Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

Long-term results of organ procurement from burn victims.

BACKGROUND: With the increasing success of organ transplantation, many traditional contraindications to organ procurement are being reconsidered. Burn disease has constituted a traditional contraindication to solid organ procurement because of concerns that such organs may have been compromised by ischemia secondary to burn shock and contaminated by bacteremia. With the current shortage of solid organs, the transplant community continues to look for ways to increase the number of organ donors, including the use of marginal donors. METHODS: Between 1999 and 2009 we have successfully procured 14 organs from four burn patients, who had suffered concurrent anoxic brain injury. There were one male and three female patients with an average age of 43.3 years and a total burned body surface area of 32.5%. Organ transplantation was performed at an average of 4.75days after the injury. Eight kidneys, three livers, two hearts and one pancreas were procured and transplanted into 13 patients. RESULTS: We were able to follow-up on the organ recipients for an average of 80.5 months. The 5-year survival of the donated organs following transplant was 78.6% and the 5-year organ recipient survival was 92.3%. CONCLUSIONS: Organ procurement after burns is not contraindicated and transplantation can be performed with good long-term results.

Macro- and microcirculation patterns of intrahepatic blood flow changes in patients with hereditary hemorrhagic telangiectasia.

AIM: To evaluated vascular dynamic processes in the liver of hereditary hemorrhagic telangiectasia (HHT) patients by ultrasound (US) considering quantitative analytic methods. METHODS: The imaging features on US and contrast-enhanced ultrasound (CEUS) in 18 patients diagnosed with HHT were retrospectively analyzed. Regarding CEUS, real-time contrast harmonic imaging and sulfur hexafluoride-filled microbubbles were used. RESULTS: HVaMs were identified in all 18 patients. By US, the two major Caselitz criteria could be detected in 55.6% patients. "Color spots" were detected in 72.2% of the cases. Respecting sonographic grading criteria by Buscarini, grade 3 could be demonstrated most frequent (40%). By CEUS, all the patients showed quick and early hyperenhancement during the arterial phase. Significant lowest time to peak (TTP) and highest area under the curve (AUC) values were identified in the hepatic artery (TTP: 69.8%; AUC: 100%) and highest TTP and lowest AUC in the hepatic parenchyma and the portal vein. CONCLUSION: For the first time we analyzed CEUS findings of a group of HHT patients regarding macro- and microcirculation. Our data demonstrate significant differences in TTP and AUC values in the four selected regions: hepatic artery, shunt region, portal vein and hepatic parenchyma.

Percutaneous biopsies of splenic lesions--a clinical and contrast enhanced ultrasound based algorithm.

OBJECTIVE: Splenic lesions are rare and characterization is difficult. Secondary spread is more frequent than primary malignant lesions. Thus clinical circumstances are important in the general work-up. Contrast enhanced ultrasound (CEUS) had high accuracy in recent studies but the positive predictive value is low. Biopsy is considered dangerous. Recent studies have brought back this method into focus showing an excellent efficacy and safety. The aim of this study was to estimate the rate of relevant biopsy results in patients with splenic lesions concerning the clinical circumstances. DESIGN: Patients with unclear splenic lesions which appeared progressively hypoenhancing in the late phase of CEUS with BR1 were included. Biopsy was performed with ultrasound guidance. Patients were sorted into 5 groups according to their clinical symptoms. RESULTS: 44 patients were enrolled, 59% had benign lesions. 73% were rated relevant. For the subgroups the rate was: patients with hints for hemato-oncological diseases 83%, patients without symptoms 38%, patients with infections of unknown origin 100%, patients with suspicion of metastases 33%, immunocompromised patients 100%. One bleeding could be managed conservatively, another bleeding was detected incidentally 2 weeks later. CONCLUSION: Percutaneous biopsy of unclear splenic lesions which appear hypoenhancing in the late phase of CEUS with BR1 results in a high rate of relevant lesions. The results should be tested in larger numbers of patients.

Multicentric evaluation of model for end-stage liver disease-based allocation and survival after liver transplantation in Germany--limitations of the 'sickest first'-concept.

