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Mechanism of Acute Antibody-Mediated Rejection in ABO-Incompatible Kidney Transplantation: Which Anti-A/Anti-B Antibodies are Responsible, Natural or de Novo?

Takahashi, Kota; Saito, Kazuhide; Nakagawa, Yuki; Tasaki, Masayuki; Hara, Noboru; Imai, Naofumi

doi: 10.1097/TP.0b013e3181c89307
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Division of Urology; Department of Regenerative and Transplant Medicine; Graduate School of Medical and Dental Sciences; Niigata University, Niigata, Japan (Takahashi, Saito, Nakagawa, Tasaki, Hara)

Division of Clinical Nephrology and Rheumatology; Department of Homeostatic Regulation and Developments; Graduate School of Medical and Dental Sciences; Niigata University, Niigata, Japan (Imai)

Address correspondence to: Kota Takahashi, M.D., Ph.D., Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi 1-757, Chuo-Ku, Niigata 951-8510, Japan.

E-mail: kota@med.niigata-u.ac.jp

Takahashi and Hara participated in research design, supervised throughout the study, and wrote the paper. Imai, Saito, Nakagawa, and Tasaki contributed to clinical data acquisition and analyses.

Received 15 October 2009.

Accepted 16 October 2009.

ABO-incompatible living kidney transplantation (ABO-I KTx) has played a role in alleviating the shortage of donor kidneys in countries such as Japan (1). The advent of new immunosuppressive agents and advances in immunosuppressive therapy based on delineation of the mechanism of acute antibody-mediated rejection (AMR) have markedly improved outcomes after ABO-I KTx (2–6). However, acute AMR remains a challenging problem in ABO-I KTx (3, 4, 6). We examined the time course of the complement 4d (C4d) deposition status in peritubular capillaries (PTCs) before and after ABO-I KTx to determine (1) when serum anti-A, anti-B antibodies react with ABO histo-blood group antigens on endothelial cells in PTCs; and (2) which anti-A/anti- B antibodies are responsible, natural or de novo.

We studied 31 consecutive recipients who underwent ABO-I KTx based on three renal graft biopsies in time series between January 2000 and December 2008. As a control group, we also studied 37 patients who underwent ABO-compatible (ABO-C) KTx during the same period. Patients' characteristics, including the age of donors and recipients, relationship between them, and the number of human leukocyte antigen mismatches, were not different between the ABO-I KTx and ABO-C KTx groups. Preoperative complement-dependent cytotoxicity, and flow cytometry crossmatch were negative in all patients.

A 0-hr biopsy of the renal graft was performed immediately after removal of the graft kidney and flushing with Collin's solution. A 1-hr biopsy was performed 1 hr after the resumption of blood flow to the graft. A protocol biopsy was performed 1 month after transplantation, and when the renal graft function was impaired within 2 months after transplantation, an episode biopsy was performed. Acute rejection and staining for C4d deposition in PTCs were determined according to the diagnostic criteria proposed at the 2007 Banff Conference (6).

In the ABO-C KTx group, calcineurin inhibitor (cyclosporin or tacrolimus)-based, triple-drug therapy, including methylprednisolone and mycophenolate mofetil, was started 2 days before transplantation. Basiliximab was given twice after transplantation. In the ABO-I KTx group, triple-drug desensitization therapy was initiated 2 to 4 weeks before transplantation; splenectomy was performed in seven patients concurrently with transplantation, and rituximab was given twice preoperatively instead of splenectomy in the 24 patients (5). The pretransplant serum anti-A/anti-B antibody titers were maintained at 1:16 or less by double- filtration plasmapheresis. Maintenance immunosuppression with calcineurin inhibitor-based, triple-drug therapy was comparable between the ABO-C KTx and ABO-I KTx groups.

Patient survival rates were 100% both in the ABO-C KTx and ABO-I KTx groups. The graft survival rate did not differ between the ABO-C KTx and ABO-I KTx groups at 9 years (100 vs. 90.3%, P=0.05, log-rank test). There was no acute AMR in the ABO-C KTx group, and acute AMR developed in 4 patients (12.9%) in the ABO-I KTx group (P=0.04). Three of these patients had grade III acute AMR, resulting in graft loss. The remaining one patient successfully recovered with treatment for rejection and maintains an excellent renal graft function at present, 2 years after acute AMR.

