title: Hamster to rat kidney xenotransplantation. Effects of FK 506, cyclophosphamide, organ perfusion, and complement inhibition.
abstract: Hamster to rat renal xenotransplantation was performed with recipient nephrectomies. Recipients were treated beginning on day 0 with continuous FK 506 monotherapy, a 7-day or open-ended monotherapeutic course of cyclophosphamide (CP), and the two drug regimens combined. CP alone (10 mg/kg/day) prevented a xenospecific antibody response and tripled median survival of the kidney (defined as recipient death) from 6 (control) to 18.5 days whereas FK 506 alone had no effect. The drugs in combination were no better than CP alone (15 days) unless the 5-day course of CP was given at a higher dose (15 mg/kg) and started 3 days preoperatively (79 days). In further experiments, adjuvant measures were added to the minimally effective FK 506/7-day CP regimen which gave a median survival of only 15 days. In the most successful modification, intraoperative antibody depletion by the temporary transplantation of third party hamster liver or en bloc kidneys increased median survival from 15 to 34 and 48 days, respectively. An intraoperative i.v. dose administration of the anticomplement drug K76 instead of antibody depletion increased survival to 26 days. Although the events of kidney rejection were similar to those of heart xenografts and partially forestalled by the antibody inhibiting CP treatment, or by antibody depletion, survival for > 100 days was accomplished in only 5 of 86 treated animals. The poorer survival previously reported with cardiac xenotransplantation is largely explained by the life support requirement of the kidneys. Renal failure was responsible for almost all deaths before 60 days, and subnormal renal failure was a pervasive adverse factor thereafter, frequently caused by pyelonephritis which is suspected to have had an immunologic etiology.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: H
authors.initials: H
authors.lastname: Miyazawa
authors.forename: N
authors.initials: N
authors.lastname: Murase
authors.forename: A J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: Q
authors.initials: Q
authors.lastname: Ye
authors.forename: R
authors.initials: R
authors.lastname: Manez
authors.forename: S
authors.initials: S
authors.lastname: Todo
authors.forename: T E
authors.initials: TE
authors.lastname: Starzl
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000473:pathology; D003176:Complement C3 / Q000032:analysis / Q000378:metabolism; D006224:Cricetinae; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006085:Graft Survival; D006877:Hydroxamic Acids / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D011292:Premedication; D051381:Rats; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods / Q000473:pathology
chemical_list: D003176:Complement C3; D006877:Hydroxamic Acids; C003486:2-methyl-3-(4-phenylpiperidino)propionohydroxamic acid hydrochloride; D003520:Cyclophosphamide; D016559:Tacrolimus