Abstract: OBJECTIVES: Markers of non-specific inflammation, such as C-reactive protein (CRP) or leukocyte count are increased in end-stage renal disease patients. Recent studies have shown positive associations between inflammatory markers and cardiovascular mortality in kidney transplant recipients, but these analyses had been limited by sample size. The aim of our study was to determine the association between pretransplant CRP levels and leukocyte counts with posttransplant outcome in a prospectively enrolled cohort of kidney transplant recipients. METHODS: 459 consecutive patients transplanted from July 1995 to December 2007 were analyzed. Both markers were obtained prior to transplantation and patients were grouped according to baseline CRP levels (<5mg/l or >/=5mg/l) or leukocyte counts (<10,000/mul or >/=10,000/mul). RESULTS: Major cardiac events were associated with elevated pretransplant CRP levels (p<0.00003) but not leukocyte counts. Furthermore, more acute rejection episodes within 4 weeks or 6 months, as well as a lower probability of survival at 6 months were found in patients with elevated pretransplant CRP levels or leukocyte counts. CONCLUSION: Elevated pretransplant serum CRP level is a risk predictor for major cardiac events in renal transplant patients. It is also predictive, besides leukocyte counts, for acute rejection episodes. Elevated CRP levels and initial high leukocyte counts may prove to be useful markers for posttransplant course and warrant the close follow-up of such patients.
Abstract: BACKGROUND: Following a motorcycle accident, a 30-year-old male with multiple traumas-including liver rupture, traumatic fractures, cerebral hemorrhage, hepatic hematoma and respiratory failure-was referred to a university medical center. After initial stabilization, the patient developed pneumonia, acute kidney failure requiring intermittent hemodialysis, superinfection of the hepatic hematoma and systemic bacterial infection with multiple drug-resistant bacteria. The patient developed acute liver failure 8 weeks after the initial trauma. INVESTIGATIONS: Laboratory investigations, Doppler ultrasound, CT, ultrasound, angiography, endoscopic retrograde cholangiography, liver biopsy, bacteriology and X-ray. DIAGNOSIS: Sclerosing cholangitis in a critically ill patient. MANAGEMENT: Orthotopic liver transplantation.
Abstract: Ischemia/reperfusion (I/R) injury is an unavoidable barrier that significantly affects outcome of solid organ transplantation. Here, we establish a protein transduction system to extend graft preservation time and to prevent I/R injury in heart transplantation. We generated a recombinant heme oxygenase-1 (HO-1) protein containing a modified protein transduction domain (PTD). PTD could cross cover cell membrane and carry target molecule to parenchymal cells of cold-preserved heart grafts. The newly generated PTD-HO-1 protein localized mainly in subcellular membrane organelle and nucleus after delivery that significantly prolonged cold preservation of heart grafts. This effect was associated with significantly less endothelial cell activation, less neutrophil and macrophage infiltration in PTD-HO-1-transduced heart grafts after reperfusion as compared with controls. In addition, transduction of PTD-HO-1 protein to heart graft significantly suppressed the I/R injury-associated myocardiocyte apoptosis. The infarct areas of heart graft after I/R injury were significantly reduced after PTD-HO-1 protein treatment. We show here for the first time that PTD can maintain its biological activities during cold preservation. Transduction of cell penetrating HO-1 protein significantly prolongs the cold preservation time and protects the graft from the I/R injury. This approach represents a novel method for the improvement of the overall outcome of organ transplantation.
Abstract: BACKGROUND AND AIMS: Adult living donor liver transplantation (LDLT) has been established as elective procedure or urgent procedure to save the life of patients with terminal liver diseases. The outcome of LDLT varies between transplant centers. Here, we aim to evaluate the outcome of LDLT in our center and to identify the risk factors that are associated with hospital mortality of recipients. PATIENTS AND METHODS: A cohort study with 32 consecutive cases of adult living donor liver transplantation was conducted in two cooperated medical centers. Perioperative data, incidence of postoperative complications, and hospital mortality were analyzed. RESULTS: No major surgical complications and no hospital mortality were observed in all 32 donors. All donors were discharged with normal liver function with median intensive care unit (ICU) stay of 1 day and median hospital stay of 10 days. All recipients had normal liver function in early posttransplant period. Eighty-one percent of the recipient survived with normal liver function for more than 1 year. The pretransplant ICU stay, renal failure, international normalized ratio (>1.8), and Model for End-stage Liver Disease (MELD) score (>20) were independent risk factors for hospital mortality of recipients. CONCLUSIONS: Adult living donor liver transplantation should be reserved to less "sick" patients in the era of organ allocation based on MELD score.