Since the introduction of model for end-stage liver disease (MELD) in 2006, post-orthotopic liver transplantation (OLT) survival in Germany has declined. The aim of this study was to evaluate risk factors and prognostic scores for outcome. All adult OLT recipients in seven German transplant centers after MELD implementation (December 2006-December 2007) were included. Recipient data were analyzed for their influence on 1-year outcome. A total of 462 patients (mean calculated MELD = 20.5, follow-up: 1 year) were transplanted for alcoholic cirrhosis (33.1%), hepatocellular carcinoma (26.6%), Hepatitis-C (17.1%), Hepatitis-B (9.5%), primary sclerosing cholangitis (5.6%) and late graft-failure after first OLT before December 2006 (8.7%). 1-year patient survival was 75.8% (graft survival 71.2%) correlating with MELD parameters and serum choline esterase. MELD score >30 [odds ratio (OR) = 4.17, confidence interval: 2.57-6.78, 12-month survival = 52.6%, c-statistic = 0.669], hyponatremia (OR = 2.07), and pre-OLT hemodialysis (OR = 2.35) were the main death risk factors. In alcoholic cirrhosis (n = 153, mean MELD = 21.1) and hepatocellular carcinoma (n = 123, mean MELD = 13.5), serum bilirubin and the survival after liver transplantation score were independent outcome parameters, respectively. MELD >30 currently represents a major risk factor for outcome. Risk factors differ in individual patient subgroups. In the current German practice of organ allocation to sicker patients, outcome prediction should be considered to prevent results below acceptable standards.

Liver transplanted patients with preoperative autoimmune hepatitis and immunological disorders are at increased risk for Post-Transplant Lymphoproliferative Disease (PTLD).

BACKGROUND: Long term immunosuppression and therapy of acute rejections result in a 20-120-fold increased risk to develop Non Hodgkin lymphoma (NHL). Since immunosuppressive therapy and immunological disorders are major risk factors for the development of NHL in the non-transplant population we aimed to analyze risk factors for PTLD in our cohort of liver transplanted (LT) patients. METHODS: We analyzed retrospectively 431 patients liver transplanted between 1998 and 2008. RESULTS: PTLD was diagnosed in eleven of 431 patients (2.6%). PTLD, especially late PTLD, was significantly more frequent in patients who received steroids before LT (Kaplan-Meier: p<0.001). Moreover PTLD in immunocompromised patients with preoperative steroid treatment occurred at a significantly younger age (49.5+/-4.7 years) compared to patients without steroids (60.6+/-5.1 years; p=0.006). Multivariate analysis revealed pretransplant steroid treatment and liver transplantation for autoimmune hepatitis as main risk factors for the development of PTLD after liver transplantation (p<0.001). CONCLUSION: Liver transplanted patients who received steroids before LT due to immunological disorders and patients with autoimmune hepatitis seem to be at particular high risk to develop PTLD. Prospective cohort studies including immunoepidemiologic investigations of abnormalities of cellular, humoral and innate immunity should be carried out to identify predictive factors and patients at risk.

Control of organ transplant-associated graft-versus-host disease by activated host lymphocyte infusions.

BACKGROUND: Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. METHODS: Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). RESULTS: Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. CONCLUSIONS: aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.

GM-CSF restores innate, but not adaptive, immune responses in glucocorticoid-immunosuppressed human blood in vitro.

Infection remains the major complication of immunosuppressive therapy in organ transplantation. Therefore, reconstitution of the innate immunity against infections, without activation of the adaptive immune responses, to prevent graft rejection is a clinically desirable status in transplant recipients. We found that GM-CSF restored TNF mRNA and protein expression without inducing IL-2 production and T cell proliferation in glucocorticoid-immunosuppressed blood from either healthy donors or liver transplant patients. Gene array experiments indicated that GM-CSF selectively restored a variety of dexamethasone-suppressed, LPS-inducible genes relevant for innate immunity. A possible explanation for the lack of GM-CSF to restore T cell proliferation is its enhancement of the release of IL-1betaR antagonist, rather than of IL-1beta itself, since exogenously added IL-1beta induced an IL-2-independent Con A-stimulated proliferation of glucocorticoid-immunosuppressed lymphocytes. Finally, to test the in vivo relevance of our findings, we showed that GM-CSF restored the survival of dexamethasone- or cyclosporine A-immunosuppressed mice from an otherwise lethal infection with Salmonella typhimurium. In addition to this increased resistance to infection, GM-CSF did not induce graft rejection of a skin allotransplant in cyclosporine A-immunosuppressed mice. The selective restoration potential of GM-CSF suggests its therapeutic use in improving the resistance against infections upon organ transplantation.