Beneficial effect of antibody removal and enhanced immuno suppression in flow cytometry cross match-positive and ABO-incompatible renal transplantation

Katayama, Akio; Kobayashi, Takaaki; Uchida, Kazuharu; Goto, Norihiko; Matsuoka, Susumu; Sato, Tethuhiko; Haba, T; Tominaga, Yoshihiro; Kohara, Setsuko; Kamura, Hiromi; Liu, D; Yokoyama, Itsuo; Oikawa, Tadashi; Takeda, Asami; Morozumi, Kunio; Nakao, Akimasa

doi:10.1016/s0041-1345(02)03404-8

Cited by 2 publications

(3 citation statements)

References 7 publications

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“…Recently, higher doses of MZ (5 mg/kg) compared with the clinically approved dosage (2–3 mg/kg) have been attempted for the treatment of renal diseases or autoimmune disease as well as organ transplantation, and demonstrated its versatile efficacy [8,11,24–26]. Very high doses of MZ (10 mg/kg) were effective in treating patients with frequently relapsing nephritic syndrome, showing that C2 levels reached over 3 μ g/ml [24].…”

Section: Discussionmentioning

confidence: 99%

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Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study

Liu¹,

Kobayashi²,

Nagasaka³

et al. 2007

Transplant Int

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Summary Although mizoribine (MZ), which inhibits inosine monophosphate dehydrogenase in the same way as mycophenolate mofetil, recently proved more effective when higher doses were administered than previously approved, neither the optimal dosage nor blood concentration has yet been clarified. We aimed at investigating the effect of high‐doses of MZ on prevention of anti‐donor antibody (Ab) production and acute Ab‐mediated rejection (AMR) on the basis of the pharmacokinetic profile in a pig kidney transplantation model. Group 1 (n = 5) received cyclosporin microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg). Groups 2, 3 and 4 (each n = 5) were treated, respectively, with 30, 10 and 3 mg/kg of MZ in addition to cyclosporin and prednisolone. The incidences of AMR in groups 1, 2, 3 and 4 were 5/5, 1/5, 3/5 and 5/5, respectively. Anti‐donor IgG/IgM Ab levels (relative to pretransplantation levels) on day 14 in groups 1, 2, 3 and 4 were 10.3/9.3, 1.8/1.0, 2.3/1.8 and 6.5/3.5, respectively. While only 2 (28.6%) of seven pigs with Cmax > 3 μg/ml during the first 2 weeks had AMR, 7 (87.5%) of eight pigs with Cmax < 3 μg/ml elicited anti‐donor Abs and experienced AMR (P = 0.0406). Effective Cmax seemed to be over 3 μg/ml at minimum. Higher doses of MZ efficiently prevented AMR. However, therapeutic drug monitoring is essential before clinical application.

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Section: Discussionmentioning

confidence: 99%

“…Recently, 2–3 mg/kg of MZ, which was originally registered as the clinically approved dosage, was found to be too small to obtain satisfactory efficacy, because such a dosage is much lower than the one for MMF (20–60 mg/kg) [8,11]. The efficacy of high‐dose therapy (>5 mg/kg) has been shown in several studies.…”

Section: Introductionmentioning

confidence: 99%

Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study

Liu¹,

Kobayashi²,

Nagasaka³

et al. 2007

Transplant Int

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show abstract

“…MZ at the dose of 2-3 mg/kg has been registered for prevention of rejection after renal transplantation in Japan. It has been recently reported that a relatively high dose (6 mg/kg) of MZ was effective for prevention of antibody-mediated rejection in ABO-incompatible renal transplantation [8]. The purpose of this study was to examine whether a much higher dose of MZ would also be effective in reversing ongoing acute humoral rejection like MMF, in an experimental transplantation model using pigs.…”

Section: Discussionmentioning

confidence: 99%

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

et al. 2005

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Summary Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2–5 mg/kg) is much lower than that of MMF (20–60 mg/kg). The purpose of this study was to examine whether high‐dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti‐donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high‐dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 μg/ml. Treatment with high‐dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.

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Beneficial effect of antibody removal and enhanced immuno suppression in flow cytometry cross match-positive and ABO-incompatible renal transplantation

Cited by 2 publications

References 7 publications

Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study

Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

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