Future liver remnant augmentation preceding ex vivo hepatectomy with IVC replacement: a strategy to achieve R0 margins.

PURPOSE: Ex vivo hepatectomy with autotransplantation (EHAT) provides opportunity for R0 resection. As EHAT outcomes after future liver remnant (FLR) augmentation techniques are not well documented, we examine results of EHAT after augmentation for malignant tumors. METHODS: Retrospective analysis of six cases of EHAT was performed. Of these, four occurred after preoperative FLR augmentation between 2018 and 2022. RESULTS: Six patients were offered EHAT of 26 potential candidates. Indications for resection were involvement of hepatic vein outflow and inferior vena cava (IVC) with metastatic colorectal carcinoma (n = 3), cholangiocarcinoma (n = 2), or leiomyosarcoma (n = 1). Five patients were treated with neoadjuvant chemotherapy and four had preoperative liver augmentation. One hundred percent of cases achieved R0 resection. Of the augmented cases, three patients are alive after median follow-up of 28 months. Postoperative mortality due to liver failure was 25% (n = 1). CONCLUSIONS: For select patients with locally advanced tumors involving all hepatic veins and the IVC for whom conventional resection is not an option, EHAT provides opportunity for R0 resection. In addition, in patients with inadequate FLR volume, further operative candidacy with acceptable results can be achieved by combined liver augmentation techniques. To better characterize outcomes in this small subset, a registry is needed.

Ex vivo liver resection coupled with associated liver partition and portal vein ligation: Combining existing techniques to achieve surgical resectability.

Incorporation of liver transplant techniques in hepatopancreaticobiliary surgery has created an opportunity for the resection of locally advanced hepatic tumors formerly considered unresectable. A 73-year-old woman presented with cholangiocarcinoma involving inferior vena cava, all three hepatic veins, and right anterior portal pedicle, initially deemed nonoperative. This case demonstrates the first combined application of associating liver partition and portal vein ligation for staged hepatectomy and ex vivo resection to perform an R0. For diseases dependent upon resection, surgical advances and innovations expand the spectrum of interventions through interdisciplinary techniques.

Strategies That Reduce 90-Day Readmissions and Inpatient Costs After Liver Transplantation.

Liver transplantation (LT) is hospital-resource intensive and associated with high rates of readmission. We have previously shown a reduction in 30-day readmission rates by implementing a specifically designed protocol to increase access to outpatient care. The aim of this work is to determine if the strategies that reduce 30-day readmission after LT were effective in also reducing 90-day readmission rates and costs. A protocol was developed to reduce inpatient readmissions after LT that expanded outpatient services and provided alternatives to readmission. The 90-day readmission rates and costs were compared before and after implementing strategies outlined in the protocol. Multivariable analysis was used to control for potential confounding factors. Over the study period, 304 adult primary LTs were performed on patients with a median biological Model for End-Stage Liver Disease of 22. There were 112 (37%) patients who were readmitted within 90 days of transplant. The readmission rates before and after implementation of the protocol were 53% and 26%, respectively (P < 0.001). The most common reason for readmission was elevated liver tests/rejection (24%). In multivariable analysis, the protocol remained associated with avoiding readmission (odds ratio, 0.33; 95% confidence interval, 0.20-0.55; P < 0.001). The median length of stay after transplant before and after protocol implementation was 8 days and 7 days, respectively. A greater proportion of patients were discharged to hospital lodging after protocol implementation (10% versus 19%; P = 0.03). The 90-day readmission costs were reduced by 55%, but the total 90-day costs were reduced by only 2.7% because of higher outpatient costs and index admission costs. In conclusion, 90-day readmission rates and readmission costs can be reduced by improving access to outpatient services and hospital-local lodging. Total 90-day costs were similar between the 2 groups because of higher outpatient costs after the protocol was introduced.

A prospective study of a protocol that reduces readmission after liver transplantation.

