Advantages of Mizol"ibine Over Azathioprine in Combination Therapy
`With Cyclosporine for Renal Transplantation
`
`K. Mita, N. Akiyama, T. Nagao, H. Sugimoto, S. Inoue, T. Osakabe, Y. Nakayama, K. Yokota,
`K. Sato, and H. Uchida
`
`ent age and sex, donor age and sex, or donor-recipient relation(cid:173)
`ships between the groups (Table 1). There were also no statisti(cid:173)
`cally significant differences in the number of human leukocyte
`antigen (HLA)-A, -B, and -DR antigen matches and missmatches
`(Table 2).
`Patients and graft survival rates were calculated by actuarial
`techniques. Oraft loss was defined as either return to dialysis or
`death with a functioning graft. All causes of graft loss were
`included, as well as all deaths.
`The incidence of rejection episodes that occurred during the
`initial 3 months was calculated and comparisons were made be(cid:173)
`tween the two groups. Miscellaneous complications arising within
`3 months after transplantation were also collected and compared.
`Hepatic dysfunction was defined as the development of high
`SOPT or SOOT levels (> 100 lUlL) in at least one set of repeated
`blood collections. Bone marrow suppression was defined as a
`decrease in the number of peripheral WBC to less than 3000/mm.3
`Patients with immunosuppression-induced diabetes were defined
`as those who needed insulin therapy duJing the postoperative
`course. Patients who needed insulin therapy before transplanta(cid:173)
`tion were not included in this study.
`
`RESULTS
`Actuarial Patient and Graft Survival Rates
`Actuarial patient and graft survival rates are summarized
`in Figs 1 and 2. In both groups we experienced no patient
`
`Table 1. Recipient and Donor Profile in Two Treatment Groups
`
`Group I'
`
`Group lit
`
`Recipient
`
`Donor
`
`Kidney source
`
`Male/female
`Age (y)
`Male/female
`Age (y)
`Parent
`Sibling
`'Group I. mizoribine + cyclosporine + steriods.
`tGroup II. azathioprine + cyclosporine + steriods.
`
`40/8
`31.4 ± 8.4
`19/29
`54.6 ± 11.0
`38
`10
`
`10/3
`31.5 ± 5.3
`3/10
`55.3 ± 11.0
`11
`2
`
`R EMARKABLE improvements in clinical renal allo(cid:173)
`
`transplantation have been achieved since the intro(cid:173)
`duction of cyclosporine (CyA), as evidenced by a signifi(cid:173)
`cantly higher graft survival than in the pre-CyA era.
`Powerful as an immunosuppressant, Cy A has never been
`used without fear of its nephrotoxicity. 1.2 In an attempt to
`minimize the nephrotoxicity of Cy A and optimize its
`immunological potential, the protocol of triple therapy that
`combines reduced dose of Cy A with azathioprine (Aza)
`and steroids (St) has been widely accepted, becoming the
`mainstay of current immunosuppressive regimen in organ
`transplantation. 3 ,4 However, the administration of Aza
`tends to be limited because of its untoward bone marrow
`suppression and hepatotoxicity as well, both being m<\ior
`adverse side effects of the agent. Mizoribine (Mz), a
`product of Toyo-Jozo Co, Japan,s which was shown to be
`less toxic than Aza in these regards,6 came into clinical use
`in 1980 in our country.7.S Soon we started to use Mz in
`place of Aza in that combination therapy.
`This study compared renal recipients given Mz with
`those given Aza to examine if Mz had any advantage over
`Aza in clinical results, when used as part of combination
`therapy with Cy A and st.
`
`MATERIALS AND METHODS
`
`Sixty-one consecutive renal transplantations were performed
`from one-haplotype-identical, living, related donor between Oc(cid:173)
`tober 1984 and March 1989. Oroup I comprised 48 recipients and
`was treated with Mz, in combination with CyA and St. The start(cid:173)
`ing and maintenance doses of Mz were 2 mg/kg/d, with a trough
`level of 1.04 ± 0.65 /-Lg/mL. The dose ofCyA was 6 to 10 mg/kg/d
`initially and 2 to 4 mg/kg/d during maintenance. This was tapered
`down by 0.2 mg/kg/d every week to a maintenance dose of 0.2
`mg/Kg/d 2 to 3 months later. Oroup II compJised 13 recipients and
`was treated with Aza in place of Mz. The initial and maintenance
`doses of Aza were 1 mg/kg/d. The initial and maintenance doses of
`Cy A and St were the same as those in group I. Potential recipients
`in group II who showed hepatic functional abnormalities indicated
`by high serum glutamic-oxaloacetic transaminase (SOOT) and/or
`serum glutamic-pyruvic transaminase (SOPT) (>50 IU/L) levels
`or demonstrated low peripheral white blood cell count (WBC)
`«4000/mm3
`) at transplant surgery were allocated to group I.