Abstract: Doenecke A, Tsui T-Y, Zuelke C, Scherer MN, Schnitzbauer AA, Schlitt H-J, Obed A. Pre-existent portal vein thrombosis in liver transplantation: influence of pre-operative disease severity. Clin Transplant 2009 DOI: 10.1111/j.1399-0012.2009.00977.x (c) 2009 John Wiley & Sons A/S.Abstract: Background: Portal vein thrombosis (PVT) is a surgical challenge in liver transplantation (LTx). In contrast to LTx in decompensated liver disease, which are associated with a higher morbidity and mortality, PVT influence on outcome is still under debate. To evaluate this influence at different stages of liver decompensation, we compared the outcome of patients suffering from PVT to patients with patent portal vein within different score ranges. Methods: We included 193 LTx (24 with PVT) in our study, transplanted between 2004 and 2007 at our institution. Patients were divided into four Model of End-Stage Liver Disease (MELD) score groups, and outcome was compared between PVT- and non-PVT patients. Results: In non-decompensated liver disease (MELD <15), we found a significantly decreased survival in patients suffering from PVT (one-yr survival 57% vs. 89%). By contrast, MELD score >15 (decompensated liver disease) leads to an equal or even better survival in PVT-patients compared with patients without PVT (one-yr survival 91% vs.75%), with an only slightly increased morbidity. Conclusion: Outcome in patients with PVT seems to be dependent on pre-operative disease severity. In contrast to compensated liver disease, no influence of PVT on outcome could be found in decompensated liver disease, and should therefore not be considered as a contraindication in LTx.
Abstract: Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.
Abstract: Due to the late onset of symptoms, retroperitoneal liposarcoma are often diagnosed in advanced stages when adjacent organs have been infiltrated and the tumours have reached extensive sizes. Surgery remains the first choice of therapy. We report on the primary resection of a 45-kg liposarcoma that was removed en-bloc including the left kidney and descending colon with -tumour-free margins. Nine months later, the follow-up revealed a right-sided recurrence of the tumour, which was surgically removed including the right ureter. Since then, the patient has been without any signs of tumour recurrence or metastases. This report demonstrates that even extreme-ly large tumours can be removed safely and that the size is not a contraindication for primary surgical treatment. Local recurrence is common as seen in our case, and occurs even after R0 resection up to 10 years after the first operation. Recurrences should be surgically removed as this is the only treatment which has been shown to increase survival in even R1 and R2 situations.
Abstract: BACKGROUND: At present, inflammation is considered to be one of the key players in the development and maintenance of atherosclerosis, with ample impact on renal transplant outcomes. Interleukin-6 (IL-6) levels and the underlying genetically determined "high-producer" status impact cardiovascular morbidity and mortality. In end-stage renal disease (ESRD) patients, the role of genetically determined IL-6 differences in cardiovascular and renal outcomes of kidney transplantation is controversial. In this study, we sought to clarify the influence of IL-6 haplotypes on cardiovascular and renal outcomes among kidney transplant recipients. METHODS: Three hundred fifty-two first kidney transplant patients were genotyped for the two "clade" IL-6 polymorphisms ((-174)G/C and (1888)G/T) and two missense polymorphisms (Pro32Ser, Asp162Val), which are known to influence IL-6 levels and outcome. RESULTS: We observed four IL-6 haplotypes among our population: CCAG: 57.0%, CCAT: 2.8%, GCAT: 39.2%, GCTT: 1.0%. After stratifying the haplotypes into diplotypes in three different models, we failed to observe associations with early or late graft outcomes, or with all-cause or cardiovascular mortality. These findings were also confirmed when we separately analyzed each polymorphism. CONCLUSION: Despite evidence of associations in other transplant and ESRD cohorts, we could not confirm any association between IL-6 haplotypes/diplotypes and cardiovascular or graft-related outcomes among our population at high risk for inflammatory diseases.
