Static Cold Storage with Mitochondria-Targeted Hydrogen Sulfide Donor Improves Renal Graft Function in an Ex Vivo Porcine Model of Controlled Donation-after-Cardiac-Death Kidney Transplantation.

The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD.

The Impact of Nutritional Supplementation on Donor Kidneys During Oxygenated Ex Vivo Subnormothermic Preservation.

Unlabelled: Evidence suggests that nutritional supplementation during normothermic ex vivo perfusion improves organ preservation. However, it is unclear whether the same benefit is observed during room temperature (subnormothermic) oxygenated perfusion. In this study, we tested the impact of providing complete nutrition during subnormothermic perfusion on kidney outcomes.

Supplemental hydrogen sulfide in models of renal transplantation after cardiac death.

Background: The increasing use of kidneys from donations after cardiac death (DCD) for renal transplantation is hindered by negative outcomes owing to organ injury after prolonged warm and cold ischemia-reperfusion. Recently, hydrogen sulfide (HS) has shown cytoprotective effects against ischemia-reperfusion injury; however, its effectiveness in the context of DCD renal transplantation is unknown.

Methods: We tested a novel 30-day in vivo syngeneic murine model of DCD renal transplantation, in which the donor kidney was clamped for 30 minutes and stored for 18 hours in cold University of Wisconsin (UW) solution or UW with 150 μM sodium hydrogen sulfide (UW + NaHS) before transplantation.

Sodium thiosulfate-supplemented UW solution protects renal grafts against prolonged cold ischemia-reperfusion injury in a murine model of syngeneic kidney transplantation.

Introduction: Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (HS) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved HS donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation.

HS donor molecules against cold ischemia-reperfusion injury in preclinical models of solid organ transplantation.

Cold ischemia-reperfusion injury (IRI) is an inevitable and unresolved problem that poses a great challenge in solid organ transplantation (SOT). It represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays graft function. This complicates graft quality, post-transplant patient care and organ transplantation outcomes, and therefore undermines the success of SOT.

Evaluating the Effects of Subnormothermic Perfusion with AP39 in a Novel Blood-Free Model of Ex Vivo Kidney Preservation and Reperfusion.

The use of blood for normothermic and subnormothermic kidney preservation hinders the translation of these approaches and promising therapeutics. This study evaluates whether adding hydrogen sulfide donor AP39 to Hemopure, a blood substitute, during subnormothermic perfusion improves kidney outcomes. After 30 min of renal pedicle clamping, porcine kidneys were treated to 4 h of static cold storage (SCS-4 °C) or subnormothermic perfusion at 21 °C with Hemopure (H-21 °C), Hemopure + 200 nM AP39 (H200nM-21 °C) or Hemopure + 1 µM AP39 (H1µM-21 °C).

Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms.

Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (HS), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities.

Subnormothermic Perfusion with HS 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 (HS) has gained momentum. In this study, we investigated whether adding HS donor AP39 to porcine blood during subnormothermic perfusion at 21 °C improves renal graft outcomes.

Patterns of Expression of HS-Producing Enzyme in Human Renal Cell Carcinoma Specimens: Potential Avenue for Future Therapeutics.

Background: Renal cell carcinoma (RCC) is the most common cancer of the kidney. The most common histotype is clear-cell (cc) RCC. Hydrogen sulfide (HS) is an angiogenic and anti-apoptotic gasotransmitter that is elevated under pseudohypoxic conditions.

Hydrogen Sulfide: Emerging Role in Bladder, Kidney, and Prostate Malignancies.

Hydrogen sulfide (HS) is the latest member of the gasotransmitter family and known to play essential roles in cancer pathophysiology. HS is produced endogenously and can be administered exogenously. Recent studies showed that HS in cancers has both pro- and antitumor roles.

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.

Reconstitution of T-Cell Subsets Following Thymoglobulin-Induced Depletion in High Immunologic Risk and Donation After Cardiac Death Renal Transplant Recipients.

Introduction: Depletion therapy in high immunologic risk (HR) patients by antithymocyte globulin (rATG) induces lymphopenia and subsequent compartmental repopulation of T-cell subsets. rATG is also given to patients receiving kidneys from donations after cardiac death (DCDs) to mitigate innate immune activation associated with the DCD process.

Methods: We compared the T-cell response with rATG in both HR and DCD kidney recipients.

Supplementing preservation solution with mitochondria-targeted H S donor AP39 protects cardiac grafts from prolonged cold ischemia-reperfusion injury in heart transplantation.

Heart transplant has been accepted as the standard treatment for end-stage heart failure. Because of its susceptibility to ischemia-reperfusion injury, the heart can be preserved for only 4 to 6 hours in cold static preservation solutions. Prolonged ischemia time is adversely associated with primary graft function and long-term survival.

Novel therapeutic strategies for renal graft preservation and their potential impact on the future of clinical transplantation.

Purpose Of Review: The current review aims to examine recent evidence about improvements, therapeutics and novel approaches for renal graft preservation along with presenting a pragmatic outlook on their potential for clinical translation.

Recent Findings: Modifying established cold preservation methods (4 °C) with oxygenation, gene therapies and gasotransmitters such as hydrogen sulfide has been shown to improve renal graft outcomes with minimum modifications to current protocols. These strategies have also shown promise in the context of normothermic preservation (34-37 °C), which circumvents the damage caused by cold preservation.

Endogenous HS production deficiencies lead to impaired renal erythropoietin production.

Introduction: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (HS), an endogenously derived renal oxygen sensor.

HS supplementation: A novel method for successful organ preservation at subnormothermic temperatures.

Renal transplantation is the preferred treatment for end-stage renal disease. Currently, there is a large gap between the supply and demand for transplantable kidneys. The use of sub-optimal grafts obtained via donation after cardiac death (DCD) is on the rise.

Nonspecific CD8 T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8 T Cell-Mediated Clusters against Malaria Liver-Stage Infection.

CD8 T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around -infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8 T cells in cluster formation and protective immunity. To this end, we used ANKA expressing ovalbumin as well as CD8 T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8 T cells specific for an unrelated antigen, respectively.

Is hydrogen sulfide a potential novel therapy to prevent renal damage during ureteral obstruction?

In prolonged complete unilateral ureteral obstruction, reduced renal blood flow places the kidney in a state of ischemia, which can cause tubular injury and inflammation. Infiltrating inflammatory cells release transforming growth factor beta 1, which is a cytokine that initiates fibrosis through the epithelial-mesenchymal-transition pathway. Persistent fibrosis can lead to irreversible renal injury and loss of function.