Health care has shifted to placing priority on quality and value instead of volume. Liver transplantation uses substantial resources and is associated with high readmission rates. Our goal was to determine if a protocol designed to reduce readmission after liver transplant was effective. We conducted a prospective study of a protocol designed to reduce readmission rates after liver transplantation by expanding outpatient services and alternatives to readmission. The 30-day readmission rate 1 year after implementing the protocol was compared to the 30-day rate for 2 years prior to implementation. Multivariate analysis was used to control for potential confounding factors. Over the study period, 167 adult primary liver transplants were performed with a mean biological Model for End-Stage Liver Disease score of 21 ± 8. Fifty-seven (34%) patients were readmitted. The most common reason for readmission was biliary complications (n = 13). The 30-day readmission rate decreased from 40% before implementing the protocol to 20% after implementation (P = 0.02). In multivariate analysis, the protocol remained associated with readmission (odds ratio, 0.39; 95% confidence interval, 0.16-0.92; P = 0.03). The mean length of stay after transplant was 13 ± 12 days preprotocol and 9 ± 5 days postprotocol (P = 0.09). Alternatives to readmission, including hospital lodging and observation status, were main factors in reducing readmission rates. If the most recent definitions of inpatient admission and observation status were applied over the entire study period, then the readmission rates preprotocol and postprotocol were 31% and 20% indicating that the revised definition of observation status accounted for 45% of the reduction in the readmission rate. Readmission after liver transplantation can be reduced without increasing length of stay by implementing a specifically designed protocol that expands outpatient services and alternatives to inpatient admission. Liver Transplantation 22 765-772 2016 AASLD.

Abdominal transplantation for unresectable tumors in children: the zooming out principle.

PURPOSE: To present our experience in abdominal transplantations to manage unresectable abdominal neoplasms in children and to describe the role of extensive surgeries in such cases. METHODS: This is a retrospective study of 22 abdominal transplantations in 21 patients for abdominal tumors over 16 years. Transplantation techniques included liver transplant (LT), multivisceral transplant (MVTx), and intestinal autotransplant (IA). Follow-up intervals ranged from 0.3 to 168 months (median 20 months). RESULTS: LT alone was performed in 15 patients for primary malignant (11) and benign (4) liver tumors. Pathological classification included HB hepatoblastoma (6), HCC hepatocellular cancer (3), hepatic epithelioid hemangioendothelioma HEH (1), angiosarcoma (1), benign vascular tumors (3), and adenoma (1). IA was performed in four patients for lesions involving the root of the mesentery; tumors of the head of pancreas (3) and mesenteric hemangioma (1). MVTx was performed in 2 patients for malignancies; pancreaticoblastoma (1), recurrent hepatoblastoma (1), and in one patient as a rescue procedure after IA failure. Four of the eleven patients who underwent LT for malignant liver tumor had metastatic disease at presentation. Six of them died of recurrent neoplasm (3), transplant-related complications (2), and underlying disease (1). All LT patients who had benign tumors are alive with functioning grafts. All IA patients survived and are on an oral diet, with one patient requiring TPN supplementation. One of the three patients who underwent MVTx died of metastatic disease. CONCLUSIONS: Allo/auto transplantation for abdominal tumors is a valuable modality when conventional treatments fail or are not feasible.

Liver transplantation for metastatic neuroendocrine tumors: Outcomes and prognostic variables.

BACKGROUND: Patient selection for liver transplantation for metastatic neuroendocrine tumors remains a topic of debate. There is no established MELD exception, making it difficult to obtain donor organs. METHODS: A multicenter database was created assessing outcomes for liver and multivisceral transplantation for metastatic neuroendocrine tumors and identifying prognostic factors for survival. Demographic, transplant, primary tumor site and management, pathology, recurrent disease and survival data were collected and analyzed. Survival probabilities were calculated using the Kaplan-Meier method. RESULTS: Analysis included 85 patients who underwent liver transplantation November 1988-January 2012 at 28 centers. One, three, and five-year patient survival rates were 83%, 60%, and 52%, respectively; 40 of 85 patients died, with 20 of 40 deaths due to recurrent disease. In univariate analyses, the following were predictors of poor prognosis: large vessel invasion (P < 0.001), extent of extrahepatic resection at liver transplant (P = 0.007), and tumor differentiation (P = 0.003). In multivariable analysis, predictors of poor overall survival included large vessel invasion (P = 0.001), and extent of extrahepatic resection at liver transplant (P = 0.015). CONCLUSION: In the absence of poor prognostic factors, metastatic neuroendocrine tumor is an acceptable indication for liver transplantation. Identification of favorable prognostic factors should allow assignment of a MELD exception similar to hepatocellular carcinoma.