Abstract: BACKGROUND: Transplant renal artery stenosis (TRAS) is a frequent complication after renal transplantation, however long-term follow-up data after interventional treatment are rare. PATIENTS: In our transplant center 11 of 264 consecutive renal transplant recipients (4.17%) were diagnosed with TRAS. In addition, TRAS occurred in 2 renal transplant recipients that had been transplanted at other centers but who had their follow-up examinations in our center. Either a rise of the serum creatinine level and/or worsened systemic hypertension or routine examination with color Doppler sonography were indications for further diagnostic workup. METHODS: Direct angiography of the transplant renal artery was performed followed by percutaneous transluminal angioplasty (PTA) after the diagnosis of TRAS was confirmed in all of these patients. RESULTS: The immediate success rate for PTA was 92.3% (12/13). Only 1 patient with a severe kinking of the transplant renal artery had to undergo surgery to restore renal function. No complications occurred after the interventions. Thereafter the patients were monitored for a mean observation period of 33.15 months. Serum creatinine levels were significantly lower after the intervention, and estimated glomerular filtration rate (eGFR) increased accordingly. With regard to blood pressure there was only a trend for lower blood pressure levels and less antihypertensive use, whereas the dose of the prescribed drugs decreased significantly with time after interventional treatment of TRAS. In addition, a long-lasting rise of the hemoglobin levels could also be demonstrated. CONCLUSION: In summary, the beneficial effect of PTA of TRAS on renal function is long-lasting. Therefore, PTA, usually combined with stent placement, should be first-line treatment in TRAS in all patients. Surgical revascularization is only warranted, if PTA fails.
Abstract: Summary We report on the successful regrafting of a transplanted kidney. The donor kidney was first transplanted into a 32-year-old patient with renal atrophy. More than 2 years later, he suffered from severe grand mal seizure with brain edema and the patient met the criteria for brain death. The well-functioning graft was recovered and subsequently transplanted into a 66-year-old woman with chronic glomerular nephritis. Neither the first nor the second recipient experienced any acute rejection. To date, more than 14 years later, she is in good health with excellent graft function. This case report implies that excellent long-term graft function is viable in a graft reused 2 years after the initial transplantation.
Abstract: BACKGROUND AND AIMS: Activation of the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC. MATERIALS AND METHODS: Human HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model. RESULTS: NVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells. CONCLUSIONS: Combined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC.
Abstract: Increased serum C-reactive protein (CRP) levels have been associated with all-cause and cardiovascular mortality after kidney transplantation. As genetic variations within the CRP gene determine CRP serum levels, we analyzed the association of both serum CRP levels, and post-transplant morbidity/mortality with CRP-genotypes/haplotypes. We determined CRP levels pretransplant, at 3 and 6 months post-transplant in 402 first kidney recipients, genotyped the three functionally distinct polymorphisms, and subsequently reconstructed the different haplotypes. Four different CRP-haplotypes were observed with a frequency >1%: CGC (33.3%), CGT (30.2%), CAT (29.7%) and GGT (6.8%). CRP levels pretransplantation or 3 and 6 months post-transplant were not different in patients with different CRP-haplotypes. Furthermore, no association of CRP-haplotypes/diplotypes was found with acute rejection, delayed graft function, all-cause mortality or cardiovascular events. In our renal transplant population, we found no association of CRP-haplotypes/diplotypes with either CRP levels or with post-transplant morbidity/mortality. In this inflammation-prone population, rather small genetically determined differences in serum CRP observed in normal populations presumably are overridden by background inflammation. Life long genetically determined increased serum CRP levels appear not to have an impact in our study, implying that CRP is more likely only a marker of current inflammation than a causative agent of cardiovascular morbidity and mortality.
Abstract: BACKGROUNDS: Liver transplantation is considered as one of therapeutic approaches to hepatocellular carcinoma (HCC). The present study aims to evaluate the efficacy of various therapeutic options for HCC. MATERIALS AND METHODS: One hundred twenty patients with known HCC in various tumour stages were evaluated in the present study. Patients were treated either with primary tumour resection, transarterial chemoembolisation (TACE) or liver transplantation (LTx) by an interdisciplinary team. RESULTS: The overall 1-year and 5-year survivals of patients in LTx group were 95 and 57%, respectively, which were significantly higher than those in primary tumour resection group (65 and 33%, P < 0.01) and those in TACE group (44 and 4%, P < 0.01). In parallel, 1-year and 5-year tumour-free survivals of patients in LTx group (75 and 62%) were significantly higher than those in primary tumour resection group (50 and 11%, P < 0.01). There were no significant differences in 1- and 5-year survivals of patients with early tumour stage received LTx or primary tumour resection, whereas patients in advanced tumour stage based on pathological findings of explanted liver significantly benefited from LTx as compared to primary resection. CONCLUSIONS: LTx can be a curative approach for patients with advanced HCC without extrahepatic metastasis. However, organ shortage is a major limiting factor in the selection of HCC patients for LTx.
