A case for a national registry of red blood cell antibodies.

BACKGROUND AND OBJECTIVES: Red blood cell (RBC) antibody levels diminish over time and negative antibody screen are commonly seen in patients with a history of antibodies. Most hospitals do not have access to a shared registry of antibodies previously detected at other hospitals. MATERIALS AND METHODS: We describe a case where the patient was found to be at high risk of bleeding during liver transplantation. Antibody screen on admission was negative but a history of anti-Jka was identified on reviewing patient's history in local registry of RBC antibodies. The surgery was pushed back to arrange for antigen-negative units. The patient received a total of 16 Jk(a-) RBC units during the admission. RESULTS: No acute or delayed transfusion adverse reactions were seen. However, if the history of anti-Jka identified at another local hospital was not known, approximately three-quarters of the units transfused would have been Jk(a+). Transfusing Jk(a+) units could have potentially exposed the patient to risk of developing an acute and/or delayed haemolytic transfusion reaction which could have led to significant morbidity and perhaps mortality. CONCLUSION: With this case report, we build a case for developing a national registry of RBC antibodies to help improve patient safety and outcomes.

Hepatic explant pathology of pediatric intestinal transplant recipients previously treated with omega-3 fatty acid lipid emulsion.

OBJECTIVE: To evaluate and compare the biochemical and histologic effect of parenteral fish oil lipid emulsion that is rich in omega-3 polyunsaturated fatty acids (O3FAs), Omegaven (Fresenius Kabi AG, Bad Homburg, Germany) with standard omega-6 polyunsaturated fatty acid (O6FA) parenteral nutrition. STUDY DESIGN: Comparison of hepatic explant pathology and biochemical outcome on pediatric patients with intestinal failure treated with either parental O3FA or O6FA who had received a liver-inclusive intestine transplant. RESULTS: Seven liver-inclusive intestinal transplants were performed in 7 patients who received O3FA for a mean of 62% ± 13% of total patient life-span (16.1 ± 7.0 months) before transplant. Median total bilirubin fell from 6.9 mg/dL at the start of treatment to 0.7 mg/dL at the time transplant (P < .02), which was a significant decrease compared with the similarly matched O6FA cohort (P = .012). All 7 of the 03FA-treated patients received a liver-inclusive intestinal transplant had advanced fibrosis (stage 3 or 4) noted on explant pathologic examination, despite a resolution of cholestasis at the time of transplant. Histologic inflammatory scores were lower (P = .056) in the 03FA group with similar degrees of advanced fibrosis as in the O6FA group. CONCLUSIONS: In a matched comparison of patients undergoing intestinal transplantation with a history of extended O3FA lipid emulsion therapy that successfully reversed hyperbilirubinemia, significant hepatic fibrosis was present in the explanted livers despite a reduction in inflammation. This result confirms concern that the use of O3FA may have a limited role in altering the development of hepatic fibrosis from parenteral nutrition.

Preoperative comorbidity correlates inversely with survival after intestinal and multivisceral transplantation in adults.

We investigated the relationship between preoperative comorbidity and postoperative survival after intestinal transplantation. Each patient received a score for preoperative comorbidity. Each comorbidity was given a score based on the degree it impaired function (score range 0-3). A total score was derived from the summation of individual comorbidity scores. Patients (72 adults (M : F, 33 : 39)) received an isolated intestinal graft (27) or a cluster graft (45). Mean (standard deviation) survival was 1501 (1444) days. The Kaplan-Meier analysis revealed a significant inverse association between survival and comorbidity score (logrank test for trend, P < 0.0001). Patients grouped into comorbidity scores of 0 and 1, 2 and 3, 4 and 5, 6, and above had hazard ratios (95% confidence intervals) for death (compared to group 0 + 1), which increased with comorbidity scores: 1.945 (0.7622-5.816), 5.075 (3.314-36.17), and 13.77 (463.3-120100), respectively, (P < 0.0001). Receiver-operator curves at 1, 3, 5, and 10 years postoperative had "C" statistics of 0.88, 0.85, 0.88, and 0.92, respectively. When evaluating patients for transplantation, the degree of comorbidity should be considered as a major factor influencing postoperative survival.

Use of airway pressure release ventilation in a child with refractory hepatopulmonary syndrome after liver transplantation.

