Proteinuria after pig kidney xenotransplantation: A potential unifying hypothesis linking mechanical, innate, and adaptive injury pathways.

Persistent proteinuria remains a major barrier to successful pig-to-nonhuman primate kidney xenotransplantation and may become an important issue in clinical renal xenotransplantation. However, published human renal xenotransplant reports to date have not established severe proteinuria as a consistent clinical finding, and its relevance in living human recipients should, therefore, be regarded as an important unresolved question. In pig-to-nonhuman primate models, severe proteinuria may also be accompanied by urinary loss of therapeutic monoclonal antibodies, including anti-CD154, potentially compromising rejection prophylaxis. Proteinuria in this setting may occur in association with heterogeneous and overlapping patterns of immune-mediated and nonimmune-mediated injury, including rejection-associated endothelial, microvascular, and humoral lesions such as thrombotic microangiopathy, capillaritis, C4d deposition, and xenograft glomerulopathy. Hemodynamic mismatch should currently be regarded as a possible but unproven contributor rather than a dominant initiating trigger. We, therefore, propose a unifying hypothesis based on an evidence-informed, testable framework rather than a definitive causal cascade, which we hope will stimulate discussion. Clarifying the dominant mechanisms in individual cases, correlating proteinuria with biopsy findings, and prospectively monitoring urinary drug loss will be essential for developing rational preventive and therapeutic strategies.