Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery.

Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy.

A multicenter study of 30 days complications after deceased donor liver transplantation in the model for end-stage liver disease score era.

Knowledge of risk factors for posttransplant complications is likely to improve patient outcomes. Few large studies of all early postoperative complications after deceased donor liver transplantation (DDLT) exist. Therefore, we conducted a retrospective, cohort study of 30-day complications, their risk factors, and the impact on outcomes after DDLT. Three centers contributed data for 450 DDLTs performed from January 2005 through December 2009. Data included donor, recipient, transplant, and outcome variables. All 30-day postoperative complications were graded by the Clavien-Dindo system. Complications per patient and severe (≥ grade III) complications were primary outcomes. Death within 30 days, complication occurrence, length of stay (LOS), and graft and patient survival were secondary outcomes. Multivariate associations of risk factors with complications and complications with LOS, graft survival, and patient survival were examined. Mean number of complications/patient was 3.3 ± 3.9. At least 1 complication occurred in 79.3%, and severe complications occurred in 62.8% of recipients. Mean LOS was 16.2 ± 22.9 days. Graft and patient survival rates were 84% and 86%, respectively, at 1 year and 74% and 76%, respectively, at 3 years. Hospitalization, critical care, ventilatory support, and renal replacement therapy before transplant and transfusions during transplant were the significant predictors of complications (not the Model for End-Stage Liver Disease score). Both number and severity of complications had a significant impact on LOS and graft and patient survival. Structured reporting of risk-adjusted complications rates after DDLT is likely to improve patient care and transplant center benchmarking. Despite the accomplished reductions in transfusions during DDLT, opportunities exist for further reductions. With increasing transplantation of sicker patients, reduction in complications would require multidisciplinary efforts and institutional commitment. Pretransplant risk characteristics for complications must factor in during payer contracting.

Does liver ischemic preconditioning in brain death donors induce kidney preconditioning? A retrospective analysis.

BACKGROUND: It is unclear whether ischemic preconditioning (IPC) of solid organs induces remote IPC (RIPC) in donors after brain death (DBD). METHODS: Outcomes in kidney recipients from 163 DBD in two randomized trials of liver IPC (5 min=62 and 10 min=101) were obtained retrospectively from the Scientific Registry of Transplant Recipients. Controls were kidney recipients from donors without IPC. Mean cold ischemia times were less than 20 hr. Primary outcomes were delayed graft function, defined as dialysis during the first posttransplantation week, and death-censored graft survival. Secondary outcomes were duration of initial hospital stay, patient survival, and estimated glomerular filtration rate 6, 12, 36, and 60 months after transplantation. RESULTS: After exclusions (40 kidneys not recovered, 21 not transplanted, 8 en bloc, 23 with extrarenal organs, and 6 with missing records), 228 recipients were included. Delayed graft function occurred in 23% of No RIPC and 28% of RIPC kidneys (P=0.54). One- and 3-year graft survival rates were 92% and 90%, respectively, in the No RIPC and 90% and 81%, respectively, in the RIPC group (P=0.12), and mean hospital stay was 9.3±13.9 and 9.7±8.2 days, respectively (P=0.15). There were no significant between group differences in patient survival and estimated glomerular filtration rate at any time point. CONCLUSIONS: Despite design and power limitations, our results suggest that liver IPC in DBD is of no clinical benefit to kidney recipients. Inconsistent efficacy and impracticality severely limit the usefulness of IPC in DBD. Other modalities of preconditioning should be tested.