`In both groups of recipients the original immunosuppressive
`dose schedules were occasionally changed because of various
`complications. After the complications had been treated, care was
`taken to return to the original dose schedule.
`A rejection crisis was treated by two to four boluses of
`methylprednisolone (10 mg/kg), supplemented at times by local
`irradiation.
`There were no statistically significant differences in the recipi-
`
`From the Departments of Surgery and Organ Transplantation,
`Institute of Medical Science, University of Tokyo (K.M., N.A., T.N.,
`H.S., S.I., H.U.), Minato-ku, Tokyo; and the Department of Surgery
`(T.O., Y.N., KY., K.S.), Kitasato University, Sagamihara, Kana(cid:173)
`gawa, Japan.
`Supported in part by Research Grant C63570607 from the
`Ministry of Education.
`Address reprint requests to K. Mita, MD, Department of Organ
`Transplantation, Institute of Medical Science, Tokyo University,
`4-6-1 Shirokanedai, Minato-ku, Tokyo, 108, Japan.
`© 1990 by Appleton & Lange
`0041-1345/90/$3.00/+0
`
`Transplantation Proceedings, Vol 22, No 4 (August), 1990: pp 1679-1681
`
`1679
`
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`MITA, AKIYAMA, NAGAO ET AL
`
`Table 2. Human Leukocyte Antigen Missmatches Between the
`Two Groups
`
`No. of DR missmatches*
`
`No. of A and B missmatches*
`
`2
`10
`1
`0
`'Group I, mizoribine + cyclosporine + steriods.
`tGroup II, azathioprine + cyclosporine + steriods.
`*Not significant.
`
`Group I'
`
`Group lit
`
`29
`19
`30
`18
`
`5
`8
`8
`5
`
`loss during the observation period. The actuarial graft
`survival rate in group I was 97.9% at 1 year, decreasing
`slightly thereafter. The graft survival rates in groups II
`were 90.9%, at 1 year and remained stable at 3 years. None
`of the differences in graft survival rates between groups I
`and II was statistically significant.
`
`Comparison of Incidence of Rejection Episodes
`Acute rejection occurred in 18 of 48 recipients (37.5%)
`within 3 months after transplantation in group I. Likewise
`in group II episodes of acute rejection were observed in 4
`of 13 (30.8%) (Table 3). The incidence of acute rejection
`was not significantly different between groups I and II.
`
`Comparison of Renal Function
`Renal function, expressed as the level of serum creatinine,
`in both groups is summarized in Fig 3. A gradual increase
`in serum creatinine level occurred in both groups during 3
`years after transplantation. Between 1 year and 3 years
`after transplantation, there were no statistically significant
`differences in serum creatinine levels between groups I and
`II.
`
`Comparison of Incidence of Miscellaneous Complications
`Due to Immunosuppression Within 3 Months
`Bone marrow suppression occurred in 3 of 48 recipients
`(6.3%) in groups I and 5 of 13 recipients (38.5%) in group
`
`%
`100~oo-~--oo-------oo-------oo
`
`80
`
`60
`
`- - Group I
`0--0 Group II
`
`i
`3 years
`
`Group I : Mz+CyA+St
`Group II : Aza+CyA+St
`
`Fig 1. Actuarial life survival rate of renal allotransplant one(cid:173)
`haplotype-indentical, living, related reCipients.
`
`%
`100
`
`80
`
`60
`
`01
`0
`
`I
`- - Group
`0--0 Group II
`
`I
`1
`
`I
`2
`
`I
`3 years
`
`Group I : Mz+CyA+St
`Group II : Aza+CyA+St
`
`Fig 2. Actuarial graft survival rate of renal allotransplant one(cid:173)
`haplotype-identical, living, related recipients.
`
`II. There was a significant difference between groups I and
`II (P < .005).
`Severe systemic infections such as bacterial, fungal,
`protozoal, and viral lung or central nervous system infec(cid:173)
`tions occurred in 5 of 48 recipients (10.4%) in group I and
`5 of 13 recipients (38.5%) in group II. The difference was
`statistically significant (P < .02) (Table 4).
`There were no significant differences in the incidence of
`hepatic dysfUnction or immunosuppression-induced diabe(cid:173)
`tes.
