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In 2017, 18 136 of 96 120 eligible patients received kidney transplants in the United States. (1) As demand for donor kidneys continues to exceed current supply, the use of [...], 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 ([H.sub.2]S) 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 [micro]M sodium hydrogen sulfide (UW + NaHS) before transplantation. We also tested a 7-day in vivo porcine model of DCD renal autotransplantation, in which the left kidney was clamped for 60 minutes and preserved for 24 hours using hypothermic perfusion with UW or UW + 150 [micro]M NaHS before autotransplantation. We collected blood and urine samples periodically, and collected kidney samples at the end point for histopathology and quantitative reverse transcription polymerase chain reaction. Results: Rats that received [H.sub.2]S-treated kidneys showed significantly higher survival, faster recovery of graft function and significantly lower acute tubular necrosis than controls. Pig kidneys perfused with UW + NaHS showed significantly higher renal blood flow and lower renal resistance than control kidneys after 24 hours of perfusion. After autotransplantation, pigs that received [H.sub.2]S-treated kidneys showed significantly lower serum creatinine on days 1 and 7 after transplantation. Rat and pig kidneys treated with [H.sub.2]S also showed more protective gene expression profiles than controls. Conclusion: Our findings support the potential use of [H.sub.2]S-supplemented UW solution during cold storage as a novel and practical means to improve DCD graft survival and function. Contexte : Il est difficile d&apos;accroitre l&apos;utilisation de reins provenant de dons apres deces car-diocirculatoire (DDC) aux fins de transplantation renale en raison des resultats negatifs dus aux lesions d&apos;organe apres une ischemie-reperfusion chaude et froide prolongee. On a observe recemment que le sulfure d&apos;hydrogene ([H.sub.2]S) exercait des effets cytoprotecteurs contre les lesions d&apos;ischemie-reperfusion, mais on ignore encore s&apos;il est efficace dans un contexte de transplantation renale provenant d&apos;un DDC. Methodes : Nous avons mis a l&apos;essai un nouveau modele murin syngenique in vivo de transplantation renale provenant d&apos;un DDC sur 30 jours, dans lequel le rein du donneur a ete clampe pendant 30 minutes et conserve pendant 18 heures dans une solution froide de l&apos;Universite du Wisconsin (UW) (UW + 150 [micro]m d&apos;hydrogenosulfure de sodium [NaSH]) avant la transplantation. Nous avons egalement mis a l&apos;essai un modele porcin in vivo d&apos;autotransplantation renale provenant d&apos;un DDC sur 7 jours, dans lequel le rein gauche a ete clampe pendant 60 minutes et conserve pendant 24 heures par perfusion hypothermique (avec UW ou UW + 150 [micro]M de NaSH) avant l&apos;autotransplantation. Nous avons recueilli des echantillons de sang et d&apos;urine regulierement et avons preleve des echantillons de rein au point final en vue de l&apos;histopathologie et d&apos;un test d&apos;amplification en chaine par polymerase quantitative couple a une transcription inverse. Resultats : On a observe chez les rats ayant recu des reins traites au [H.sub.2]S un taux de survie significativement plus eleve, une recuperation plus rapide de la fonction du greffon et une necrose tubulaire aigue significativement plus faible que chez les temoins. Les reins de porc perfuses (UW + NaSH) ont montre un debit sanguin renal significativement plus eleve et une resistance renale plus faible que les temoins a la fin de la periode de perfusion de 24 heures. Apres l&apos;autotransplantation, les porcs ayant recu des reins traites au [H.sub.2]S presentaient une creatinine serique significativement plus faible aux jours 1 et 7 apres la transplantation. Les reins de rat et de porc traites au [H.sub.2]S ont egalement montre des profils d&apos;expression genique plus << protecteurs >> que les temoins. Conclusion : Nos conclusions appuient une eventuelle utilisation d&apos;une solution UW enrichie en [H.sub.2]S pendant la conservation a froid comme nouveau moyen pratique d&apos;ameliorer le taux de survie et la fonction du greffon lors de DDC.

We recently reported in a rat model of kidney transplantation that the addition of sodium thiosulfate (STS) to organ preservation solution improved renal graft quality and prolonged recipient survival. The present study investigates whether STS pre-treatment would produce a similar effect. In vitro, rat kidney epithelial cells were treated with 150 μM STS before and/or during exposure to hypoxia followed by reoxygenation. In vivo, donor rats were treated with PBS or 2.4 mg/kg STS 30 min before donor kidneys were procured and stored in UW or UW+150 μM STS solution at 4 °C for 24 h. Renal grafts were then transplanted into bilaterally nephrectomised recipient rats which were then sacrificed on post-operative day 3. STS pre-treatment significantly reduced cell death compared to untreated and other treated cells in vitro (p < 0.05), which corresponded with our in vivo result (p < 0.05). However, no significant differences were observed in other parameters of tissue injury. Our results suggest that STS pre-treatment may improve renal graft function after transplantation. [ABSTRACT FROM AUTHOR]

Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia–reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia–reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications. [ABSTRACT FROM AUTHOR]

Chronic allograft nephropathy (CAN), the most common cause of late kidney allograft failure, is not effectively prevented by immunosuppressive regimens. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) via MEK mediates actions of various growth factors, including transforming growth factor (TGF)-[beta]1, which plays a key role in CAN. Hence, we tested the therapeutic potential of MEK-ERK1/2 signaling disruption to prevent CAN. Kidneys from C57BL/6J ([H-2.sup.b]) mice were transplanted to bilaterally nephrectomized BALB/c ([H-2.sup.d]) mice. At 14 days after transplantation, the recipients were subjected to 28 days of treatment with the MEK inhibitor CI-1040. All six CI-1040-treated allografts survived, while two of seven grafts in the vehicle-treated group were lost. At the end of the experiment, the function and structure of grafts in the CI-1040-treated group were significantly preserved, as indicated by lower levels of serum creatinine or blood urea nitrogen than in the vehicle-treated group [30 [+ or -] 6 vs. 94 [+ or -] 39 [micro]M creatinine (P = 0.0015) and 22 [+ or -] 8 vs. 56 [+ or -] 25 mM BUN (P = 0.0054)] and reduced CAN in the CI-1040-treated group compared with vehicle controls (CAN score = 4.2 vs. 10.3, P = 0.0119). The beneficial effects induced by CI-1040 were associated with reduction of ERK1/2 phosphorylation and TGF[beta]1 levels in grafts. Also, CI-1040 potently suppressed not only TGF[beta] biosynthesis in kidney cell cultures but also antiallograft immune responses in vitro and in vivo. Our data suggest that interference of MEK-ERK1/2 signaling with a pharmacological agent (e.g., CI-1040) has therapeutic potential to prevent CAN in kidney transplantation. kidney transplantation; experimental therapy; transforming growth factor-[beta]1