Early predictors of prolonged intensive care utilization following liver transplantation.

INTRODUCTION: Creatinine, bilirubin, and fibrinolysis resistance are associated with multi-organ dysfunction and likely risk factors for prolonged intensive care unit (pICU) stay following liver transplantation (LT). We hypothesize postoperative day-1 (POD-1) labs will predict pICU. METHODS: LT recipients had clinical laboratories and viscoelastic testing with tissue plasminogen activator thrombelastography (tPA TEG) to quantify fibrinolysis resistance (LY30) on POD-1. pICU was defined as one week or longer in the ICU. Logistic regression was used to identify the relationship between POD-1 labs and pICU. RESULTS: Of 304 patients, 50% went to the ICU, with 15% experiencing pICU. Elevated creatinine (OR 6.6, P â€‹< â€‹0.001) and low tPA TEG LY30 (OR 3.7, P â€‹= â€‹0.004) were independent predictors of pICU after controlling for other risk factors. A 9-fold increase in the rate of 90-day graft loss (19% vs 2% p â€‹< â€‹0.001) was observed patients who had these risk factors for pICU. CONCLUSION: Elevated creatine and fibrinolysis resistance are associated with pICU and poor outcomes following LT.

American Society of Transplant Surgeons recommendations on best practices in donation after circulatory death organ procurement.

The American Society of Transplant Surgeons supports efforts to increase the number of organs that are critically needed for patients desperately awaiting transplantation. In the United States, transplantation using organs procured from donation after circulatory death (DCD) donors has continued to increase in number. Despite these increases, substantial variability in the utilization and practices of DCD transplantation still exists. To improve DCD organ utilization, it is important to create a set of best practices for DCD recovery. The following recommendations aim to provide guidance on contemporary issues surrounding DCD organ procurement in the United States. A work group was composed of members of the American Society of Transplant Surgeon Scientific Studies Committee and the Thoracic Organ Transplantation Committee. The following topics were identified by the group either as controversial or lacking standardization: prewithdrawal preparation, definition of donor warm ischemia time, DCD surgical technique, combined thoracic and abdominal procurements, and normothermic regional perfusion. The proposed recommendations were classified on the basis of the grade of available evidence and the strength of the recommendation. This information should be valuable for transplant programs as well as for organ procurement organizations and donor hospitals as they develop robust DCD donor procurement protocols.

Low viscoelastic clot strength, platelet transfusions, and graft dysfunction are associated with persistent postoperative ascites following liver transplantation.

INTRODUCTION: High output, persistent ascites (PA) is a common complication following liver transplant (LT). Recent work has identified that platelets help maintain endothelial integrity and can decrease leakage in pathological states. We sought to assess the association of PA following LT with platelet count and platelet function. METHODS: Clot strength (MA) is a measure of platelet function and was quantified using thrombelastography (TEG). Total drain output following surgery was recorded in 24-h intervals during the same time frame as TEG. PA was considered >1 L on POD7, as that much output prohibits drain removal. RESULTS: 105 LT recipients with moderate or high volume preoperative ascites were prospectively enrolled. PA occurred in 28%. Platelet transfusions before and after surgery were associated with PA, in addition to POD5 TEG MA and POD5 MELD score. Patients with PA had a longer hospital length of stay and an increased rate of intraabdominal infections. CONCLUSION: Persistent ascites following liver transplant is relatively common and associated with platelet transfusions, low clot strength, and graft dysfunction.

Measuring the effect of the COVID-19 pandemic on solid organ transplantation.

BACKGROUND: The COVID-19 pandemic has uniquely affected the United States. We hypothesize that transplantation would be uniquely affected. METHODS: In this population-based cohort study, adult transplantation data were examined as time series data. Autoregressive-integrated-moving-average models of transplantation rates were developed using data from 1990 to 2019 to forecast the 2020 expected rates in a theoretical scenario if the pandemic did not occur to generate observed-to-expected (O/E) ratios. RESULTS: 32,594 transplants were expected in 2020, and only 30,566 occurred (O/E 0.94, CI 0.88-0.99). 58,152 waitlist registrations were expected and 50,241 occurred (O/E 0.86, CI 0.80-0.94). O/E ratios of transplants were kidney 0.92 (0.86-0.98), liver 0.96 (0.89-1.04), heart 1.05 (0.91-1.23), and lung 0.92 (0.82-1.04). O/E ratios of registrations were kidney 0.84 (0.77-0.93), liver 0.95 (0.86-1.06), heart 0.99 (0.85-1.18), and lung 0.80 (0.70-0.94). CONCLUSIONS: The COVID-19 pandemic was associated with a significant deficit in transplantation. The impact was strongest in kidney transplantation and waitlist registration.

