The immunosuppressive agent FK permitted increased kidney transplant survival in dogs over a wide dose range, but with weight loss and manifold evidence of toxicity. The best use of FK at low doses was in combination with CyA and Pred

Casavilla, A

Cemaj, S

Demetris, AJ

Ghalab, A

Imventarza, O

Makowka, L

Mazzaferro, V

Okuda, K

Rhoe, BS

Starzl, TE

Todo, S

Tonghua, Y

Ueda, Y

English

Name not available

Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids

D-Scholarship@Pitt

Canine Kidney Transplantation With FK-506 Alone or in Combination With Cyclosporine and Steroids S. Todo, A.J. Demetris, Y. Ueda, O. Imventarza, K. Okuda, A. Casavilla, S. Cemaj, A. Ghalab, V. Mazzaferro, B.S. Rhoe, Y. Tonghua, L. Makowka, and T.E. Starzl I N THIS STUDY, the new drug FK-S06 (FK) was tested in dogs for its ability to prevent rejection of kidneys when given alone, with small doses of cyclosporine or steroids, or both. MATERIALS AND METHODS Mongrel donors weighing 13 to 15 kg provided kidneys for beagle recipients of the same size under 25 mg/kg pentobarbital anesthesia intravenously. When needed, supplementary pentobarbital or ketamine, 2 mg/kg, or both, were given intravenously. The renal grafts were placed intraabdominally by connecting the renal artery and vein to the recipient iliac vessels and using uretero-neocystotomies. The recipient native kidneys were removed at the same operation. One gram of cephalospo-rin was given intravenously or intramuscularly during the operation and for three days afterwards. A diet was started the next day. All immunosuppressive drugs were given orally start-ing on the morning after transplantation and continuing daily. To prevent vomiting caused by FK or other postop-erative factors, 2 mg atropine sulphate was given intra-muscularly twice a day for the first week and once a day for the second week. During the third week, the atropine dose was reduced to I mg/d. The FK was provided in powder form by the Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan, and placed in commercial capsules. The dogs were docile well-trained beagles who allowed deep digital placement of the cap-sules in the oropharynx. Prednisone (Pred) was given as a 5 mg tablet. Cyclosporine (CyA) in the commercial oil carrier used clinically was given orally by syringe. FK Administration Alone FK was the sole immunosuppressive treatment. The animals were placed in four groups: I, untreated control, n - 6; II, FK (0.5mg/kg/d), n - 6; III, FK (1.0 mg/kg/d), n ~ 6; and IV, FK (1.5 mg/kg/d), n = 6. FK in Combination The smallest dose in the foregoing studies (group II, 0.5 mg/kg/d) or half this dose was combined with small doses of other agents as follows: group V, FK (0.5 mg/kg/d), CyA (5.0 mg/kg/d), Pred (5.0 mg/d), n - 6; group VI, FK (0.25 mg/kg/d), eyA (2.50 mg/kg/d), Pred (2.5 mg/d), n = 6; and group VII, CyA (5.0 mg/kg/d), Pred (5.0 mg/d), n - 6. The results in group II were considered to be a single-agent control for those obtained with the triple-drug combination of group V. The animals of group VII who received CyA and Pred were considered controls for the triple-drug, FK-containing regimen of group V. Biochemical and Pathological Studies Blood samples were taken every three mornings for the measurement of levels of blood urea nitrogen, creatinine, SGOT, and total bilirubin. Complete postmortem exami-nation was performed immediately after the animals died. Tissues were fixed with formalin and stained with hema-toxylin and eosin. Histopathologic changes were scored blindly according to a subjective scale from I to 4. Statistics The Wilcoxon rank sum test and Student's t test were applied for the stitistical analysis. RESULTS The outcome in each individual experiment is summarized in 'Table 1. The untreated animals died of rejection in eight to 19 days. Survival was significantly prolonged with all doses of FK, the best results being with 1.S mg/kg. With this high dose, rejection as judged