When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases.

OBJECTIVE: To identify complications associated with different techniques utilized to treat portal vein thrombosis (PVT) during primary liver transplantation and their impact on survival. BACKGROUND: PVT remains an intricate problem in liver transplantation, and the long-term outcomes of patients with PVT who undergo transplantation are not well defined. METHODS: We performed a retrospective cohort analysis of all consecutive adult patients who underwent primary isolated liver transplantation from 1998 to 2009 (median follow-up period, 89 months). The outcomes of patients with PVT were compared with those without PVT. RESULTS: Among 1379 recipients, 174 (12.6%) had PVT at the time of transplantation [83 (48%) complete and 91 (52%) partial]. Among PVT patients with reestablished physiological portal inflow (PVT: physiological group; n = 149), 123 underwent thrombectomies, 16 received interpositional vein grafts, and 10 received mesoportal jump grafts. In 25 patients, physiological portomesenteric venous circulation was not reconstituted (PVT: nonphysiological group; 18 underwent cavoportal hemitranspositions, 6 renoportal anastomoses, and 1 arterialization). The PVT: nonphysiological group suffered a significantly increased incidence of rethrombosis of the portomesenteric veins and gastrointestinal bleeding, with a marginal 10-year overall survival rate of 42% (no PVT, 61%; P = 0.002 and PVT: physiological, 55%; P = 0.043). The PVT: physiological and no PVT groups exhibited comparable survival rates (P = 0.13). No significant differences in survival were observed between complete and partial PVT as long as physiological portal flow was reestablished. CONCLUSIONS: The subset of PVT patients requiring nonphysiological portal vein reconstruction was associated with higher complication rates and suffered diminished long-term prognoses. For the most severe PVT cases, a comprehensive approach is critical to further improve outcomes.

Excessive immunosuppression as a potential cause of poor survival in simultaneous liver/kidney transplantation for hepatitis C.

Appropriate recipient selection of simultaneous liver/kidney transplantation (SLKT) remains controversial. In particular, data on liver graft survival in hepatitis C virus-infected (HCV+) SLKT recipients are lacking. We conducted a single-center, retrospective study of HCV+ SLKT recipients (N = 25) in comparison with HCV- SLKT (N = 26) and HCV+ liver transplantation alone (LTA, N = 296). Despite backgrounds of HCV+ and HCV- SLKT being similar, HCV+ SLKT demonstrated significantly impaired 5-year liver graft survival of 35% (HCV- SLKT, 79%, P = 0.004). Compared with HCV+ LTA, induction immunosuppression was more frequently used in HCV+ SLKT. Five-year liver graft survival rate for HCV+ SLKT was significantly lower than that for LTA (35% vs. 74%, respectively, P < 0.001). Adjusted hazard ratio of liver graft loss in HCV+ SLKT was 4.9 (95% confidence interval 2.0-12.1, P = 0.001). HCV+ SLKT recipients were more likely to succumb to recurrent HCV and sepsis compared with LTA (32% vs. 8.8%, P < 0.001 and 24% vs. 8.8%, P = 0.030, respectively). Ten HCV+ SLKT recipients underwent anti-HCV therapy for recurrent HCV; only 1 achieved sustained virological response. HCV+ SLKT is associated with significantly decreased long-term prognosis compared with HCV- SLKT and HCV+ LTA.

Irreversible Electroporation as a Valid Treatment Option for Hepatic Epithelioid Hemangioendothelioma: An International Multicenter Experience.

