After confirming a negative C1q-binding DSA, we decided to perform KT accepting a positive AHG-CDC XM of 1:8 at the time of transplantation. The kidney appeared well perfused and did not show evidence of hyperacute rejection.
The patient did not receive posttransplant PP + IVIG treatment, and his postoperative course was uneventful. The protocol biopsy performed at postoperative month 3 showed mild tubular dilatation with a few casts. Peritubular C4d staining was negative under immunofluorescence, and no endothelial swelling or peritubular capillary changes were present on examination via electron microscopy. Additional kidney injury molecule-1 immunohistochemistry for the evaluation of acute tubular injury showed negative staining in proximal tubules (Fig. 3). Currently, at 12 months post-transplantation, the patient continues to do well with a baseline creatinine level of 1.0 mg/dL and a urinary protein-to-creatinine ratio of less than 0.1 (g/gCr). Anti-HLA-B59 DSA remains at MFI 7815, but no HLA antibody reaction has been detected by C1q assay. The patient did not suffer acute rejection or infectious complication during follow-up.
The study procedures were in accordance with the Declaration of Helsinki. All procedures were performed after obtaining informed consent. A single patient case report does not require institutional review board approval according to our board policy.
Historically, several cases of transplantation with a positive CDC XM at transplantation were performed in the past prior to the introduction of solid-phase tests or new interventions.[4,7] In those cases, most patients had poor outcomes, but some cases did have acceptable outcomes. The reasons for the different courses remain unknown, but a positive CDC XM is a contraindication to transplantation. Afterward, despite advances in desensitization protocols and immunologic testing, most KTs are performed after achievement of a negative CDC XM. In this report, we present a successful case of KT with a persistently positive CDC XM (T-AHG 1:8 at the time of transplantation) following C1q assay-directed, bortezomib-assisted desensitization.
KT is the treatment of choice for end-stage renal disease patients. However, over 30% of patients on a waiting list are sensitized to HLA due to pregnancy, blood transfusion, or previous transplantation. These sensitized patients are less likely to find compatible deceased donors and thus have a prolonged waiting time. In addition, they have a limited possibility of undergoing a paired kidney exchange. Desensitization protocols to overcome the HLA barrier have become increasingly popular because of organ shortages and have increased the opportunity for transplantation in sensitized patients.[4,5,9]
Despite a low incidence of hyperacute rejection and acceptable short-term outcomes in sensitized patients, antibody-mediated rejection remains a significant challenge even after successful desensitization. Concern that relevant DSA are not being detected by less sensitive assays has led to the development of more sensitive XM techniques. Paradoxically, CDC XM has been used as a minimum requirement for KT due to its low sensitivity. However, recent studies have demonstrated that KT recipients from HLA incompatible donors exhibit a substantial survival benefit compared to that in patients who did not undergo transplantation and those who waited for transplants from deceased donors, regardless of DSA levels. Therefore, accurate analysis of an individual's DSA, which helps in the decision on whether to proceed with a transplantation, is critical for a patient.
Although the development of solid-phase assays has greatly elucidated the role of DSA in the immune response to allografts, it is difficult to determine an MFI cutoff value suitable for proceeding to transplantation. In fact, MFI values determined with conventional solid-phase assays do not accurately correlate with the complement-binding DSA. In contrast, the C1q assay directly discriminates the ability of a particular complement-binding DSA. It is quite important in a clinical setting considering that the DSA mediated complement cascade is the hallmark of in vivo graft injury. The classic CDC XM is neither sensitive nor specific enough to detect complement fixation.[15,16] In our case, the AHG-CDC-XM result was 1:8 positive, but the NIH-CDC-XM and C1q DSA results were negative at KT. Hence, we decided to perform KT considering not only the CDC XM indicators, but also the results of the solid-phase tests. To the best of our knowledge, this is the first report of successful KT following C1q assay-directed desensitization.
Desensitization protocols have been based on PP and/or IVIG, which physically remove or inhibit the circulating DSA. In addition, rituximab is widely used for reducing B-cells.[4,9] Nevertheless, prior desensitization protocols have demonstrated varying degrees of efficacy and durability. A potential explanation for the variation among results is the failure to inhibit plasma cells, the source of antibodies.
Bortezomib, a proteasome inhibitor, exerts an inhibitory effect directly on antibody-secreting plasma cells. Prior study using bortezomib-based desensitization represented a significant and sustained reduction in DSA, which may allow for increased transplantability. We achieved a negative C1q conversion in this highly sensitized patient by using bortezomib as an additional therapy. In addition, the patient did not suffer clinical rejection in the absence of postoperative PP and IVIG. The protocol biopsy also demonstrated no evidence of subclinical rejection.
Interestingly, the patient showed positive AHG-CDC XM without C1q-binding DSA. Therapeutic agents used in desensitization protocols have been shown to cause interference in XM results. In our case, however, the positive CDC XM is hard to be deemed a false positive considering the high MFI of DSA at the time of transplantation. Rather, epitope analysis can provide a possible explanation for the positive CDC XM reaction. Epitopes are parts of an antigen recognized by antibodies. As epitope reaction depends on the 3-dimensional structure, changes in this structure may lead to changes in the antibody reactivity. If there is an insufficient conformational area due to a structural change, even though some C1q epitope reactions were positive, but overall C1q DSA could be negative. After the desensitization, the HLA-B59 DSA itself turned into negative in the C1q assay, but multiple donor-specific epitope reactions remained positive in the IgG assay with several epitope reactions in the C1q assay. These complement-binding antibodies against donor-specific epitopes with high concentrations of noncomplement-binding antibodies might induce a positive AHG-CDC XM reaction even after desensitization.
In conclusion, we report a successful KT across a positive CDC XM at the time of transplantation, by using C1q assay-directed, bortezomib-assisted desensitization. The goal of desensitization is to maximize the opportunity for transplantation, with improved mortality and quality of life compared with that associated with dialysis. However, for over 40 years, transplantation decision making has been based on the CDC XM, regardless of the presence of more sensitive and more accurate immunologic tests. The cost of continuing the historical approach is that of eliminating some patients that could have undergone a successful transplant. Therefore, the results of XM tests and solid-phase assays must be interpreted in the context of the individual patient.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
bortezomib; C1q-binding antibody; crossmatch; desensitization; donor-specific antibody; hyperacute rejection; kidney transplantation