No abstract

Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/protein deacetylases (HDACs) regulate gene accessibility and higher order protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class-specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24–96 hours (p < 0.001). Treated mice developed significantly less fibrosis at 30 days (p < 0.0004). Class I HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p < 0.008) with a trend toward improved cold ischemic survival in TSA-treated mice. These effects were not accompanied by induction of typical ischemic tolerance pathways or by priming of heat shock protein expression. In fact, heat shock protein 70 deletion or overexpression did not alter renal ischemia tolerance. Micro-RNA 21, known to be enhanced in vitro in renal tubular cells that survive stress, was enhanced by treatment with HDACi, pointing to possible mechanism.

Cardiac arrest associated with reperfusion of the liver allograft in a euvolemic patient is a rare but potentially devastating event. There are few case series describing experience with this complication and no published management protocols guiding treatment. This article is a retrospective case series of patients experiencing post-reperfusion intraoperative cardiac arrest between 1997 and 2011. Among 1581 liver transplants, 16 (1%) patients experienced post-reperfusion cardiac arrest. Among patients with intraoperative arrests, 14 (88%) patients required open cardiac massage. Seven (44%) were placed on cardiopulmonary bypass (CPB) when cardiac activity failed to adequately recover. Placement on CPB reversed cardiac pump failure and established a perfusing rhythm in six of seven (86%) recipients, leading to one of seven (14%) intraoperative mortality. Recovery of myocardial function was associated with low early survival with only 3/7 (43%) patients who underwent CPB surviving until discharge. Among all patients who survived the perioperative period, one-yr survival was 70% (N = 7), and five-yr survival was 50% (N = 5). Cardiac arrest during liver transplantation is associated with a poor prognosis during the perioperative period. In patients who do not recover cardiac activity after standard resuscitative measures, progression to physiologic support with systemic anticoagulation and CPB may allow correction of electrolyte derangements, maintenance of cerebral perfusion, and myocardial recovery.

No abstract

Patients with pretransplant DT of ≥10 years had worse outcomes than patients pre-emptively transplanted or transplanted with shorter DT. Durations of dialysis dependence beyond 10 years were associated with further deterioration in short-term but not long-term post-transplant outcomes.

Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis.

Early studies of national data suggest that the Share 35 allocation policy increased liver transplants without compromising post-transplant outcomes. Changes in center-specific volumes and practice patterns in response to the national policy change are not well characterized. Understanding center-level responses to Share 35 is crucial for optimizing the policy and constructing effective future policy revisions. Data from the United Network for Organ Sharing were analyzed to compare center-level volumes of allocation-MELD ≥35 transplants pre- and post-policy implementation. There was significant center-level variation in the number and proportion of allocation-MELD ≥35 transplants performed from the pre- to post-Share 35 period; eight centers accounted for 33.7% of the total national increase in allocation-MELD ≥35 transplants performed in the 2.5-year post-Share 35 period, while 25 centers accounted for 65.0% of the national increase. This trend correlated with increased listing at these centers of patients with MELD ≥35 at the time of initial listing. These centers did not over-represent the total national volume of liver transplants. Comparison of post-Share 35 allocation-MELD to calculated time-of-transplant laboratory MELD showed that only 69.6% of patients transplanted with allocation-MELD ≥35 maintained a calculated laboratory MELD ≥35 at the time-of-transplant. Conclusion Share 35 increased transplantation of allocation-MELD ≥35 recipients on a national level, but the policy asymmetrically impacted practice patterns and volumes of a subset of centers. Longer-term data is necessary to assess outcomes at centers with markedly increased volumes of high-MELD transplants post-Share 35.

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.