HPS is a life-threatening condition in patients with end-stage liver disease, in which intrapulmonary vascular dilatations result in intrapulmonary shunts and hypoxemia. The only successful treatment is liver transplantation. Hypoxemia may be severe prior to transplantation; however, it can worsen or become refractory after liver transplantation and result in increased post-operative mortality. Here, we present the case of a 10-month-old female infant with progressive end-stage liver disease and severe HPS, who developed refractory hypoxemia after a successful liver transplantation. After 19 days of unsuccessful attempts to reverse the hypoxemia using conventional mechanical ventilation and HFOV, the patient responded dramatically to APRV, with rapid improvement in her PaO2 and sharp decline in her OI. She was able to begin weaning from APRV two days later and was extubated within seven days. APRV was successful in treating refractory hypoxemia in this patient with severe HPS after liver transplantation, possibly by modifying distribution of pulmonary blood flow. Although we cannot rule out coincidental natural resolution of the HPS, APRV could be a useful rescue therapy in patients with HPS and refractory hypoxemia.

Nonsurgical care of intestinal and multivisceral transplant recipients: a review for the intensivist.

Intestinal and multivisceral transplantation has evolved from an experimental procedure to the treatment of choice for patients with irreversible intestinal failure and serious complications related to long-term parenteral nutrition. Increased numbers of transplant recipients and improved survival rates have led to an increased prevalence of this patient population in intensive care units. Management of intestinal and multivisceral transplant recipients is uniquely challenging because of complications arising from the high incidence of transplant rejection and its treatment. Long-term comorbidities, such as diabetes, hypertension, chronic kidney failure, and neurological sequelae, also develop in this patient population as survival improves. This article is intended for intensivists who provide care to critically ill recipients of intestinal and multivisceral transplants. As perioperative care of intestinal/multivisceral transplant recipients has been described elsewhere, this review focuses on common nonsurgical complications with which one should be familiar in order to provide optimal care. The article is both a review of the current literature on multivisceral and isolated intestinal transplantation as well as a reflection of our own experience at the University of Miami.

Association between donor-specific antibodies and acute rejection and resolution in small bowel and multivisceral transplantation.

BACKGROUND: Donor-specific antibodies (DSA) are associated with acute kidney graft rejection, but their role in small bowel/multivisceral allograft remains unclear. We carried out a prospective study to understand the impact of DSA in the setting of intestinal allograft rejection. METHODS: Thirteen patients (15 grafts) were serially evaluated for DSA levels pre- and posttransplant. DSA was determined by Luminex and the results were interpreted as fluorescence intensity (FI), with FI more than 3000 considered positive. RESULTS: The clinical rejection episodes in allografts were significantly associated with the presence of DSA (P=0.041).We obtained 291 biopsy samples from graft ileum and date-matched DSA assay reports. Sixty-three (21.65%) of the biopsies showed acute rejection. The appearance of DSA were preformed (n=5, anti-human leukocyte antigen class II=3, anti-class I and II=2), de novo (n=4, 15.25±4.72 days after transplantation, anti-class II=1, and anti-class I and II=3) and never (n=6). Among the 63 biopsies, 30(47.6%) had significant correlations with positive DSA (kappa=0.30, P<0.001) and manifested severe rejection grade (P=0.009). CONCLUSIONS: In this cohort of small bowel/multivisceral transplantation patients, there was a high incidence of DSA. The presence of DSA should alert the clinical team of a higher risk of rejection, and reduction of the FI is clinically associated with resolution. Serial endoscopy guided biopsies combined with simultaneous DSA measurement in postintestinal transplantation follow-up is an effective means of screening for cellular and humoral-based forms of acute rejection.

Characteristic immune, apoptosis and inflammatory gene profiles associated with intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies.

Small bowel transplantation (SBT) is becoming a preferred treatment for patients with irreversible intestinal failure. Despite continuous improvement of immunosuppression, SBT is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need for reliable detection markers and novel immunosuppressive strategies that can achieve better control of ACR. We hypothesized that particular transcriptomes provide critical regulation of the intragraft immune response. The aim of our study was to detect potential molecular biomarkers for identifying ACR in minute mucosal biopsies. We examined 30 intestinal mucosal biopsies (AR/NR; 17/13) obtained from recipients after SBT or multivisceral transplantation. We utilized TaqMan® Gene Signature Arrays (immune, inflammation and apoptosis) and investigated the expression of 280 genes. As one of our validations, we performed immunohistochemistry for selected targets. We detected 252 mRNAs in total, 92 of which were found with significantly different expression levels between the AR and NR groups. Immunohistochemistry showed significantly increased staining for IL1R2, ICAM1, GZMB, and CCL3 (P < 0.05) during ACR. For the first time, we characterize the potential molecular changes that are associated with modulation of histological appearances of intestinal ACR. These differences in transcriptome patterns can be used to identify robust biomarkers and potential novel therapeutic targets for immunosuppressive agents.