Voucher-Based Kidney Donation and Redemption for Future Transplant.

Importance: Policy makers, transplant professionals, and patient organizations agree that there is a need to increase the number of kidney transplants by facilitating living donation. Vouchers for future transplant provide a means of overcoming the chronological incompatibility that occurs when the ideal time for living donation differs from the time at which the intended recipient actually needs a transplant. However, uncertainty remains regarding the actual change in the number of living kidney donors associated with voucher programs and the capability of voucher redemptions to produce timely transplants. Objective: To examine the consequences of voucher-based kidney donation and the capability of voucher redemptions to provide timely kidney allografts. Design, Setting, and Participants: This multicenter cohort study of 79 transplant centers across the US used data from the National Kidney Registry from January 1, 2014, to January 31, 2021, to identify all family vouchers and patterns in downstream kidney-paired donations. The analysis included living kidney donors and recipients participating in the National Kidney Registry family voucher program. Exposures: A voucher was provided to the intended recipient at the time of donation. Vouchers had no cash value and could not be sold, bartered, or transferred to another person. When a voucher was redeemed, a living donation chain was used to return a kidney to the voucher holder. Main Outcomes and Measures: Deidentified demographic and clinical data from each kidney donation were evaluated, including the downstream patterns in kidney-paired donation. Voucher redemptions were separately evaluated and analyzed. Results: Between 2014 and 2021, 250 family voucher-based donations were facilitated. Each donation precipitated a transplant chain with a mean (SD) length of 2.3 (1.6) downstream kidney transplants, facilitating 573 total transplants. Of those, 111 transplants (19.4%) were performed in highly sensitized recipients. Among 250 voucher donors, the median age was 46 years (range, 19-78 years), and 157 donors (62.8%) were female, 241 (96.4%) were White, and 104 (41.6%) had blood type O. Over a 7-year period, the waiting time for those in the National Kidney Registry exchange pool decreased by more than 3 months. Six vouchers were redeemed, and 3 of those redemptions were among individuals with blood type O. The time from voucher redemption to kidney transplant ranged from 36 to 155 days. Conclusions and Relevance: In this study, the family voucher program appeared to mitigate a major disincentive to living kidney donation, namely the reluctance to donate a kidney in the present that could be redeemed in the future if needed. The program facilitated kidney donations that may not otherwise have occurred. All 6 of the redeemed vouchers produced timely kidney transplants, indicating the capability of the voucher program.

Relationship between bovine carotid artery grafts for hemodialysis access and human leukocyte antigen sensitization.

INTRODUCTION: Bovine carotid artery (BCA) Artegraft is a biologic graft that can be utilized as a conduit for permanent hemodialysis access and has been shown to outperform polytetrafluoroethylene grafts. However, concern regarding immunologic sensitization may limit the use of BCA in the transplant candidate. Panel reactive antibody (PRA) is an immunological test utilized in transplant recipient selection whereas increases in PRA limit access to transplantation. The purpose of our study was to determine whether BCA graft placement was adversely associated with increases in PRA. METHODS: Of patients listed for kidney transplant at our institution, we identified 10 patients who underwent BCA placement for hemodialysis access and a matched cohort of 10 patients who underwent native arteriovenous fistula (AVF) creation between 2014 and 2017. The PRA value nearest to the surgery date was compared to postsurgery PRA value for the BCA and AVF patients using a paired t test. Presurgery PRAs were also compared to the maximum PRA at 0 to 6, 6 to 12, 12 to 18, and 18 to 24 months postsurgery. FINDINGS: Prior to the dialysis access operation, the mean PRA was 14.1% ± 23.5% vs. 17.1% ± 29.0% (P = 0.76) and the median postsurgery follow-up time was 16 and 15 months for BCA and AVF cohorts, respectively. There were no statistically significant differences between presurgery and postsurgery PRA for BCA and AVF patients, regardless of time interval postsurgery. The difference in presurgery/postsurgery PRA change between cohorts was not statistically significant for PRAs closest to surgery (0.2% ± 40.6% vs. 1.0% ± 2.8%, P = 0.95, at a median 4 and 3 months postsurgery, respectively) or when using the maximum in any postsurgery interval. Prior to their dialysis access surgery, there were 16 sensitizing events in 5 patients in the BCA group compared to 10 events in 5 patients in the AVF group (P = 0.20). Only 1 of the 10 patients in the BCA group had a clinically relevant and sustained increase in PRA following their dialysis access operation vs. no patients in the AVF group (P > 0.99). However, this patient had a known sensitizing event (blood transfusion) between the BCA surgery and the postoperative PRA. Three of 10 patients in the BCA cohort vs. 5 of 10 patients in the AVF cohort went on to have successful kidney transplants (P = 0.65). DISCUSSION: The utilization of BCA for dialysis access was not associated with statistically significant changes in PRA. These data suggest that implantation of BCA will not affect access to organ transplantation.