Vasopressor administration during liver transplant surgery and its effect on endotracheal reintubation rate in the postoperative period: a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: End-stage liver disease (ESLD) is associated with a low systemic vascular resistance due to peripheral vasodilatation. This phenomenon is aggravated by general anesthesia (GA) administered during liver transplantation, resulting in precipitous decreases in blood pressure. The excessive amounts (>3 mL/1 mL blood loss) of IV fluid administered to maintain hemodynamic stability during surgery promotes a fluid shift in the lung, which may lead to hypoxia in the immediate postoperative period. This pathophysiologic state may necessitate endotracheal reintubation and mechanical ventilation of the lungs, thus exposing the patient to a risk for morbidities related to laryngoscopy and endotracheal intubation, including deleterious cardiovascular responses to laryngoscopy, endotracheal damage due to laryngoscopic instrumentation, alteration in pulmonary mechanics secondary to controlled mechanical ventilation of the lungs, and delayed recovery associated with the sedation needed to perform these maneuvers. OBJECTIVE: The aim of this study was to determine whether the use of a vasopressor to antagonize the vasodilatory effect of GA would reduce the amount of IV fluids administered during liver transplantation, and whether the subsequent amelioration of fluid shift in the postoperative period would reduce the need for ventilatory support and endotracheal reintubation. METHODS: This prospective, randomized, double-blind, placebo-controlled study was conducted at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey. Patients aged > or =18 years scheduled to undergo orthotopic liver transplantation for ESLD were enrolled. The effect of use of an adjuvant vasopressor, together with controlled fluid administration (ie, the volume of IV fluid needed to maintain hemodynamic parameters at > or =80% of preoperative levels) (vasopressor group), was compared with that of fluid administration only (placebo group). We determined various postoperative outcome measures, primarily the amount of fluid administered and the need for endotracheal reintubation. RESULTS: Sixty-five patients were enrolled (44 men, 21 women; vasopressor, 33 patients; placebo, 32 patients). Sex distribution showed 19 men and 14 women in the vasopressor group and 25 men and 7 women in the placebo group (both, P < 0.05). The 2 treatment groups were statistically similar with regard to the rest of the baseline demographic and clinical characteristics and duration of surgery. The vasopressor group had a significantly lower prevalence of endotracheal reintubation compared with the placebo group (RR, 1:6; P < 0.05). The other postoperative parameters were statistically similar between the 2 groups. CONCLUSION: In this study of adults undergoing orthotopic liver transplantation for ESLD, use of an adjuvant vasopressor, together with controlled fluid administration, to maintain a stable hemodynamic status during GA reduced the need for endotracheal reintubation and its associated morbidities in the postoperative period compared with placebo.

Minimally invasive optimization of organ donor resuscitation: case reports.

Increased use of expanded donors requires optimal organ perfusion to prevent graft damage. In this regard, pulmonary artery catheters have been advocated to monitor hemodynamic status. Cost, catheter placement, and inconsistent management preclude broad use of pulmonary artery catheters. Esophageal Doppler monitoring also monitors hemodynamic status and can be instituted in minutes by an organ procurement coordinator, Concomitant assessment of acid-base balance using base excess and/or anion gap can help determine resuscitation efficacy. Esophageal Doppler monitoring is described to help salvage 2 hemodynamically deteriorating donors. Anion gap and corrected base excess identified poor resuscitation status in both donors and normalized after improvement in hemodynamic status. Compared to pulmonary artery catheters, esophageal Doppler monitoring may provide a more accessible means to assess and improve hemodynamic status. Base deficit and/or anion gap may determine resuscitation efficacy by exposing acid-base imbalance resulting from poor tissue perfusion. The full efficacy of this approach remains to be determined.

Ischemic preconditioning in deceased donor liver transplantation: a prospective randomized clinical trial of safety and efficacy.

Ischemic preconditioning (IPC) has the potential to decrease graft injury and morbidity after liver transplantation. We prospectively investigated the safety and efficacy of 5 minutes of IPC induced by hilar clamping in local deceased donor livers randomized 1:1 to standard (STD) recovery (N = 28) or IPC (N = 34). Safety was assessed by measurement of heart rate, blood pressure, and visual inspection of abdominal organs during recovery, and efficacy by recipient aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT], both measured in U/L), total bilirubin, and international normalized ratio of prothrombin time (INR) after transplantation. IPC performed soon after laparotomy did not cause hemodynamic instability or visceral congestion. Recipient median AST, median ALT, and mean INR, in STD vs. IPC were as follows: day 1 AST 696 vs. 841 U/L; day 3 AST 183 vs. 183 U/L; day 1 ALT 444 vs. 764 U/L; day 3 ALT 421 vs. 463 U/L; day 1 INR 1.7 +/- .4 vs. 2.0 +/- .8; and day 3 INR 1.3 +/- .2 vs. 1.4 +/- .3; all P > .05. No instances of nonfunction occurred. The 6-month graft and patient survival STD vs. IPC were 82 vs. 91% and median hospital stay was 10 vs. 8 days; both P > .05. In conclusion, deceased donor livers tolerated 5 minutes of hilar clamping well, but IPC did not decrease graft injury. Further trials with longer periods of preconditioning such as 10 minutes are needed.

