De novo membranous nephropathy in a pig-to-baboon kidney xenograft: A new xenograft glomerulopathy

Abstract

De novo membranous nephropathy (dnMN) is an uncommon immune complex-mediated late complication of human kidney allografts that causes proteinuria. We report here the first case of dnMN in a pig-to-baboon kidney xenograft. The donor was a double knockout (GGTA1 and β4GalNT1) genetically engineered pig with a knockout of the growth hormone receptor and addition of 6 human transgenes (hCD46, hCD55, hTBM, hEPCR, hHO1, and hCD47). The recipient developed proteinuria at 42 days posttransplant, which progressively rose to the nephrotic-range at 106 days, associated with an increase in serum antidonor IgG. Kidney biopsies showed antibody-mediated rejection (AMR) with C4d and thrombotic microangiopathy that eventually led to graft failure at 120 days. In addition to AMR, the xenograft had diffuse, global granular deposition of C4d and IgG along the glomerular basement membrane on days 111 and 120. Electron microscopy showed extensive amorphous subepithelial electron-dense deposits with intervening spikes along the glomerular basement membrane. These findings, in analogy to human renal allografts, are interpreted as dnMN in the xenograft superimposed on AMR. The target was not identified but is hypothesized to be a pig xenoantigen expressed on podocytes. Whether dnMN will be a significant problem in other longer-term xenokidneys remains to be determined.

Keywords: antibody-mediated rejection; kidney; membranous nephropathy; proteinuria; transplantation; xenograft kidney; xenotransplantation.

Figure 1.

Immunosuppressive regimen included induction therapy using ATG 5 mg/kg on days -2 and 0, rituximab 5 mg/kg on day -1, and C1-esterase inhibitor 17.5 IU/kg on days 0 and 2. TNX-1500 was administered intravenously at 30 mg/kg on days 0, 2, 7, and 14, then 20 mg/kg weekly from days 21 to 175. The recipient was also given rapamycin beginning 5 days before the transplant.

Figure 2.

Clinical course of the recipient showing rising creatinine beginning 110 days posttransplant. This was associated by a decrease in platelet counts and rise in white blood cell (WBC) counts. BUN, blood urea nitrogen; LYM, lymphocytes.

Figure 3.

(A) Xenograft kidney at 71 days posttransplant showing focal microaneurysms (blue arrow) and thickened glomerular capillary walls (black arrows) (PAS, 400×). (B) There is extensive C4d deposition along peritubular and glomerular capillaries. (C) Immunofluorescence studies using an antibody against human IgG on the xenograft kidney at autopsy show diffuse granular (inset) to confluent and almost linear staining of the glomerular capillary walls at 120 days posttransplant. (D) The electron-dense deposits are subepithelial in location, right beneath podocyte foot processes (yellow arrows; original magnification, 2800×).