Introduction: Here we describe the clinical management of the longest living recipient of a porcine xenokidney and the infectious and immunosuppressive complications that eventually led to graft loss.
Methods: A 10 gene-edit porcine kidney (GGTA1, CMAH, B4GALNT2, and GHR gene inactivations; hCD46, hCD47, hCD55, hTHBD, hPROCR, and hHMOX1 human transgene insertions) was transplanted into a 53-year-old female prior living donor, on hemodialysis for 9 years, with a cPRA of 99.98%. No experimental immunosuppressive medications were used.
Results: Immediate graft function was evidenced by a mean serum creatine (sCr) and urinary protein-to-creatinine ratios (UPCR) of 1.2 mg/dL and 1.4 g/g, respectively, for the first two weeks post-transplant. UPCR increased to 12.7 g/g along with a rise in IgG and IgM on flow crossmatch. A biopsy performed on POD 17 demonstrated glomerulitis, peritubular capillaritis, diffuse C4d staining (Banff g2 t0 i0 ptc0-1 v0 c4d3, cg0 ct0 mm2 ci0 ti0 cv0 ah0 i-ifta0), C3 deposition in the glomeruli, and 90% podocyte foot process effacement. The AMR treatment plan included 10 plasmapheresis sessions, low dose IVIG, C3/C3b complement inhibitor, and 3 mg/kg rATG. POD 57 and 85 biopsies confirmed absence of AMR and resolution of foot process effacement. On POD 73 the patient was administered IL-6 receptor blockade for a monocyte rich transcriptomics signature on POD 57 biopsy. Following the establishment of histologic immunologic quiescence the patient was started on anti-proteinuric agents to lower her still-present nephrotic range proteinuria. Unfortunately, despite these agents the patient remained with proteinuria that averaged 5.8 ± 5.8 g/g daily. She continued to maintain excellent xenograft function, however, with a stable sCr of 1.59 ± 0.32 mg/dL that increased to 2.06 mg/dL once fully optimized on anti-proteinuric agents. The development of two severe soft tissue infections of the skin, the second of which was accompanied by gram-negative bacteremia prompted the cessation of IL-6 receptor blockade and a reduction in calcineurin inhibitor goal by 50%. The patient was maintained on mycophenolate mofetil, prednisone, belatacept, and complement inhibition. On POD 125, the patient was noted to have a rise in sCr from a baseline of 2.05 mg/dL to 3.99 mg/dL. Her kidney function continued to rapidly decline, with sCr peaking at 10.56 mg/dL. POD 128 biopsy demonstrated loss of normal renal architecture and extensive, severe interstitial hemorrhage. The patient underwent explant on POD 130 and returned to dialysis.
Conclusions: Following successful treatment of an early episode of AMR, we were able to maintain a Xenokidney in a living human being for 130 days, establishing the longest surviving recipient of a xenotransplant. The patient’s xenograft failed in the setting of reduced immunosuppression due to recurrent infections and the likely loss of monoclonal drug in her urine due to persistent, nephrotic range proteinuria.