Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2026 Jan 1;110(1):e141-e153.
doi: 10.1097/TP.0000000000005508. Epub 2025 Oct 7.

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

Kohei Kinoshita  1 , Akihiro Maenaka  1 , Maho Terashita  1 , Ivy A Rosales  2 , Yuji Hidaka  1 , Gweneth Eliza Lavalla  1 , Madelyn Ma  1 , Zahra Habibabady  1 , David Ayares  3 , Seth Lederman  4 , Robert B Colvin  2 , Richard N Pierson 3rd  1 , Tatsuo Kawai  1 , David K C Cooper  1
Affiliations

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

Kohei Kinoshita et al. Transplantation. .

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.

PubMed Disclaimer

Conflict of interest statement

D.K.C.C. is a consultant to eGenesis Bio in Cambridge, MA. D.A. is the CEO of Revivicor in Blacksburg, VA. S.L. is the CEO of Tonix Pharmaceuticals in Chatham, NJ. The other authors declare no conflicts of interest.

References

    1. Anand RP, Layer JV, Heja D, et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature. 2023;622:393–401.
    1. Iwase H, Hara H, Ezzelarab M, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation. 2017;24:e12293.
    1. Cooper DKC, Hara H, Iwase H, et al. Justification of specific genetic modifications in pigs for clinical organ xenotransplantation. Xenotransplantation. 2019;26:e12516.
    1. Kinoshita K, Maenaka A, Rosales IA, et al. Novel factors potentially initiating acute antibody-mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen. Xenotransplantation. 2024;31:e12859.
    1. Bikhet M, Iwase H, Yamamoto T, et al. What therapeutic regimen will be optimal for initial clinical trials of pig organ transplantation? Transplantation. 2021;105:1143–1155.

MeSH terms