histopathologically was absent or mild in the two animals who provided tissue for histopathologic analysis. The other four are alive after 39 to 71 days. Increases in serum creatinine levels caused by rejection were From the Department of Surgery, University Health Center of Pittsburgh, and the Veterans Administration Medical Center, Pittsburgh. Supported by research grants from the Veterans Administration and Project Grant No. AM-29961 from the National Institutes of Health, Bethesda, MD. Address reprint requests to T.E. Starzl, MD, PhD. Department of Surgery, 3601 Fifth Ave, Folk Clinic. Pittsburgh, PA 15213. © 1987 by Grune & Stratton, Inc. 0041-1345/87//905-6011$03.0010 Transplantation Proceedings, Vol XIX, No 5, Suppl6 (October), 1987: pp 57-61 57 Table 1. Effect of FK Dose on Results of Canine Kidney Transplantation Latest Value Histological OralOosage Animal Cause of Severity of Groups (mg/kg/d) No. Survival (d) Oeath BUN (mg/d..) Cr (mg/d..) Rejection 0 3 19 Rejection 359 14.1 Severe 4 9 Rejection 154 8.2 Severe 5 12 Rejection 142 16.0 Severe 6 11 Rejection 271 13.5 Severe 7 8 Rejection 193 13.0 Severe 8 11 Rejection 135 8.7 Severe \I 0.5 102 16 Rejection 172 13.5 Moderate 104 24 Intussusception 44 1.1 Mild 109 >70 77 4.3 112 44 Rejection 195 5.1 Moderate 121 13 Rejection 336 7.7 Moderate 122 28 Rejection 140 14.4 Severe III 1.0 101 37 Unknown 154 2.5 Moderate 105 63 Unknown 24 1.0 Severe 108 16 Rejection 219 6.3 Severe 114 21 Unknown 59 2.9 Severe 123 14 Unknown 39 2.0 None 124 35 Unknown 41 1.5 Moderate IV 1.5 103 >71 20 1.0 107 28 Pancreatitis (?) 108 8.8 Mild 113 >67 20 1.3 125 17 Unknown 42 1.2 None 127 >44 19 0.9 133 >39 95 4.0 Abbreviation: Cr. creatinine. 25 ::J 20 "0 .... 01 E Q) c: c: to Q) ... U E ~ ... Q) rn 15 10 5 GROUP GROUP II GROUP III GROUP IV FK FK 0.5mg/kg/day FK 1.0mg/kg/day FK 1.5mg/kg/day Omg/kg/day o 20 40 0 20 40 60 80 o 20 40 60 80 o 20 40 60 80 Days after Kidney Transplantation * Alive Fig 1. Influence of FK dose on serum creatinine level. The rises in the serum creatinine concentration in animals of all groups were usually celJsed by rejection. FK-506 IN DOGS 59 Table 2. Histological Changes in Extrarenal Organs After Kidney Transplantation Under FK Liver HeM! Pancreas: " Acinar Cell Dosage Swelling of Fatty Change Infarction Degeneration Group (mg/kg/d) Hepatocytes of Hepatocytes Arteritis (Focal Large) (Focal Necrosis) 0 0/6 (0%) 1/6 (16%) 0/6 (0%) 0/6 (0%) 0/6 (0%) II 0.5 1/5 (20%) 1/5 (20%) 0/5 (0%) 0/5 (0%) 0/5 (0%) III 1.0 1/6 (16%) 0/6 (0%) 2/6 (33%) 2/6 (33%) 3/6 (50%) IV 1.5 1/2 (50%) 0/2 (0%) 1/2 (50%) 1/2 (50%) 2/2 (100%) minimized or avoided in animals receiving 1.0 and 1.5 mg/kg/d (Fig O. With doses of 0.5 mg/kg/d, rejection was always found histo-pathologically (Table 1), and elevated creati-nine levels were the rule (Fig 1). However, animals treated with the higher doses of FK had significant evidence on histo-pathologic examination of toxicity involving the liver, heart, and pancreas (Table 2). The findings were similar to those reported else-where in this symposium in dogs not subjected to transplantation. Vomiting and weight loss were common in all of the treatment groups. Severe emaciation with loss of more than 30% of the body weight was seen in four of the 18 FK-treated animals. Two animals each in groups II and III died with severe rejection plus lethal emaciation. FK in Combination Five of six dogs in group V that were treated with 0.5 mg/kg FK, 5 mg/kg CyA, and 5 mg Pred are alive with normal renal function after 51 to 71 days. The survival results (Table 3) were better than those in group II in which 0.5 mg/kg FK was used alone (P < .01) and better than those in group VII in which 5 mg/kg Cy A and Pred were given (P < .01). None of the animals in group V lost body weight. The superiority of the triple-drug combina-tion of group V was also evident from the serum creatinine levels (Fig 2). However, the three drugs when given at half dosage (group