Friday, June 2, 2023

Comparison of high-dose IVIG and rituximab versus rituximab as a preemptive therapy for de novo donor-specific antibodies in kidney transplant patients – Scientific Reports

In this open-label randomized controlled trial, we found that preemptive treatment in patients with dnDSA was associated with a reduction in dnDSA MFI. However, compared with the use of rituximab alone, combination of IVIG to rituximab did not provide additional benefit for dnDSA reduction. dnDSA-induced vascular inflammation and microangiopathy play a major role in antibody-mediated rejection, leading to kidney allograft loss6,16,17,18,19. dnDSA often induced subclinical antibody-mediated rejection as well as overt acute and chronic antibody-mediated rejection4,5. For example, over 40% of patients with dnDSA are diagnosed with biopsy-proven subclinical antibody-mediated rejection, leading to progressive graft injury20. Subclinical antibody-mediated rejection has also been associated with poor allograft survival, although clinical rejection is associated with worse allograft survival3,4,21. However, treatment of subclinical rejection using plasmapheresis, rituximab, and/or IVIG improved graft outcomes to a greater extent than clinical antibody-mediated rejection14,21. These results suggest a potential role of early detection and intervention for dnDSA, which can often be combined with subclinical antibody-mediated rejection.

Most previous studies examined the reduction of DSA titer in pre-transplant desensitization of highly sensitized recipients9,10 or the treatment of overt rejection using rituximab or rituximab with IVIG11. A combination of rituximab and IVIG was used as a desensitization treatment for highly sensitized candidates with preexisting DSA9. Desensitization treatment, including rituximab, significantly decreased the incidence of dnDSA 2 years after kidney transplantation10. A prospective observational study of patients with dnDSA within 1 year after kidney transplantation and no histological evidence of rejection showed that high-dose IVIG alone was insufficient to reduce MFI to prevent acute antibody-mediated rejection22. In contrast, another study on pediatric kidney transplant patients demonstrated that treatment using various combinations of high-dose IVIG, rituximab, and plasmapheresis according to dnDSA strength and biopsy findings significantly reduced class II dnDSA in 11 (73.3%) of 15 patients with subclinical or clinical rejection23. However, we excluded plasmapheresis in pre-emptive treatment for subclinical dnDSA, because it needs admission and a relatively long hospital stay compared with convenient therapy of IVIG and rituximab.

No randomized controlled study has investigated the effectiveness of pre-emptive treatment in kidney transplant patients with dnDSA. Therefore, it is not established whether preemptive treatment for dnDSA could be useful or which treatment is better in kidney transplant patients. This randomized clinical trial showed that rituximab alone or combination therapy of rituximab and high-dose IVIG treatment reduced dnDSA MFI. However, our study did not demonstrate clear additional benefits of IVIG combination compared to rituximab alone. As clinical antibody-mediated rejection was not observed in either treatment group during the study period, we could not assess impact of each treatment on the occurrence of antibody-mediated rejection.

Among class II dnDSA, anti-DQ dnDSA showed poorer response to treatment than anti-DR dnDSA. In the previous study, most of the immune-dominant DSAs detected in patients with late rejection were anti-DQ DSA and their titer did not respond well to the rejection treatment24. However, the reason why anti-DQ DSA did not respond has not been clearly identified. Further studied to investigate this phenomenon would be needed since anti-DQ dnDSA was associated with poor graft outcome after KT25,26,27.

Considering the poor prognosis of dnDSA and the accompanying antibody-mediated rejection, early detection, and preemptive treatment of dnDSA with or without subclinical rejection could be important. Furthermore, preventive strategies are of course more important. Since class II eplet mismatch is an important immunologic risk factor for dnDSA, good eplet matching can be an important method to reduce the development of DSA28. Noncompliance is found in 90% of cases with DSA and clinical rejection and 24% of cases with DSA and subclinical rejection4. Therefore, monitoring and preventing non-compliance with immunosuppressants is the most important effort against dnDSA development29,30. Immunosuppression-independent risk factors for dnDSA development include younger age, African American, and male31. We had better regularly monitor the development of dnDSA, especially in high-risk patients.

This study has several limitations. First, this study enrolled a relatively small number of patients and most of the patients had living-related kidney transplant. Therefore, the potential selection bias could not be ruled out. In addition, the short follow-up duration made it impossible to investigate preemptive treatment’s effect on antibody-mediated rejection, kidney function, and graft loss. To overcome this limitation, MFI change was defined as primary endpoint in this study. Based on this study, further large-scale studies with long-term follow-up are needed to assess the long-term benefits of preemptive treatment for dnDSA. Secondly, the lack of allograft biopsy findings at the time of dnDSA detection in this study could not determine the presence of subclinical antibody-mediated rejection. However, the necessity for allograft biopsy in patients with subclinical dnDSAs has not been established in large clinical trials4. Third, our additional analysis to compare the preemptive treatment group and the no-treatment group was not a randomized controlled comparison but a preliminary comparison.

Nevertheless, this study is the first, randomized, controlled study to assess effectiveness of preemptive therapy for subclinical dnDSA and determine a better treatment regimen for subclinical dnDSA in kidney transplant patients. This study could contribute to the field by providing baseline data for establishing effective preemptive treatment of subclinical dnDSA.

In conclusion, the preemptive administration of high-dose IVIG combined with rituximab did not show an additional benefit in reducing dnDSA compared to the administration of rituximab alone, although both treatments reduced dnDSA.

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