (hyperacute rejection) 39 kidneys were sent out of the OPO area Kidneys from NHBD: 75% primary function (12 transplanted, 4 discarded) 25% ATN with late function

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