VI) were no longer effective (Table 3 and Fig 2). Table 3. Combination Therapy With Low Doses of FK. CyA. and Prad After Canine Kidney qrans~lantation Treatment Dose Animal Cause of Latest Value Groups (Oral) No. Survival (d) Death BUN (mg/c:l.) Cr (mg/c:l.) V FK. 0.5 mg/kg/d 106 >71 16 1.0 eVA, 5/0 mg/kg/d 115 23 Unknown 159 3.2 Pred, 5.0 mg/d 116 >60 24 1.3 118 >53 16 1.2 119 >51 29 1.0 120 >51 24 1.2 VI FK, 0.25 mg/kg/d 129 13 Rejection 94 6.6 eVA. 2.5 mg/kg/d 130 19 Rejection 113 22.4 Pred, 2.5 mg/d 132 31 Rejection 107 6.2 134 30 Rejection 176 11.6 135 19 Rejection 123 6.5 136 26 Rejection 105 9.3 VII eyA, 5.0 mg/kg/d 137 . >24 30 1.9 Pred, 5.0 mg/d 138 12 Rejection 288 13,3 139 12 Rejection 181 8.9 140 12 Rejection 147 15.5 141 >12 120 12.5 142 >12 52 2.8 60 25 ....... 20 ..J "0 ..... Ol E 15 Q) c c: 11l ~ 10 U E :J ... Q) C/') 5 1 ~ 0 10 GROUP V FK 0.5mg/k g/da y CyA 5mg/kg/day Pred 5 mg/day ~~ ** * ~t:t* .. ~* 20 30 40 50 60 70 TODO ET AL GROUP VI GROUP VII FK O. 25m 9 / kg/ day CyA2.5mg/kg/day CyA 5mg/kg/day Pred 2.5mg/day Pred 5mg/day * 0 10 20 30 0 10 20 30 * Alive Days after Kidney Transplantation Fig 2. Serum creatinine levels in dogs treated with drug combinations. Note the superior results in group V. DISCUSSION The principal studies of FK-506 in dogs by Ochiai et ai' and those by us2 have not yet been published. Ochiai's Chiba University group had almost universal survival after canine renal transplantation without much evidence of toxicity.' Our findings were less dramatic or favorable. Rejection often was not controlled, even at doses that led to profound illness or sometimes fatal emaciation. In addi-tion, there was histopathologic evidence of toxicity in mUltiple extrarenal organs. The toxicity of dogs may be a species-specific phenomenon. Rats have tolerated high-dose FK therapy wellY The effect of FK on subhuman primates is under study at sev-eral institutions, but no results are available at this time. However, even if FK proves to have substantial dose-related toxicity in all species including humans, it could still be a valuable agent for clinical use. The synergism of small doses of FK with suboptimal doses of Cy A and steroids was striking in our canine experi-ments herein reported. The results were con-sonant with those using the same drug combi-nation in rats submitted to heterotopic heart transplantation.5 With in vitro studies of human lymphocytes, Zeevi et al6 also have obtained convincing evidence for a true syner-gism as opposed to an additive effect of FK and CyA. More and more, polypharmaceutical ther-apy has been used to allow potent immunosup-pressive agents to be used in doses small enough so that side effects inherent with high doses of single agents can be avoided. SUMMARY The immunosuppressive agent FK permit-ted increased kidney transplant survival in dogs over a wide dose range, but with weight loss and manifold evidence of toxicity. The best use of FK at low doses was in combina-tion with CyA and Pred. FK-506 IN DOGS 61 REFERENCES I. Ochini T, Nagata M, Nakajima K, et al: Transplan-tation 1987 (in press) 2. Todo S, Makowka L, Starzl TE: Surg Res Comm 1987 (in press) 3. Ochiai T, Nakajima K, Nagata M, et al: Transplant Proc 19: 1284, 1987 4. Lee P, Murase N, Todo S, et al: Surg Res Comm 1987 (in press) 5. Murase N, Lee P, Lei H, et al: Transplant Proc (this issue) 6. Zeevi A, Duquesnoy R, Eiras G, et al: Transplant Proc (this issue) 

Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids.

S. Todo

A .J. Demetris

Y . Ueda

O. lmventarza

K . Okuda

A . Casavilla

S. Cemaj

A . Ghalab

V. Mazzaferro

B. .S. Rhoe

Y. Tonghu

L . Makowka

T.E. Starzl

AIR Universita degli studi di Milano

http://d-scholarship.pitt.edu/4158/1/31735062129253.pdf

Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids.

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D-Scholarship@Pitt

AIR Universita degli studi di Milano

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