Primary non-Hodgkin's lymphoma of the bile ducts mimicking cholangiocarcinoma.

BACKGROUND: Primary non-Hodgkin's lymphoma (NHL) of the liver and bile duct mimicking cholangiocarcinoma is rare. METHODS: The clinical and radiologic features and the treatment of 2 patients with primary NHL of the bile ducts are presented and analyzed together with cases collected from a review of the English literature between 1966 and 2003. RESULTS: Fifteen patients with primary NHL, including our 2 patients, presented with clinical features mimicking cholangiocarcinoma. All had jaundice; 9 had systemic symptoms; 7 had abdominal pain; and 5 had mass lesions. All had biliary strictures as shown on cholangiography. Two patients were infected with human immunodeficiency virus-1. In only 1 patient was the diagnosis established without surgery. Immunophenotyping in 10 patients showed 9 B-cell tumors and 1 T-cell tumor. Twelve patients underwent resection. Seven received chemotherapy immediately after the diagnosis was made. Only 3 patients have survived more than 3 years, with the longest survival being 68 months. CONCLUSIONS: Non-Hodgkin's lymphoma of the liver and bile duct must be considered in the differential diagnosis of patients with obstructive jaundice. If the correct diagnosis is made before surgery, current protocols of chemotherapy may be the primary modality of therapy. Surgical resection should be reserved to address complications of biliary obstruction or the failure of chemotherapy to eradicate localized disease.

Donors with cardiac arrest: improved organ recovery but no preconditioning benefit in liver allografts.

BACKGROUND: Historically, organ recovery rates in donors with cardiac arrest (CA) have been low, presumably from hemodynamic instability. We hypothesized that donor resuscitation has improved hemodynamic stability and organ recovery in CA donors, and that CA triggers ischemic preconditioning (IP) in liver grafts. METHODS: A total of 131 donor pairs with and without CA were matched in age, gender, and year of recovery. Hemodynamic stability was determined by vasopressor use. Abdominal and thoracic organs recovered and livers transplanted were compared between the groups. Liver graft function, injury, and IP benefit were examined by comparing liver chemistries after transplantation and postperfusion biopsies between recipients of grafts from both groups (n=40 each). RESULTS: Hemodynamic stability was similar in both groups, but recovery of thoracic organs was significantly lower in CA versus non-CA donors (35 vs. 53%, P<0.01). On the other hand, recovery rates of three or more abdominal organs from CA donors approached those of non-CA donors (77 vs. 87%, not significant). Although significantly fewer livers were transplanted from CA donors (69 vs. 85%, P<0.01), posttransplantation graft function and injury parameters were similar between the two groups, and CA did not appear to trigger IP. CONCLUSION: Compared with historical data, cardiovascular stability and abdominal organ recovery rates have improved considerably in CA donors. Liver grafts from CA donors function similarly to grafts from non-CA donors with no IP from CA. Our data support the increased use of livers and other organs from donors with CA.

De novo diagnosis of portopulmonary hypertension following liver transplantation.

Portopulmonary hypertension occurs in 2-8% of liver recipients. However, new onset of pulmonary hypertension following liver transplantation has been reported only once. We report de novo occurrences of portopulmonary hypertension in two liver recipients following successful liver transplantation. Although both patients had recurrent hepatitis C after the transplant, both had excellent clinical graft function. In one patient, upper endoscopy and aortogram showed evidence of persistent venous collaterals in the abdomen. Both patients presented with shortness of breath. Portopulmonary hypertension was diagnosed late, thus contributing directly to their deaths. Autopsy in one patient confirmed the absence of significant liver pathology and failed to demonstrate any source of deep venous thrombosis. This, and our earlier case report, highlights the potential for the occurrence of pulmonary hypertension following liver transplantation. Further studies are needed to determine the scope of the problem and identify patients at risk for this complication.