Andrew M. Cameron

Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux

The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppressive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca(2+)-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP3R Ca2+ channels in the absence of FK506, with added FK506 disrupting these complexes. Dissociation of FKBP12 results in alteration of channel Ca2+ conductance in both cases. We now report that calcineurin is physiologically associated with the IP3R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin. Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux.

Optimal Utilization of Donor Grafts With Extended Criteria: A Single-Center Experience in Over 1000 Liver Transplants

Objective:Severely limited organ resources mandate maximum utilization of donor allografts for orthotopic liver transplantation (OLT). This work aimed to identify factors that impact survival outcomes for extended criteria donors (ECD) and developed an ECD scoring system to facilitate graft-recipient matching and optimize utilization of ECDs. Methods:Retrospective analysis of over 1000 primary adult OLTs at UCLA. Extended criteria (EC) considered included donor age (>55 years), donor hospital stay (>5 days), cold ischemia time (>10 hours), and warm ischemia time (>40 minutes). One point was assigned for each extended criterion. Cox proportional hazard regression model was used for multivariate analysis. Results:Of 1153 allografts considered in the study, 568 organs exhibited no extended criteria (0 score), while 429, 135 and 21 donor allografts exhibited an EC score of 1, 2 and 3, respectively. Overall 1-year patient survival rates were 88%, 82%, 77% and 48% for recipients with EC scores of 0, 1, 2 and 3 respectively (P < 0.001). Adjusting for recipient age and urgency at the time of transplantation, multivariate analysis identified an ascending mortality risk ratio of 1.4 and 1.8 compared to a score of 0 for an EC score of 1, and 2 (P < 0.01) respectively. In contrast, an EC score of 3 was associated with a mortality risk ratio of 4.5 (P < 0.001). Further, advanced recipient age linearly increased the death hazard ratio, while an urgent recipient status increased the risk ratio of death by 50%. Conclusions:Extended criteria donors can be scored using readily available parameters. Optimizing perioperative variables and matching ECD allografts to appropriately selected recipients are crucial to maintain acceptable outcomes and represent a preferable alternative to both high waiting list mortality and to a potentially futile transplant that utilizes an ECD for a critically ill recipient.

FKBP12 Binds the Inositol 1,4,5-Trisphosphate Receptor at Leucine-Proline (1400–1401) and Anchors Calcineurin to this FK506-like Domain

The immunophilin FKBP12 is one of the most abundant and conserved proteins in biology. It is the primary receptor for the immunosuppressant actions of the drug FK506 in whose presence FKBP12 binds to and inhibits calcineurin, disrupting interleukin formation in lymphocytes. The physiologic functions of FKBP12 are less clear, although the protein has been demonstrated to physiologically interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the ryanodine receptor, and the type 1 transforming growth factor β receptor. We now report that FKBP12 binds the IP3R at residues 1400–1401, a leucyl-prolyl dipeptide epitope that structurally resembles FK506. We further demonstrate that binding to IP3R at this site enables FKBP12 to interact with calcineurin, presumably to anchor the phosphatase to IP3R and modulate the receptor’s phosphorylation status. We propose that FK506 promotes an FKBP12-calcineurin interaction by mimicking structurally similar dipeptide epitopes present within proteins that use FKBP12 to anchor calcineurin to the appropriate physiologic substrates.

Recurrence of Hepatocellular Carcinoma Following Liver Transplantation A Review of Preoperative and Postoperative Prognostic Indicators

