Subnormothermic Perfusion with H2S Donor AP39 Improves DCD Porcine Renal Graft Outcomes in an Ex Vivo Model of Kidney Preservation and Reperfusion.

Cold preservation is the standard of care for renal grafts. However, research on alternatives like perfusion at higher temperatures and supplementing preservation solutions with hydrogen sulfide (H2S) has gained momentum. In this study, we investigated whether adding H2S donor AP39 to porcine blood during subnormothermic perfusion at 21 °C improves renal graft outcomes. Porcine kidneys were nephrectomized after 30 min of clamping the renal pedicles and treated to 4 h of static cold storage (SCS) on ice or ex vivo subnormothermic perfusion at 21 °C with autologous blood alone (SNT) or with AP39 (SNTAP). All kidneys were reperfused ex vivo with autologous blood at 37 °C for 4 h. Urine output, histopathology and RNAseq were used to evaluate the renal graft function, injury and gene expression profiles, respectively. The SNTAP group exhibited significantly higher urine output than other groups during preservation and reperfusion, along with significantly lower apoptotic injury compared to the SCS group. The SNTAP group also exhibited differential pro-survival gene expression patterns compared to the SCS (downregulation of pro-apoptotic genes) and SNT (downregulation of hypoxia response genes) groups. Subnormothermic perfusion at 21 °C with H2S-supplemented blood improves renal graft outcomes. Further research is needed to facilitate the clinical translation of this approach.

Daily use of a muscle pump activator device reduces duration of hospitalization and improves early graft outcomes post-kidney transplantation: A randomized controlled trial.

INTRODUCTION: Kidney and simultaneous pancreas-kidney (SPK) transplant recipients can have prolonged postoperative hospitalization due to edema. Thrombo-embolic-deterrent (TED) stockings with intermittent pneumatic compression devices (TED+IPC) have been used to improve venous return during the perioperative period. The objective of this trial was to evaluate the effects of TED+IPC vs. muscle pump activator (MPA) devices on factors that could reduce postoperative complications and duration of hospitalization. METHODS: In this single-center, prospective, randomized, controlled trial, 221 kidney and SPK transplant recipients were randomized to either wearing TED+IPC or MPA for six days postoperatively. Groups were compared with respect to postoperative urine output, lower limb edema, weight, days in hospital, mobility, serum creatinine, delayed graft function, need for dialysis, and lower extremity blood flow. RESULTS: Patients in the MPA group had significantly higher urine output and less increase in mid-calf leg circumference and weight gain compared to the TED+IPC group (p=0.003, p=0.001, and p=0.003, respectively). The MPA group also experienced shorter hospitalization (p=0.038), higher femoral vein velocity (p=0.001), and took more steps (p=0.009). Incidence of delayed graft function (p=0.72) and number of dialysis runs (p=0.39) was not different between study groups. Subgroup analysis of primary endpoints in donation after cardiac death recipients and SPK recipients did not yield any significance between the study arms. CONCLUSIONS: Postoperative use of the MPA device increases urine output, decreases leg edema, minimizes weight gain, and decreases duration of hospitalization after kidney transplantation. A larger and longer-term trial is needed to evaluate the impact on graft function.

Renal Protection Against Ischemia Reperfusion Injury: Hemoglobin-based Oxygen Carrier-201 Versus Blood as an Oxygen Carrier in Ex Vivo Subnormothermic Machine Perfusion.

BACKGROUND: The optimal method of oxygen delivery to donor kidneys during ex vivo machine perfusion has not been established. We have recently reported the beneficial effects of subnormothermic (22°C) blood perfusion in the preservation of porcine donation after circulatory death kidneys. Since using blood as a clinical perfusate has limitations, including matching availability and potential presence of pathogen, we sought to assess hemoglobin-based oxygen carrier (HBOC-201) in oxygen delivery to the kidney for renal protection. METHODS: Pig kidneys (n = 5) were procured after 30 minutes of warm in situ ischemia by cross-clamping the renal arteries. Organs were flushed with histidine tryptophan ketoglutarate solution and subjected to static cold storage or pulsatile perfusion with an RM3 pump at 22°C for 4 hours with HBOC-201 and blood. Thereafter, kidneys were reperfused with normothermic (37°C) oxygenated blood for 4 hours. Blood and urine were subjected to biochemical analysis. Total urine output, urinary protein, albumin/creatinine ratio, flow rate, resistance were measured. Acute tubular necrosis, apoptosis, urinary kidney damage markers, neutrophil gelatinase-associated lipocalin 1, and interleukin 6 were also assessed. RESULTS: HBOC-201 achieved tissues oxygen saturation equivalent to blood. Furthermore, upon reperfusion, HBOC-201 treated kidneys had similar renal blood flow and function compared with blood-treated kidneys. Histologically, HBOC-201 and blood-perfused kidneys had vastly reduced acute tubular necrosis scores and degrees of terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining versus kidneys treated with cold storage. Urinary damage markers and IL6 levels were similarly reduced by both blood and HBOC-201. CONCLUSIONS: HBOC-201 is an excellent alternative to blood as an oxygen-carrying molecule in an ex vivo subnormothermic machine perfusion platform in kidneys.