Kidney transplantation remains the ultimate treatment option for patients with end-stage renal disease. However, the global shortage in donor kidneys, exacerbated by challenges such as ischemia–reperfusion injury (IRI), reduces renal graft viability and negatively impacts post-transplant outcomes. Static cold storage, the gold standard of organ preservation, reduces metabolic demand but increases the risk of cold-induced mitochondrial dysfunction and IRI, especially in marginal kidneys. The introduction of machine perfusion techniques allows renal grafts and other solid organ grafts to be preserved at a wider range of temperatures. Organ preservation temperatures play an important role in determining post-transplant outcomes in the transplantation of the kidney and other transplantable solid organs. Therefore, determining the optimal preservation temperature may help increase organ utilization by avoiding unnecessary graft discards and increasing the safe use of marginal organs. This review discusses the impact of various preservation temperatures and methods of preservation on post-transplant outcomes in renal grafts and other organ grafts. Drawing from preclinical, clinical, and meta-analytic studies, we compare hypothermic (0–4 °C), moderate hypothermic (10 °C), subnormothermic (20–32 °C), normothermic (35–37 °C), and subzero preservation strategies, and cellular and molecular changes that occur in renal grafts and other solid organ grafts during preservation at these temperatures. Overall, temperature-controlled machine perfusion outperforms static preservation of renal grafts and other solid organ grafts from marginal and deceased donors, potentially expanding donor pools and improving long-term graft survival, and suggests the need for future research to determine optimal preservation temperature for renal grafts and other solid organ grafts to improve viability and post-transplant outcomes.

Background: Subnormothermic oxygenated machine perfusion has been shown to improve kidney preservation in the preclinical setting. However, whether oxygenated perfusion without an oxygen carrier provides superior protection over standard hypothermic machine perfusion at 4 °C in human kidneys has not been established. Methods: In this study, we assessed whether oxygenated University of Wisconsin (UW) solution perfusion at 22 °C provides improved protection compared with conventional hypothermic machine perfusion (HMP) at 4 °C using a paired human kidney model. Five pairs of discarded human kidneys were recruited for the study. For each donor pair, one kidney was randomized to 12 h oxygenated UW perfusion at 22 °C and the contralateral kidney was perfused at 4 °C with a clinically relevant kidney perfusion pump. After preservation, both kidneys were reperfused with whole blood at 37 °C for 4 h. Hemodynamic and functional parameters were assessed during preservation and reperfusion, including vascular resistance, renal blood flow, creatinine clearance, blood urea nitrogen, electrolyte levels, tissue oxygenation, and urine output. Histological injury was evaluated and a panel of kidney injury biomarkers were also measured. Results: Vascular resistance during the preservation period was significantly lower in the kidneys preserved at 22 °C compared to the HMP group, indicating improved flow dynamics. However, the improved vascular resistance observed during 22 °C preservation did not translate into superior post-reperfusion kidney function or tissue protection compared with 4 °C HMP. Renal blood flow, creatinine clearance, tissue oxygenation, cytochrome c release and malondialdehyde (MDA) levels were comparable between groups, while kidneys preserved at 22 °C had significantly higher acute tubular necrosis scores, higher blood urea nitrogen (BUN) levels, increased calbindin, glutathione S-transferase A1, monocyte chemoattractant protein-1 levels, and lower epidermal growth factor levels. Conclusion: These data demonstrate that oxygenated UW perfusion at 22 °C fails to provide superior protection to conventional HMP at 4 °C in discarded human kidneys transplantation model.

Background: Renal ischemia–reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). It is associated with reduced blood flow as encountered in vascular surgery, including aortic aneurysm repair and kidney transplantation. In this study, we investigated whether pre- and/or post-administration of sodium thiosulfate (STS), an FDA-approved hydrogen sulfide donor drug, attenuated IRI-induced AKI in rats. Methods: AKI was induced in male rats by clamping both renal arteries for 60 min. At 30 min before clamping, and 30 min after reperfusion, STS was administered at a weigh-based dose to achieve a circulating concentration of 150 μM, after which the rats were kept in metabolic cages for urine and blood collection on postoperative days (POD) 3, 5, and 7. Rats were sacrificed on POD3, POD5, and POD7, and kidneys were harvested for analysis. Sham-operated rats received no treatment. Results: AKI was evidenced by markedly higher acute tubular necrosis score, and renal protein and gene expression of damage markers (KIM-1 and NGAL), as well as markers of oxidative stress (MDA, GSH, and SOD), inflammation (MPO, IL-6), and apoptosis (TUNEL). While significant incremental improvement was observed in the expression of these markers in the pre-treatment only and post-treatment only groups over the POD3–7 observation period compared to untreated control group (p < 0.05), superior renal protection was observed in the pre + post-treatment group (p < 0.01). Functionally, serum creatinine levels were significantly higher over the POD3–7 observation period in the untreated group relative to pre-treatment and post-treatment groups (p < 0.05), and markedly lower in the pre + post-treatment group (p < 0.001), which positively correlated with urine output. Urine osmolality was statistically similar to sham-operated rats on POD5 and 7, while all other groups showed decreased urine osmolality on POD3 and 5 (p < 0.05). Mechanistically, the protective effect of STS correlated with upregulation of PGC1α and SIRT3 protein and gene expression and downregulation of NLRP3 protein and mRNA expression in the pre + post-treatment group compared to other groups (p < 0.05). Conclusions: The present study reports for the first time the protective effect of STS against IRI-induced AKI, and indicates PGC1α, SIRT3, and NLRP3 as molecular targets of STS.

Despite their reduced viability, kidneys from donors-after-circulatory-death (DCD) increase the pool of transplantable kidneys. Molecular hydrogen (H₂) is emerging as a gas with therapeutic potential against graft injury. We investigated the effect of H₂ in an ex vivo porcine model of DCD kidney transplantation. Renal arteries of male Yorkshire pigs (n = 6) were clamped in situ for 60 min to induce ischemia, and ureters and arteries were cannulated to mimic DCD kidney injury. Upon nephrectomy, kidneys were flushed with UW solution or H₂-saturated UW solution and then preserved by machine perfusion at 4 °C for 4 h followed by a 4-h reperfusion period with warm autologous blood. Urine and arterial blood samples were collected hourly. H₂ preserved renal architecture, evidenced by significantly reduced tubular necrosis and renal expression of damage markers, which corresponded with the downregulated renal expression of pro-inflammatory genes compared to the UW-only group (p < 0.05). H₂ also markedly reduced levels of serum creatinine, BUN and intrarenal resistance, while flow rate, creatinine clearance and urine output were significantly higher, which positively correlated with Trx-1 and HO-1 expression in comparison with UW only group (p < 0.05). Improvement in renal graft quality and function is associated with Trx-1/HO-1 activation, suggesting preliminary clinical trials in kidney transplantation.