OBJECTIVE To review the preoperative and postoperative variables that predict hepatocellular carcinoma (HCC) recurrence following orthotopic liver transplantation (OLT). DATA SOURCES A collective review of the literature was conducted by searching the MEDLINE database using several key words: hepatocellular carcinoma, recurrence, liver transplantation, and salvage transplantation. STUDY SELECTION Reviews and original articles containing basic scientific observations and long-term clinical outcomes were included. DATA EXTRACTION Critical observations from peer-reviewed sources were incorporated in this review. DATA SYNTHESIS Overall, 11 studies were reviewed to determine the incidence of HCC recurrence following OLT and to identify prognostic variables of recurrence. Four studies were evaluated to determine the efficacy of salvage transplantation following liver resection. CONCLUSIONS Liver transplantation is a viable treatment option for select patients with HCC and end-stage liver disease. However, in approximately 20% of patients, recurrent HCC is the rate-limiting factor for long-term survival. Despite identification of clinical parameters that may stratify patients at high risk and exhaustive preoperative staging, cancer recurrence is likely the result of microscopic extrahepatic disease. With a desperate donor organ shortage, locoregional ablation techniques and resection are being employed in patients on the waiting list to serve as a bridge to OLT. Furthermore, some have advocated aggressive surgical resection of isolated metastasis in both the liver and extrahepatic viscera. Whether these creative strategies confer a survival advantage is unknown; it will require long-term follow-up to determine their efficacy.

Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials.

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta‐analysis and meta‐regression of 30 publications representing 19 randomized trials that compared steroid‐free with steroid‐based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid‐free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference −0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid‐free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid‐free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta‐analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid‐free regimens in LT. Liver Transpl 14:512–525, 2008.

Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: Ineffective usage of renal allografts

Background. When the United Network for Organ Sharing changed its algorithm for liver allocation to the model for end-stage liver disease (MELD) system in 2002, highest priority shifted to patients with renal insufficiency as a major component of their end-stage liver disease. An unintended consequence of the new system was a rapid increase in the number of simultaneous liver–kidney transplants (SLK) being performed yearly. Methods. Adult recipients of deceased donor liver transplants (LT, n=19,137), kidney transplants (n=33,712), and SLK transplants (n=1,032) between 1987 and 2006 were evaluated based on United Network for Organ Sharing data. Recipients were stratified by donor subgroup, MELD score, pre- versus post-MELD era, and length of time on dialysis. Matched-control analyses were performed, and graft and patient survival were analyzed by Kaplan–Meier and Cox proportional hazards analyses. Results. MELD era outcomes demonstrate a decline in patient survival after SLK. Using matched-control analysis, we are unable to demonstrate a benefit in the SLK cohort compared with LT, despite the fact that higher quality allografts are being used for SLK. Subgroup analysis of the SLK cohort did demonstrate an increase in overall 1-year patient and liver graft survival only in those patients on long-term dialysis (≥3 months) compared with LT (84.5% vs. 70.8%, P=0.008; hazards ratio 0.57 [95% CI 0.34, 0.95], P=0.03). Conclusion. These findings suggest that SLK may be overused in the MELD era and that current prioritization of kidney grafts to those liver failure patients results in wasting of limited resources.

Histidine–Tryptophan–Ketoglutarate (HTK) Is Associated with Reduced Graft Survival in Deceased Donor Livers, Especially Those Donated After Cardiac Death

Single‐center studies have reported that liver allograft survival is not affected by preservation in histidine–tryptophan–ketoglutarate (HTK) versus University of Wisconsin (UW) solution. We analyzed the UNOS database of liver transplants performed from July, 2004, through February, 2008, to determine if preservation with HTK (n = 4755) versus UW (n = 12 673) impacted graft survival. HTK preservation of allografts increased from 16.8% in 2004 to 26.9% in 2008; this was particularly striking among donor after cardiac death (DCD) allografts, rising from 20.7% in 2004 to 40.9% in 2008. After adjusting for donor, recipient and graft factors that affect graft survival, HTK preservation was associated with an increased risk of graft loss (HR 1.14, p = 0.002), especially with DCD allografts (HR 1.44, P = 0.025) and those with cold ischemia time over 8 h (HR 1.16, P = 0.009). Furthermore, HTK preservation was associated with a 1.2‐fold higher odds of early (< 30 days) graft loss as compared to UW preservation (OR 1.20, p = 0.012), with a more pronounced effect on allografts with cold ischemia time over 8 h (OR 1.31, p = 0.007), DCD allografts (OR 1.63, p = 0.09) and donors over 70 years (OR 1.67, p = 0.081). These results suggest that the increasing use of HTK for abdominal organ preservation should be reexamined.

