Inflammation in Kidney Transplantation: Could Xenotransplantation Offer Greater Benefit?

Inflammation plays a critical role in the success or failure of organ transplantation. Inflammation occurs at different magnitudes following allotransplantation using living donation, donation after brain death (DBD), or donation after circulatory death (DCD), and following xenotransplantation. The latter is particularly known to trigger a systemic inflammatory response to the pig xenograft. Inflammation is deeply intertwined with, and contributes to, the development of rejection, that is, the specific recognition and destruction of foreign antigen. Inflammation involves recruitment of innate immune cells, such as macrophages and neutrophils, activation of the complement system, and activation of endothelial cells with the upregulation of adhesion molecules. In addition, T-cell activation plays a central role in the adaptive immune response that drives rejection. As a result, inflammatory cytokines are released, effector cells and molecules are activated, and subsequent tissue injury occurs. In the current issue of Transplantation, Ubaid et al1 carefully reviewed the relative roles of inflammation in allotransplantation and xenotransplantation, focusing mainly on kidney transplantation. This review is very timely, considering the increased global interest in clinical xenotransplantation, particularly in kidney xenotransplantation.1,2 In the review, the authors systematically tackled inflammation by donor factors, recipient factors, and surgery in allotransplantation and by donor factors, recipient factors, and systemic inflammatory response in xenotransplantation. Figure 1 summarizes these factors in both allotransplantation and xenotransplantation, with risks and benefits.FIGURE 1.: Benefit and pitfalls of xenotransplantation. DBD, donation after brain death; DCD, donation after circulatory death; DPF, designated pathogen free; IRI, ischemia/reperfusion injury; IS, immunosuppression; KDPI, kidney donor profile index; SLA, swine leukocyte antigen.In allotransplantation, the type of donor (living, DBD, DCD) affects the severity of inflammation due to the degree of ischemia/reperfusion injury (IRI), age-related changes in the donor, and many other factors measured by the kidney donor profile index, whereas in xenotransplantation, donor-related inflammation is reduced by the use of live donor pigs, thereby avoiding the deleterious effects of brain or circulatory death observed in DBDs or DCDs. In that regard, xenotransplantation will be a planned elective surgery, similar to living donor kidney allotransplantation. Although genetic modifications and designated pathogen-free pig facilities will minimize many factors (ie, native immune response, viral and bacterial infections) causing inflammation in the xenograft,3 the relative distance of these designated pathogen-free facilities from transplant centers will still impose significant cold ischemic time on pig xenografts and contribute to the IRI. Machine perfusion is expected to mitigate, but not fully eliminate this effect. Recipient factors can be considered similar in allotransplantation and xenotransplantation, because the recipient does not change depending on whether an allograft or a xenograft is transplanted. However, a potential advantage of xenotransplantation lies in the ability to intervene earlier in the course of chronic disease, without waiting until marked deterioration has occurred as a result of prolonged chronic kidney disease (eg, diabetes) or extended exposure to dialysis. Both advanced chronic kidney disease and long-term dialysis are associated with systemic inflammation, characterized by upregulation of interleukin 6 and C-reactive protein, largely driven by the innate immune system.4 In fact, Ubaid et al1 reported an inverse association between reduced glomerular filtration rate and increased inflammatory biomarkers (fibrinogen, C-reactive protein, interleukin 6, tumor necrosis factor alpha), as demonstrated in the Chronic Renal Insufficiency Cohort study.4 In contrast, xenotransplantation—even under optimal conditions with young, healthy donors and minimal IRI—still induces a systemic inflammatory response5,6 due to species incompatibilities, which interact with both coagulation (coagulation dysregulation) and immunity. When considering the effect of transplant surgery on inflammation, both xenografts and allografts are subject to similar recipient surgical procedures. In this context, donor and recipient quality remain the primary determinants of inflammatory responses and, consequently, outcomes. Although robotic transplantation may reduce surgical trauma and thereby surgery-induced inflammation in allotransplantation, this approach is not yet available in xenotransplantation. However, it will likely become feasible in the future as surgical volumes increase and outcomes with open xenotransplantation continue to improve. Other important immunological factors contributing to inflammation in allotransplantation versus xenotransplantation include the following: Crossmatch testing, which is routine in allotransplantation but remains a challenge in xenotransplantation. The role of donor-specific antibodies in allotransplantation versus anti-pig antibodies in xenotransplantation, depending on specific genetic modifications. Differences in matching between HLA and swine leukocyte antigen (SLA). Interspecies incompatibilities between signals and ligands (eg, signal regulatory protein alpha-CD47 mismatch, species-specific major histocompatibility complex differences, and Natural Killer Group 2, member D–porcine UL16 binding protein 1 interactions in natural killer cells7). Advances in genetic engineering, together with a better understanding of SLA, may enable the generation of class I and/or class II SLA knockout pigs8,9 as xenograft donors, thereby overcoming species-specific major histocompatibility complex differences and reducing certain preformed anti-pig antibody responses. In addition, overexpression of selected HLA molecules in donor pigs could allow for the development of personalized xenografts in the future. Understanding the mechanisms of inflammation is critical to improving transplant survival rates, ultimately benefiting millions worldwide. Advances in (1) anti-inflammatory therapies, such as biologics targeting specific pathways; (2) genetic engineering of donor pigs to attenuate inflammatory responses, for example, through overexpression of human heme oxygenase-1; and (3) the use of the most suitable graft, whether allograft or xenograft, will further enhance outcomes. We are entering an exciting new era in transplantation with the introduction of xenografts.2 Despite existing challenges, these advances hold great promise for improving outcomes for all transplant recipients.