Department of Pathology, Immunopathology Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Am J Transplant. 2024 Jan;24(1):30-36. doi: 10.1016/j.ajt.2023.08.016. Epub 2023 Aug 25.
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.
新发膜性肾病（dnMN）是人类肾移植后罕见的免疫复合物介导的晚期并发症，可导致蛋白尿。我们在此报告首例猪-狒狒肾异种移植中的 dnMN 病例。供体是一种双重基因敲除（GGTA1 和β4GalNT1）的基因工程猪，敲除了生长激素受体，并添加了 6 个人类转基因（hCD46、hCD55、hTBM、hEPCR、hHO1 和 hCD47）。受者在移植后 42 天出现蛋白尿，在 106 天逐渐上升至肾病范围，同时血清抗供体 IgG 增加。肾活检显示伴有 C4d 和血栓性微血管病的抗体介导的排斥反应（AMR），最终导致 120 天时移植物衰竭。除 AMR 外，异种移植物在第 111 天和第 120 天显示出弥漫性、全球性颗粒状 C4d 和 IgG 在肾小球基底膜上的沉积。电子显微镜显示广泛的无定形上皮下电子致密沉积物，在肾小球基底膜上有间隔的刺突。这些发现与人类肾移植相类似，被解释为 AMR 上叠加的异种移植物中的 dnMN。靶标尚未确定，但据推测是表达在足细胞上的猪异种抗原。dnMN 是否会成为其他长期异种肾中的一个重大问题仍有待确定。