Increasing disparity in waitlist mortality rates with increased model for end‐stage liver disease scores for candidates with hepatocellular carcinoma versus candidates without hepatocellular carcinoma

Candidates with hepatocellular carcinoma (HCC) within the Milan criteria (MC) receive standardized Model for End‐Stage LIver Disease (MELD) exception points because of the projected risk of tumor expansion beyond the MC. Exception points at listing are meant to be equivalent to a 15% rusj if 90‐day mortality, with additional points granted every 3 months, equivalent to a 10% increased morality risk. We analyzed the United Network for Organ Sharing database (January 1, 2005 to May 31, 2009) to compare the 90‐day waitlist outcomes of HCC candidates and non‐HCC candidates with similar MELD scores. Two hundred fifty‐nine HCC candidates (4.1%) who were initially listed with 22 MELD exception points were removed because of death or clinical deterioration within 90 days of listing, whereas 283 non‐HCC candidates (11.0%) with initial laboratory MELD scores of 21 to 23 were removed. Ninety‐three HCC candidates (4.6%) with 25 exception points (after 3‐6 months of waiting) were removed because of death or clinical deterioration within 90 days, whereas 805 non‐HCC candidates (17.3%) with laboratory MELD scores of 24 to 26 were removed. Twenty HCC candidates (3.0%) with 28 exception points (after 6‐9 months of waiting) were removed for death or clinical deterioration within 90 days, whereas 646 non‐HCC candidates (23.6%) with laboratory MELD scores of 27 to 29 were removed. In multivariate logistic regression models, HCC candidates had significantly lower 90‐day odds of waitlist removal for death or clinical deterioration (P < 0.001). Over time, the risk of waitlist removal for death or clinical deterioration was unchanged for HCC candidates (P = 0.17), whereas it increased significantly for non‐HCC candidates. The current allotment of HCC exception points should be re‐evaluated because of the stable risk of waitlist dropout for these candidates. Liver Transpl 18:434–443, 2012.

Social media and organ donor registration: the Facebook effect.

Despite countless media campaigns, organ donation rates in the United States have remained static while need has risen dramatically. New efforts to increase organ donation through public education are necessary to address the waiting list of over 100,000 patients. On May 1, 2012, the online social network, Facebook, altered its platform to allow members to specify “Organ Donor” as part of their profile. Upon such choice, members were offered a link to their state registry to complete an official designation, and their “friends” in the network were made aware of the new status as a donor. Educational links regarding donation were offered to those considering the new organ donor status. On the first day of the Facebook organ donor initiative, there were 13 054 new online registrations, representing a 21.1‐fold increase over the baseline average of 616 registrations. This first‐day effect ranged from 6.9× (Michigan) to 108.9× (Georgia). Registration rates remained elevated in the following 12 days. During the same time period, no increase was seen in registrations from the DMV. Novel applications of social media may prove effective in increasing organ donation rates and likewise might be utilized in other refractory public health problems in which communication and education are essential.

Histidine-tryptophan-ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation.

Prior single‐center studies have reported that pancreas allograft survival is not affected by preservation in histidine‐tryptophan‐ketoglutarate (HTK) versus University of Wisconsin (UW) solution. To expand on these studies, we analyzed the United Network for Organ Sharing (UNOS) database of pancreas transplants from July 2004, through February 2008, to determine if preservation with HTK (N = 1081) versus UW (N = 3311) impacted graft survival. HTK preservation of pancreas allografts increased significantly in this time frame, from 15.4% in 2004 to 25.4% in 2008. After adjusting for other recipient, donor, graft and transplant center factors that impact graft survival, HTK preservation was independently associated with an increased risk of pancreas graft loss (hazard ratio [HR] 1.30, p = 0.014), especially in pancreas allografts with cold ischemia time (CIT) ≥12 h (HR 1.42, p = 0.017). This reduced survival with HTK preservation as compared to UW preservation was seen in both simultaneous pancreas‐kidney (SPK) transplants and pancreas alone (PA) transplants. Furthermore, HTK preservation was also associated with a 1.54‐fold higher odds of early (<30 days) pancreas graft loss as compared to UW (OR 1.54, p = 0.008). These results suggest that the increasing use of HTK for abdominal organ preservation should be re‐examined.