Liver transplantation using elderly donors: a risk factor analysis.

Survival after liver transplantation is negatively impacted by use of elderly deceased donors, but excluding them would increase waiting times and waiting list mortality. We reviewed our experience with liver transplantation (LT) utilizing livers from deceased donors 65 yr of age and older to identify those factors that impact graft survival. All adult patients (≥ 18 yr old) who underwent primary LT using deceased donor livers from donors aged ≥ 65 yr between February 1995 and November 2003 were included. With multivariate analysis we found four unfavorable characteristics significantly associated with higher post-transplant graft failure rate. These characteristics are hepatitis C as an etiology of liver disease, Model for End-Stage Liver Disease score >20, serum glucose level of donor > 200 mg/dL at the time of liver recovery, and skin incision to aortic cross-clamp time > 40 minutes in the donor surgery. The five-yr estimated graft survival rates having 0, 1, 2, 3, and 4 unfavorable characteristics were 100%, 82.0%, 81.7%, 39.3%, and 25.0%, respectively (p < 0.05). Our data demonstrated good graft survival can be achieved in LT using elderly donor liver allografts with appropriate patient selection, donor blood glucose management and efficient liver recovery with minimal manipulation of the liver during donor surgery.

Effect of liver transplantation on spleen size, collateral veins, and platelet counts.

BACKGROUND: The aim of this study was to evaluate the effect of liver transplantation on the spleen size, spontaneous splenorenal shunt (SRS) function, and platelet counts in patients with hypersplenism. METHODS: Between December 2001 and February 2007, 462 adult patients underwent orthotopic liver transplantations (OLTX) at our institution. Of these patients, CT or MRI information was reviewed retrospectively in 55 patients. Volume measurements of the spleen and liver, spleen/liver volume ratio (S/L ratio), presence and size of SRS, and platelet counts were evaluated before and after OLTX. RESULTS: Mean spleen volume decreased from 827 +/- 463 ml to 662 +/- 376 ml after OLTX (p < 0.01). Five (11%) patients returned to normal-range spleen size after OLTX. SRS was observed in 19 patients before OLTX (35%). The diameter of SRS also significantly decreased from 1.0 +/- 0.5 cm before OLTX to 0.7 +/- 0.5 cm after OLTX (p < 0.05). SRS disappeared in 16% of patients (3/19). S/L ratio significantly decreased from 0.65 +/- 0.33 to 0.38 +/- 0.17 (p < 0.01) after OLTX. Platelet counts significantly increased after OLTX (p < 0.01). Improvement of the platelet count in the group with postoperative S/L ratio >0.35 was not as good as that in the group with S/L ratio <0.35 (p < 0.01). CONCLUSIONS: Spleen size and SRS size became significantly smaller after OLTX. However, patients with postoperative S/L ratio >0.35 tend to have lower platelet counts after OLTX.

Successful treatment with bortezomib of a refractory humoral rejection of the intestine after multivisceral transplantation.

Graft rejection is a serious complication after intestinal and multivisceral transplantation. Classic anti-rejection strategies often focus on addressing the cellular component, however mounting evidence suggests that antibody mediated rejection may also play an important role in patient and graft survival. Bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, has been found to be useful in treating antibody mediated rejection in kidney transplant recipients. The following case illustrates how bortezomib was used to successfully reverse refractory rejection in a patient following multivisceral transplantation. While the rejection was able to be controlled, this patient's course was complicated by an aggressive viral infection after bortezomib therapy. Bortezomib may be a useful agent in the treatment of rejection after intestinal and multivisceral transplantation; however more data is needed to assess its impact on infectious complications in this complex group of patients.

A cause-specific hazard rate analysis of prognostic factors among 877 adults who received primary orthotopic liver transplantation.