In the ABO-C KTx group, staining for C4d deposition in PTCs was negative through 0-hr to event/protocol biopsy sessions (Fig. 1). In the ABO-I KTx group, the rates of positive staining for C4d deposition in PTCs were 0% at the 0-hr biopsy, 16.1% (5 of the 31 patients) at the 1-hr biopsy, and 70.9% (22 of the 31 patients) at the protocol or episode biopsy (Fig. 1). All four patients who experienced acute AMR showed C4d deposition in their PTCs at the episode biopsy, but it was negative at the 1-hr biopsy in all of them. None of the five patients with C4d deposition at the 1-hr biopsy experienced an episode of acute AMR.

FIGURE 1.

FIGURE 1.

In our series, acute AMR developed in 4 of the 31 patients (12.9%) in the ABO-I KTx group. We focused on the time course of C4d deposition during the posttransplant period (Fig. 1). The episode biopsy of renal grafts showed C4d deposition in all four patients who experienced acute AMR, but the 1-hr biopsy specimens were negative for C4d deposition in these four patients. Interestingly, none of the five patients with C4d deposition at the 1-hr biopsy developed acute AMR. Thus, acute AMR in them was not induced by natural antibodies remaining after pretransplant antibody removal, but was evidently associated with antibodies produced de novo after transplantation (7–9). It is therefore deemed critical to start sufficient desensitization therapy before ABO-incompatible kidney transplantation for the prevention of acute AMR, which potentially inhibits the de novo production of anti-A/anti-B antibodies (2, 3, 5, 10).

Kota Takahashi

Kazuhide Saito

Yuki Nakagawa

Masayuki Tasaki

Noboru Hara

Division of Urology

Department of Regenerative and Transplant Medicine

Graduate School of Medical and Dental Sciences

Niigata University, Niigata, Japan

Naofumi Imai

Division of Clinical Nephrology and Rheumatology

Department of Homeostatic Regulation and Developments

Graduate School of Medical and Dental Sciences

Niigata University, Niigata, Japan

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REFERENCES

1. Takahashi K, Saito K, Takahara S, et al; Japanese ABO-Incompatible Kidney Transplantation Committee. Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant 2004; 4: 1089.
2. Takahashi K, Tanabe K, Ota K, et al. Prophylactic use of new immunosuppressive agent, deoxyspergualin, in patients with kidney transplantation from ABO-incompatible or preformed antibody positive donors. Transplant Proc 1991; 23: 1078.
3. Takahashi K. ABO-incompatible kidney transplantation—Establishing a scientific framework. Amsterdam, Elsevier 2007.
4. Saito K, Nakagawa Y, Takahashi K, et al. Pinpoint targeted immunosuppression: Anti-CD20/MMF desensitization with anti-CD25 in successful ABO-incompatible kidney transplantation without splenectomy. Xenotransplant 2006; 13: 111.
5. Imai N, Nishi S, Takahashi K, et al. Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition. Nephrol Dial Transplant 2006; 21: 2589.
6. Tasaki M, Yoshida Y, Takahashi K, et al. Identification and characterization of major proteins carrying ABO blood group antigens in human kidney. Transplantation 2009; 87: 1125.
7. Rydberg L, Breimer ME, Pascher I, et al. Characterization of the anti-A antibody response following an ABO incompatible (A2 to O) kidney transplantation. Mol Immunol 1992; 29: 547.
8. Sawada T, Fuchinoue S, Teraoka S. Successful A1-to-O ABO-incompatible kidney transplantation after a preconditioning regimen consisting of anti-CD20 monoclonal antibody infusion, splenectomy, and double-filtration plasmapheresis. Transplantation 2002; 74: 1207.
9. Tyden G, Kumlien G, Fehrman I. Successful ABO incompatible kidney transplantations without splenectomy, using antigen-specific immunoadsorption and rituximab. Transplantation 2003; 76: 730.
10. Montgomery RA, Locke JE, King KE, et al. ABO incompatible renal transplantation: A paradigm ready for broad implementation. Transplantation 2009; 87: 1246.
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