PURPOSE: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor with currently no established standard of care. This international multicenter retrospective study assesses the use of percutaneous irreversible electroporation (IRE) as an ablative tool to treat HEHE and provides a clinical overview of the current management and role of IRE in HEHE treatment. MATERIAL AND METHODS: Between 2017 and 2023, 14 patients with 47 HEHE tumors were treated with percutaneous IRE using CT-scan guidance in 23 procedures. Baseline patient and tumor characteristics were evaluated. Primary outcome measures included safety and effectiveness, analyzed using Common Terminology Criteria for Adverse Events (CTCAE) and treatment response by mRECIST criteria. Secondary outcome measures included technical success, post-treatment tumor sizes and length of hospital stay. Technical success was defined as complete ablation with an adequate ablative margin (intentional tumor free ablation margin > 5 mm). RESULTS: IRE treatment resulted in technical success in all tumors. Following a median follow-up of 15 months, 30 tumors demonstrated a complete response according to mRECIST criteria. The average tumor size pre-treatment was 25.8 mm, accompanied by an average reduction in tumor size by 7.5 mm. In 38 out of 47 tumors, there was no evidence of local recurrence. In nine tumors, residual tumor was present. There were no cases of progressive disease. Median length of hospital stay was one day. Only one grade 3 CTCAE event occurred, a pneumothorax requiring chest tube placement. CONCLUSION: The current study provides evidence that IRE is a safe and efficacious minimally invasive treatment option for HEHE.

Long-term deleterious effects of aortohepatic conduits in primary liver transplantation: proceed with caution.

Aortohepatic conduits provide a vital alternative for graft arterialization during liver transplantation. Conflicting results exist with respect to the rates of comorbidities, and long-term survival data on primary grafts are lacking. To identify the complications associated with aortohepatic conduits in primary liver transplantation and their impact on survival, we conducted a single-center, retrospective cohort analysis of all consecutive adult (n = 1379) and pediatric primary liver transplants (n = 188) from 1998 to 2009. The outcomes of aortohepatic conduits were compared to those of standard arterial revascularization. Adults with a conduit (n = 267) demonstrated, in comparison with adults with standard arterialization (n = 1112), an increased incidence of late (>1 month after transplantation) hepatic artery thrombosis (HAT; 4.1% versus 0.7%, P < 0.001) and ischemic cholangiopathy (7.5% versus 2.7%, P < 0.001) and a lower 5-year graft survival rate (61% versus 70%, P = 0.01). The adjusted hazard ratio (HR) for graft loss in the conduit group was 1.38 [95% confidence interval (CI) = 1.03-1.85, P = 0.03]. Notably, the use of conduits (HR = 4.91, 95% CI = 1.92-12.58) and a warm ischemia time > 60 minutes (HR = 11.12, 95% CI = 3.06-40.45) were independent risk factors for late HAT. Among children, the complication profiles were similar for the conduit group (n = 81) and the standard group (n = 107). In the pediatric cohort, although the 5-year graft survival rate for the conduit group (69%) was significantly impaired in comparison with the rate for the standard group (81%, P = 0.03), the use of aortohepatic conduits did not emerge as an independent predictor of diminished graft survival via a multivariate analysis. In conclusion, in adult primary liver transplantation, the placement of an aortohepatic conduit should be strictly limited because of the greater complication rates (notably late HAT) and impaired graft survival; for children, its judicious use may be acceptable.

Liver natural killer cell inoculum for liver transplantation with hepatocellular carcinoma.

PURPOSE OF REVIEW: Natural killer (NK) cells are innate immune lymphocytes. NK cells contribute to host antimicrobial and antitumor immunity. Liver transplantation in patients with hepatocellular carcinoma (HCC) has increased recently. The possibility of NK cell immunotherapy for liver cancer has been studied. RECENT FINDINGS: Adoptive transfer of interleukin-2 (IL-2)-stimulated NK cells extracted from donor liver perfusate could increase an antitumor response without causing toxicity against 1-haplotype identical recipient intact tissues in patients with live donor liver transplant. Donor liver NK cells showed the most vigorous cytotoxicity against an HCC after in-vitro IL-2 stimulation, compared with donor and recipient peripheral blood NK cells and recipient liver NK cells. IL-2 stimulation led to an increased expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on liver NK cells. T-cell contamination and risk of graft-versus-host disease can be minimized with a T-cell depleting agent such as anti-CD3 antibody. SUMMARY: Allogeneic NK cells might have an advantage for adoptive immunotherapy. Liver NK cells from a deceased donor liver can be used safely as adoptive immunotherapy under current good manufacturing practice conditions for the treatment of liver transplantation with HCC. IL-2-stimulated liver NK cells have strong cytotoxicity, express TRAIL and secret interferon-γ.

Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma?