A Vascular Anastomosis Simulation Can Provide a Safe and Effective Environment for Resident Skills Development.

OBJECTIVE: Vascular anastomoses are complex surgical procedures, performed in time-sensitive circumstances, making intraoperative teaching more challenging. We sought to evaluate whether a vascular anastomosis simulation was effective in developing resident skills. DESIGN, SETTING, PARTICIPANTS: General surgery residents participated in a vascular anastomosis simulation for 1 to 2hours during their transplant rotation. An attending transplant surgeon at the University of Colorado guided the resident through end-to-end and end-to-side anastomoses using bovine carotid artery (Artegraft). The residents completed a presimulation and postsimulation survey which quantitated their confidence. They also completed the MiSSES scale, which assessed the validity of the simulation. RESULTS: Twenty residents participated in the simulation and completed the surveys. The residents reported increased understanding in how to set up an end-to-end anastomosis and an end-to-side anastomosis (p = 0.001 and p = 0.009, respectively). They reported increased ability to suture, forehand and backhand with a Castro-Viejo needle driver (both p < 0.001). The residents reported increased ability to manipulate the needle (p = 0.006), and increased ability to manipulate tissue without causing trauma (p = 0.021). They reported increased confidence in tying a surgical knot with 6-0 Prolene and in operating while wearing loupes (p = 0.002, and p < 0.001, respectively). Overall, the residents reported increased confidence when asked to perform part of a vascular anastomosis in the operating room (p < 0.001). Seventeen residents completed the MiSSES scale with median scores of "somewhat agree" to "strongly agree" on all domains of the scale. CONCLUSIONS: The use of a simple, inexpensive vascular anastomosis simulation is an effective and safe environment to improve residents' surgical skills and the residents felt that the simulation was valid.

Preclinical study of treatment response in HCT-116 cells and xenografts with (1) H-decoupled (31) P MRS.

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83 ± 5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5 ± 1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39 ± 10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies.

A prospective, randomized comparison of bovine carotid artery and expanded polytetrafluoroethylene for permanent hemodialysis vascular access.

BACKGROUND: Many patients on hemodialysis do not have adequate anatomy for native arteriovenous fistulas. In these patients, synthetic conduits remain an alternative option for permanent hemodialysis access. We sought to compare the standard cuffed expanded polytetrafluoroethylene (ePTFE) graft with the bovine carotid artery (BCA) graft. METHODS: This was a prospective, randomized controlled trial that was set in an academic medical center. We enrolled 26 patients in the BCA group and 27 patients in the ePTFE group. Primary, assisted primary, and secondary patency were calculated using the Kaplan-Meier method. Complications were monitored and are reported. RESULTS: Although there was no significant difference in secondary patency rates, primary and assisted primary patency rates were significantly higher in BCA than in the ePTFE grafts (60.5% vs 10.1% and 60.5% vs 20.8% at 1 year, respectively). The BCA graft survival advantage was most profound in the upper arm grafts with significantly higher primary and assisted patency rates (P < .0001 and .0005, respectively). The total number of interventions (upper arm grafts) and total number of angioplasties (overall and upper arm) required to maintain patency were significantly fewer in the BCA group. The most common complication was graft thrombosis which occurred 0.34 ± 0.09 times per patient year in the BCA group compared to 0.77 ± 0.16 times per patient year in the ePTFE group, P = .01. CONCLUSION: The BCA graft is an excellent option for patients on hemodialysis that are not suitable for native arteriovenous fistulas, as these grafts required fewer interventions than the ePTFE grafts to maintain patency.