BACKGROUND: In orthotopic liver transplantation (OLT) distinct causes of graft failure (GF) and death with a functioning graft (DFG) exist. Prognostic factors for one failure type may be distinctly different from those predictive of other types, and an accurate portrayal of these relationships may more clearly explain each factor's importance. METHODS: A multivariable cause-specific hazard (CSH) rate analysis using Cox stepwise regression was performed among 877 adults who received primary OLT during 1996-2004 with tacrolimus+steroids as immunosuppression. RESULTS: Older donor age (P=0.004) implied greater primary dysfunction GF, while primary sclerosing cholangitis (PSC; P=0.0002) implied greater vascular thrombosis GF. Recurrent nonmalignant liver disease GF was higher among hepatitis C virus patients (P<0.00001), and younger recipient age (P=0.005) implied greater death from recurrent (metastatic) hepatocellular carcinoma. African-American race (P<0.00001), PSC (P=0.003), and younger recipient age (P=0.005) were independently associated with greater GF due to chronic rejection. Older donor age (P=0.003) implied greater infection DFG, while older recipient age (P=0.003) and pretransplant diabetes (P=0.03) were independently associated with greater cardiovascular/cerebrovascular DFG. Finally, most of these cause-specific predictors were not significant in an overall Cox model for graft survival. CONCLUSIONS: The CSH approach should be more widely used in investigations of prognostic factors. The result of older donor age implying greater primary dysfunction GF and infection DFG but having no association with other failure types demonstrates that its impact is specific to the graft's early posttransplant functional status. In addition, while recipient age was an important prognosticator, its direction of association reverses depending upon the outcome being analyzed.

Twenty-year experience with liver transplantation for hepatocellular carcinoma.

HYPOTHESIS: Liver transplantation (LT) has become the optimal treatment for stages I and II hepatocellular carcinoma (HCC). Based on our 20-year experience, changes in staging, techniques, and patient selection have improved survival over the past 20 years. Herein, we determine if pre-LT treatment for HCC alters the long-term outcomes in patients with HCC. DESIGN: Outcomes study. SETTING: Tertiary referral center. PATIENTS: We retrospectively reviewed prospectively collected data in a cohort of 92 patients who underwent LT for HCC between 1983 and 2003. MAIN OUTCOME MEASURES: Patient demographics, tumor stage in the explant liver, patient survival, and tumor recurrence data were analyzed. RESULTS: The average follow-up was 1052 (range, 0-6491) days. The average tumor size was 3.6 cm; 40% of tumors were multifocal and 60% unifocal. Of the 92 patients, 26% were classified as stage I; 42%, stage II; 24%, stage III; and 8%, stage IV. The overall 5-year survival rate was 50%, the 10-year survival rate was 32%, and the 15-year survival rate was 27%. Improvements in staging in the last 5 years reduced the number of patients with stages III and IV HCC from 39% to 19% and increased the 5-year survival rate to 69%. Tumor recurrence was relatively rare (13%); however, recurrence resulted in a poor prognosis (75% mortality rate; P = .02). The average time to recurrence was 458 (range, 179-1195) days. CONCLUSIONS: Liver transplantation for HCC results in excellent long-term survival for patients with stages I and II HCC, with relatively few patients dying from tumor recurrence. Improvements in preoperative staging have resulted in increased 5-year survival rates. Further refinements in pre-LT staging may increase the effectiveness of LT for HCC.

Differential expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in early and late gestational mouse skin and skin wounds.

Early gestation fetal mouse skin heals without scars. Plasminogen activator inhibitor-1 (PAI-1) has been associated with postnatal organ fibrosis. We hypothesized that the relative balance between urokinase-type plasminogen activator (uPA) and PAI-1 expression in favor of uPA prevents scarring in early fetal skin wounds, whereas a change in favor of PAI-1 in late gestation results in wound scarring. To evaluate uPA and PAI-1 expression, 1-mm skin wounds were made in E14.5 and E18 mice and harvested 24, 48, or 96 hours postwounding. Aprotinin (2 mg/ml)-coated beads were injected into selected E14.5 wounds. Normal skin and skin wounds were evaluated for uPA, PAI-1, and collagen expression. We showed that in normal skin uPA level is higher in E14.5 than in E18 mice, while PAI-1 is lower in E14.5 than in E18 mice. After wounding, E14.5 wounds show a moderate increase in uPA and a minimal increase in PAI-1. E18 wounds show a transient increase in uPA but a significant, sustained increase in PAI-1. Addition of aprotinin to E14.5 wounds causes an increase in collagen deposition. We conclude that the differential expression of uPA and PAI-1 in the skin of early vs. late gestation mice may contribute to the degree of scar formation seen after cutaneous injury.