Clinicopathological findings in non‐human primate recipients of porcine renal xenografts: quantitative and qualitative evaluation of proteinuria

Abstract

The study of clinicopathological changes in cynomolgus monkey renal xenograft recipients provides a valid help in monitoring the health conditions in the post-transplant period. Moreover, the evaluation of UPC ratio and the use of SDS-AGE technique in urine samples of cynomolgus monkey renal xenograft recipients may be considered a valid, inexpensive, and less time-consuming method than more sophisticated techniques in monitoring proteinuria. Proteinuria and presence of low molecular weight (LMW) proteins were consistently found in urine after transplantation, independent of fluctuations in renal function.

Results of Life-Supporting Galactosyltransferase Knockout Kidneys in Cynomolgus Monkeys Using Two Different Sources of Galactosyltransferase Knockout Swine

“…Moreover, GalT-KO kidney function was markedly prolonged when a vascularized thymus co-transplantation was performed in baboon recipients of MGH GalT-KO kidneys, with survivals without rejection averaging 51 days and with some survivals up to 83 days (8,9). However, the graft survival of GalT-KO kidneys in non-human primates as reported by other groups were limited and most grafts were lost within 16 days following transplantation (10,11). …”

Xenotransplantation: Where Are We with Potential Kidney Recipients? Recent Progress and Potential Future Clinical Trials

“…However, Pintore et al reported that proteinuria and presence of low molecular weight proteins were consistently found in urine after kidney transplantation in a multitrangenic, including human decay accerlating factor (hDAF), GalT-KO pig-to-cynomologus model (52). In addition, we have a case of an hDAF/GalT-KO-to-cynomolgus monkey renal transplant using an anti-CD40L based regimen without vascularized thymic graft which developed proteinuria following kidney transplantation similar to baboon recipients of GalT-KO kidneys (Yamada et al, manuscript in preparation).…”

“…However, although the use of the CRISPR/CAS9 technology has made the development of new lines of GalT-KO swine far easier than previously thought, the genes responsible for development of proteinuria has not been address by others. Recent data have found that incompatibility of a porcine CD47-baboon signal regulatory protein α (SIRP-α), which is an interspecies ligand-receptor interaction, induces activation of macrophages and phagocytosis in xenogeneic combinations (52–56). Immune activation of the porcine podocyte leads to expression of CD80 which potentially downregulates SIRP-α and SMPDL-3b.…”

“…In order to address this issue more clearly, we have recently investigated whether kidneys from donors that naturally grow faster than recipients grow following the donors’ growth curve or the recipients’ growth curve (52). With long follow up periods, our data suggest that intrinsic factors within the transplanted organ are largely involved in graft growth following transplantation in both allogeneic and xenogeneic transplant models.…”

“…With long follow up periods, our data suggest that intrinsic factors within the transplanted organ are largely involved in graft growth following transplantation in both allogeneic and xenogeneic transplant models. We have recently reported that (i) if the ratio of the pig kidney volume to the recipient animal's body weight was greater than 25 cm 3 /kg there appeared to be a deleterious effect on renal function across xenogeneic barrier between pig and baboons and (ii) allogeneic kidney graft size and percentage increase of kidney volume/body weight from outbred Yorkshire swine in miniature swine increased three times more than those of grafts from miniature swine to miniature swine at 12 weeks post-transplant, and (iii) rapid growth of kidneys and lungs across allogeneic and xenogeneic models caused compartment syndrome that resulted in ischemic damage in solid organs (52). These results suggest that intrinsic factors are responsible, at least in part, for the growth of donor organs and that this property should be taken into consideration for growth-curve mismatched transplants, especially for life-supporting organs transplanted into a limited recipient space.…”