Laparoscopic incisional hernia repair after solid-organ transplantation.

HYPOTHESIS: Laparoscopic incisional hernia repair (LIHR) is efficacious in transplant recipients. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Thirty-one transplant recipients who underwent LIHR between July 9, 2004, and October 27, 2005. MAIN OUTCOME MEASURES: Operative complications and incisional hernia recurrence. RESULTS: The mean (SD) mesh size required for LIHR was 611 (307) cm2. Median (range) hospital stay was 4 (1-28) days, with follow-up of 589 (22-953) days. Eighteen patients developed a postoperative complication, most frequently seroma formation, which occurred in 13 patients (72%). The mesh size required for LIHR was significantly larger in patients with a postoperative complication (n = 18; 706 [319] cm2 vs n = 13; 480 [244] cm2; P = .04). Seroma formation was not associated with previous open hernia repair, diabetes mellitus, or corticosteroid use. No statistically significant relationship was noted between the transplanted organ and seroma development. There were no post-LIHR wound infections. In 7 patients (23%), hernia recurred. CONCLUSIONS: Laparoscopic incisional hernia repair in solid-organ transplant recipients is associated with a high rate of seroma formation but minimal long-term morbidity. The recurrence rate after LIHR is equivalent to that after open hernia repair. These results suggest that LIHR is a safe and effective alternative to open repair in this patient population.

Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells.

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations in the c-KIT gene which confers ligand-independent activation of the KIT receptor. Imatinib mesylate has been shown to effectively block constitutively active KIT and delay tumor growth. However, resistance to imatinib mesylate is emerging as a major clinical problem and novel therapies are needed. We report that treatment of GIST cells with the transcriptional inhibitor flavopiridol, initially down-regulates the antiapoptotic proteins bcl-2, mcl-1, and X-linked inhibitor of apoptosis protein which occurs as early as 4 hours after exposure. This is followed at 24 hours by the transcriptional suppression of KIT resulting in poly(ADP-ribose) polymerase cleavage and apoptosis. To separate the apoptotic effect of KIT suppression relative to the down-regulation of antiapoptotic proteins, we used small interfering RNA-directed knockdown of KIT. Results show that focused suppression of KIT alone is sufficient to induce apoptosis in GIST cells, but not to the same extent as flavopiridol. In contrast, imatinib mesylate, which inhibits KIT kinase activity but does not suppress total KIT expression, fails to cause apoptosis. We also show that flavopiridol suppresses KIT mRNA expression through positive transcriptional elongation factor inhibition and decreases KIT promoter activity. This causes a global decrease in the level of functionally mature KIT at the cell surface, resulting in a decrease in autophosphorylation at tyrosine residues 703 and 721, which characterizes activated KIT. Our results indicate that targeting KIT expression and these antiapoptotic proteins with flavopiridol represents a novel means to disrupt GIST cell dependence on KIT signaling and collectively renders these cells sensitive to apoptosis.

Water suppression without signal loss in HR-MAS 1H NMR of cells and tissues.

In cell and tissue samples, water is normally three orders of magnitude more abundant than other metabolites. Thus, water suppression is required in the acquisition of NMR spectra to overcome the dynamic range problem and to recover metabolites that overlap with the broad baseline of the strong water resonance. However, the heterogeneous cellular environment often complicates water suppression and the strong coupling of water to membrane lipids interferes with the NMR detection of membrane associated lipid components. The widely used water suppression techniques including presaturation and double pulsed field gradient selective echo result in more than a 70% reduction in membrane associated lipid components in proton spectra of cells and tissues compared to proton spectra acquired in the absence of water suppression. A water suppression technique based on the combination of selective excitation pulses and pulsed field gradients is proposed to use in the acquisition of high resolution MAS NMR spectra of tissue specimens and cell samples. This pulse sequence methodology enables efficient water suppression for intact cells and tissue samples and eliminates signal loss from cellular metabolites.