Proteinuria Remains a Significant Hurdle to Successful Pig Kidney Xenotransplantation Despite an Effective Immunosuppressive Regimen.

IF 5 2区医学 Q1 IMMUNOLOGY

Transplantation Pub Date : 2025-10-07 DOI:10.1097/TP.0000000000005508

Kohei Kinoshita, Akihiro Maenaka, Maho Terashita, Ivy A Rosales, Yuji Hidaka, Gweneth Eliza Lavalla, Madelyn Ma, Zahra Habibabady, David Ayares, Seth Lederman, Robert B Colvin, Richard N Pierson, Tatsuo Kawai, David K C Cooper

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引用次数: 0

Abstract

Background: This study evaluated the efficacy of an optimized immunosuppressive regimen, including a higher dose of anti-CD154 monoclonal antibody (TNX-1500), in prolonging graft survival in pig-to-baboon kidney xenotransplantation. Despite advances in genetic engineering of organ-source pigs and immunosuppressive regimens, we report that the development of nephrotic-range proteinuria remains a significant problem.

Methods: We assessed the TNX-1500-based immunosuppressive regimen in 9 baboon recipients of gene-edited pig kidney transplants. The regimen included induction with antithymocyte globulin, anti-CD20 monoclonal antibody (rituximab), and C1 esterase inhibitor, and maintenance with TNX-1500, rapamycin, methylprednisolone, and anti-interleukin-6 receptor blockade (tocilizumab).

Results: Although an increased dose of TNX-1500 of 30 mg/kg (higher dose, n = 6) versus 20 mg/kg (lower dose, n = 3) improved overall survival (median 214 versus 86 d; P < 0.05), 4 of 9 baboons (including 3 with higher dose) developed persistent nephrotic-range proteinuria. The histopathology of these 4 grafts revealed focal glomerular thrombotic microangiopathy (4/4), transplant glomerulopathy (3/4), focal segmental glomerulosclerosis (2/4), and/or membranous nephropathy (1/4) but no definitive features of rejection. Proteinuria was associated with decreased serum albumin and, very importantly, with loss of TNX-1500 in the urine.

Conclusions: Despite the efficacy of the immunosuppressive regimen, we suggest that proteinuria may lead to inadequate immunosuppressive therapy through loss of the therapeutic antibody, thus increasing the risk of rejection. Further research is needed to develop strategies to prevent this complication.

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尽管有有效的免疫抑制方案，蛋白尿仍然是成功的猪肾异种移植的一个重大障碍。

背景：本研究评估了一种优化的免疫抑制方案，包括更高剂量的抗cd154单克隆抗体（TNX-1500），在延长猪到狒狒肾脏异种移植中移植物存活方面的效果。尽管器官源猪的基因工程和免疫抑制方案取得了进展，但我们报告肾病范围蛋白尿的发展仍然是一个重大问题。方法：我们在9只接受基因编辑猪肾移植的狒狒中评估了基于tnx -1500的免疫抑制方案。治疗方案包括抗胸腺细胞球蛋白、抗cd20单克隆抗体（利妥昔单抗）和C1酯酶抑制剂诱导，TNX-1500、雷帕霉素、甲基强的松龙和抗白细胞介素-6受体阻断剂（托珠单抗）维持。结果：虽然TNX-1500剂量增加30 mg/kg（高剂量，n = 6）比20 mg/kg（低剂量，n = 3）提高了总生存期（中位214对86 d）； P结论：尽管免疫抑制方案有效，但我们认为蛋白尿可能导致免疫抑制治疗不足，导致治疗性抗体丧失，从而增加排斥反应的风险。需要进一步的研究来制定预防这种并发症的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Transplantation 医学-免疫学

CiteScore

8.50

自引率

11.30%

发文量

1906

审稿时长

1 months

期刊介绍： The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.