Current Status of Renal Xenotransplantation and Next Steps

Abstract

Renal transplantation is the preferred treatment of ESKD, but the shortage of suitable donor kidneys from the cadaver pool means that many patients with ESKD will not receive a kidney transplant. Xenotransplantation has long represented a solution to the kidney shortage, but the occurrence of antibody-mediated rejection has precluded its clinical development. Developments in somatic cell nuclear transfer in pigs and gene editing tools have led to the creation of new donor pigs with greatly improved crossmatches to patients. In addition, improvements in preclinical kidney xenotransplant survival using new anti-CD40/CD154-based immunosuppression have pushed xenotransplantation to the point where it is reasonable to consider initiating a clinical trial to evaluate this potential therapy in patients.

Figure 1

Analysis of human immunoglobulin binding to pig PBMC from genetically modified swine. PBMC were collected, incubated with human serum, and analyzed for IgM (y axes) and IgG (x axes) binding by flow cytometry. Dotted lines represent an MFI of 2000. (A) A single representative patient is screened on wild type, GGTA1 KO, GGTA1/CMAH KO, and GGTA1/CMAH/b4GalNt2 KO swine PBMC. (B) Sera from 44 randomly selected patients with unknown sensitization were incubated with PBMC from all four glycan backgrounds.

Figure 2

Tacrolimus-based immunosuppression fails to prolong renal xenograft survival. (A) Immunosuppression regimen including tacrolimus and tesidolumab without CD154 monoclonal antibody therapy. (B) Kaplan-Meier curve analysis reveals that a tacrolimus-based immunosuppression regimen fails to extend xenograft survival beyond 62 days despite the presence of C5 complement inhibition by tesidolumab. (C) Biopsy taken from explanted kidney at day 62 shows parenchymal hemorrhage and thrombotic microangiopathy, prominent IgG, IgM, C4d, and minimal C5b-9. (D) Creatinine and potassium levels rose above normal values days to weeks before rejection. Hemoglobin values remained relatively normal.

Figure 3

Analysis of grafts surviving to 557 days. (A) Kaplan-Meier curve analysis of recipients who received genetically engineered porcine kidneys with or without tesidolumab included in the immunosuppression regimen. (B) H&E and confocal microscope analysis of rejected xenografts. Confocal microscopy showing deposition of IgM and C4d in the control and tesidolumab-treated recipients. Tesidolumab-treated recipients had minimal histological injury, while control kidneys had parenchymal hemorrhage and thrombotic microangiopathy. Deposition of C5b-9 was reduced on xenografts in tesidolumab-treated recipients.

Figure 4

Anti‐C5 plus anti‐CD40 prolongs renal xenograft survival. (A) Creatinine is shown to be well controlled until acutely rising at time of graft failure. (B) Serum potassium was well controlled throughout, except during late graft failure because of rejection. (C) Early graft failure recipients encounter anemia as shown by decreased hemoglobin levels. Tesidolumab-treated recipients maintained hemoglobin levels at or above normal levels more frequently than control animals for the duration of graft survival.