OBJECTIVE: To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. METHODS: A retrospective, single-institution analysis of 413 HCC patients from 1999 to 2009. RESULTS: A total of 413 patients with HCC underwent surgical resection (n = 106) and transplantation (n = 270) or were listed without receiving transplantation (n = 37). Excluding transplanted patients with incidental tumors (n = 50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection versus ITT patients was similar (5-year survival of 53.0% vs 52.0%, not significant). However, for HCC patients with model end-stage liver disease (MELD) scores less than 10 and who radiologically met Milan or UCSF (University of California, San Francisco) criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD score less than 10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n = 26) versus 83.0% and 41.0% for ITT (n = 73, P = 0.036). For those with MELD score less than 10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n = 33) versus 81.0% and 40.0% for ITT (n = 78, P = 0.027). CONCLUSIONS: Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest that surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

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.

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.

Three Possible Variations in Ex Vivo Hepatectomy: Achieving R0 Resection by Auto-transplantation.

The collaboration of hepatopancreaticobiliary with transplant surgery expands technical options and opportunity for potentially curative resection in traditionally inoperable cases.  We identified and describe three different types of ex vivo hepatic resections that include (1) explantation with formal hepatectomy, (2) explantation with re-implantation of the whole liver after vascular reconstruction, and (3) explantation with formal hepatectomy after future liver remnant volume augmentation.

Analysis of acute and chronic rejection in multiple organ allografts from retransplantation and autopsy cases of multivisceral transplantation.

BACKGROUND: Small intestinal allografts in multivisceral transplantation are felt to be more susceptible to acute cellular rejection (ACR) and chronic rejection (CR) when compared with other allografts although there is little direct evidence for this impression. METHODS: A total of 48 cases of multiple allograft specimens (37 autopsy and 11 explanted allograft cases) from 41 patients were evaluated in this study. Histopathologic assessments were performed with special concern to ACR and CR in allografts. The numbers of allografts available for evaluation were liver 37, small intestine 47, stomach 41, pancreas 45, and large intestine 25. RESULTS: Among 48 cases, 15 cases showed ACR (ACR case) and 12 showed CR (CR case) in at least one organ. In ACR cases, there was a statistically significant difference of organ-specific susceptibility to ACR among multivisceral allografts with the small intestinal allograft being the most susceptible (P<0.05). Severe ACR were observed only in small and large intestinal allografts. In CR cases, there was no statistically significant difference of organ-specific susceptibility to CR among multivisceral allografts with a tendency for the pancreas allograft to be the most susceptible (P=0.35). CONCLUSIONS: Our study clearly indicated variation in organ susceptibility to ACR and CR. Small intestinal allografts were the most susceptible organ to ACR in frequency and severity. Pancreatic allografts may be more susceptible to CR in comparison with ACR.

Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation.

Abstract Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatinezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatinezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

[Critical value of citrulline for complications of intestinal transplant graft]. / Valor crítico da citrulina para as complicações do enxerto no transplante de intestino.

OBJECTIVE: A biochemical marker for detection of acute cellular rejection following small intestine transplantation has been sought. Citrulline, a non- protein amino acid synthesized mainly by functioning enterocytes, has been proposed. Trial sensitivity has been reportedly high but with low specificity. Thus, the goal was to determine, in a sufficiently large analysis, the significant value of citrulline level in the post-transplant setting, which would correlate with complications such as rejection and infection. METHODS: Since March, 2004 2,135 dried blood spot (DBS) citrulline samples were obtained from 57 small intestine transplant recipients three months or more after post-transplant, i.e., once the expected period of recovery in the citrulline levels had occurred. RESULTS: Using a <13 vs. > 13 micromoles/L cut off point, sensitivity of DBS citrulline for the detection of moderate or severe ACR was extremely high (96.4%). Furthermore, specificity estimates (given the absence of ACR and these particular infections), while controlling for time-to-DBS sample were reasonably high (54%-74% in children and 83%-88% in adults), and the negative predictive value (NPV) was >99%. CONCLUSION: Citrulline is a non-invasive marker to evaluate problems of the intestinal graft after three months post-transplant. Due to the high NPV, a moderate or severe ACR can be ruled out, based exclusively on knowledge of a high value for DBS citrulline.

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.