`
`DISCUSSION
`
`Clinical experiences of triple therapy with Mz, CyA, and
`St in renal allotransplantation have been reported from a
`number oftransplant centers in Japan,6,9,10 as well as those
`with Az, CyA, and St. To our knowledge, however, no
`reports have compared these two protocols on a prospec(cid:173)
`tive basis. Compared to Az, Mz is known to have less
`cytotoxicity to the bone marrow and liver. Whether such
`theoretical advantages can be reflected on clinical results
`has remained unknown in renal recipients on triple ther(cid:173)
`apy.
`In the present study, recipients treated with Aza, Cy A,
`and St and having normal peripheral WBC were selected.
`Still, 38.4% of the recipients had developed a decrease in
`peripheral WBC to less than 3000lmm3 3 months after
`transplantation. In contrast, only 6.3% of recipients
`treated with Mz, Cy A, and St developed bone marrow
`
`Table 3. Incidence of Rejection Episodes Within 3 Months
`
`Group I'
`
`48
`
`No. of recipients
`Rejection episodes
`Yes
`18 (37.5%)*
`No
`30 (62.5%)
`'Group I, mizoribine + cyclosporine + steroids.
`tGroup II, azathioprine + cyclosporine + steroids.
`*Not significant.
`
`Group lit
`
`13
`
`4 (30.8%)*
`11 (69.8%)
`
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`
`ADVANTAGES OF MIZORIBINE OVER AZATHIOPRINE
`
`'1681
`
`Serum
`Creat
`mg/dl
`
`3.0
`
`1.5
`
`~1 ~
`
`II----@I G ro u p
`0--0 Group
`
`I
`II
`
`1
`2
`Group I : Mz+CyA+St
`Group II : Aza+CyA+St
`
`3 years
`
`Fig 3. Levels of serum creatinine.
`
`suppression. This difference was statistically significant.
`Moreover, systemic infections were more frequently en(cid:173)
`countered in recipients treated with Aza, CyA, and those
`treated with Mz, CyA, and St. Nephrotoxicity attributable
`to CyA in both triple-drug therapies was apparently less
`significant, as indicated by serum creatinine levels. The
`rationale for triple therapy consisting of Mz, CyA, and St
`appeared to have been confirmed in the present study,
`although more randomized prospective trials will be
`needed to confirm it.
`
`CONCLUSION
`Immunosuppression by Mz, CyA, and St in one-haplo(cid:173)
`type-identical, living, related renal allotransplant recipi-
`
`Table 4. Incidence of Miscellaneous Complications Due to Im(cid:173)
`munosuppression Within 3 Months
`
`No: of recipients
`Bone marrow suppression
`Grave systemic infections
`Hepatic dysfunction
`Immunosuppression induced
`diabetes
`
`Group I'
`
`48
`3 (6.3%)*
`5 (1Q.4%)§
`3(6.3%)
`2(4.2%)
`
`Group lit
`
`13
`5 (38.5%)*
`5 (38.5%)§
`2 (18.2%)
`1 (7.7%)
`
`'Group I, mizoribine + cyclosporine + steriods.
`tGroup II, azathioprine + cyciosporine + steroids.
`*p < .005, significant.
`§ p < .02, significant.
`
`ents demonstrated the same life and graft survival rates as
`that by Aza, CyA, and St. Treatment with Mz, CyA, and
`St resulted in significantly less bone marrow suppression
`and severe systemic infection comparing with Aza, CyA,
`and St treatment. Therefore, immunosuppressive treat(cid:173)
`ment with Mz, CyA, and St appears to be superior than
`that with Aza, Cy A, and St.
`
`REFERENCES
`1. Kahn BD: Transplant Proc 17(Suppl 1):5, 1985
`2. Mihatsch MJ, Thiel G, Basler V, et al: Transplant Proc
`17(Suppll):101,1985
`3. Canafax DM, Martel EJ, Ascher NL, et al: Transplant Proc
`17: 1176, 1985
`4. Lorber MI, Flechner SM, Van Buren CT, et al: Transplant
`Proc 17(Suppl 1):282, 1985
`5. Mizuno K, Tsujino M, Takada M, et al: J Antibiot (Tokyo)
`27:775, 1974
`6. Aso K, Uchida H, Sato K, et al: Transplant Proc 19:1955,
`1987
`7. Inou T, Kusaba R, Takahashi I, et al: Transplant Proc
`13:315, 1981
`8. Yokota K, Uchida H, Osakabe T, et al: Jap J Transplant
`17(Suppl):691, 1982
`9. Takahara S, Fukunishi T, Kokado Y, et al: Transplant Proc
`20(SuppI3):147, 1988
`10. Amemiya H, Suzuki S, Watanabe H, et al: Transplant Proc
`21:956, 1989
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