Abstract: BACKGROUND: To evaluate a low-tech blunt liver dissecting technique for living-liver-donor procedures. Thirty three adult-to-adult living-donor operations were performed at Regensburg University and Jordan Hospital, Amman. PATIENTS AND METHODS: For the technique of parenchymal dissection, dissecting scissors were used for blunt preparation; branches were closed, carefully pressing into the hepatic parenchyma. Donor, surgical procedure data, and data on liver function and recovery were analyzed and compared to literature. RESULTS: Median procedure time was 280 min (210 to 420 min). Median blood loss was 350 ml (0 to 650 ml). GOT levels decreased from 260 U/l (140 to 510 U/l) on day 1 to 65 U/l (31 to 220 U/l) on day 7. Bilirubin levels were at 2.0 mmol/l (1.29 to 5.99 mmol/l) on day 1 and 1.26 mmol/l (0.63 to 4.70 mmol/l) on day 7. After 12 days (6 to 23), all donors were discharged. There was no donor mortality. One major complication (biliary leakage) and seven minor complications occurred. CONCLUSION: This technique is a low-tech but efficient donor-dissection technique in living liver transplantation, which is comparable to other well established dissection techniques utilizing technical devices in regards to risk for the donor, performance, and recovery.
Abstract: Split-liver transplantation is now established as a safe and successful technique that extends the donor pool for patients of all ages and thus reduces waiting-list mortality, although it can not solve the problem of organ shortage alone. Split-liver transplantation additionally represents an alternative to living liver transplantation without a potential risk of harm to the donor. Careful selection of donor and recipient, high technical and surgical skill, and experience are necessary to achieve results comparable to those of whole organ transplantation.
Abstract: Aldehyde oxidase 1 (AOX1) is highly abundant in the liver and oxidizes aldehydes thereby generating reactive oxygen species. Enzymes involved in detoxification of aldehydes are expressed in adipocytes and alter adipogenesis, therefore the functional role of AOX1 in adipocytes was analyzed. AOX1 mRNA was higher in visceral compared to subcutaneous human adipose tissue but AOX1 protein was detected in both fat depots. AOX1 expression in adipocytes was confirmed by immunohistochemistry and immunoblot. AOX1 was induced during adipocytic differentiation and was downregulated by fenofibrate in differentiated cells. Knock-down of AOX1 in preadipocytes led to impaired lipid storage and adiponectin release in the differentiated cells. These data indicate that AOX1 is essential for adipogenesis and may link energy and drug metabolism.
Abstract: Benign liver tumors are being detected more frequently due to the widespread use of ultrasound and complementary methods and due to improvements in diagnostic accuracy. In the case of a reliable diagnosis of asymptomatic hemangioma or focal nodular hyperplasia surgery is not indicated. Hepatic adenoma of considerable size should be resected primarily based on the risk of rupture. Improvements in diagnostic imaging as well as the optimization of surgical procedures with extremely low complication rates permit an individualized management strategy founded on evidence-based algorithms. In the case of an equivocal diagnosis, we advocate low-risk tumor resection instead of tumor biopsy due to the inherent complication rates of hemorrhage or tumor-cell dissemination and possible misleading histology.
Abstract: BACKGROUND: Genetic manipulation of the allograft is an attractive approach to prevent the graft against chronic deterioration through stable expression of immunomodulatory or protective genes. However, the best strategy for prevention of chronic allograft deterioration remains unclear. METHODS: The efficacies of adeno-associated viral vector-mediated stable expression of indoleamine 2,3-dioxygenase (IDO), cytotoxic T-lymphocyte associated antigen 4 with human immunoglobulin G(1) (CTLA4Ig) or interleukin-10 (IL-10) in the prevention of chronic allograft deterioration were compared in a rat heart transplantation model. RESULTS: Transduction of grafts with IL-10 significantly prolonged allograft survival, whereas transduction of grafts with IDO did not improve graft survival compared to controls. Analysis of long-term survived heart allografts showed that both CTLA4Ig and IL-10 could significantly reduced the T cells and macrophage infiltration. However, stable expression of CTLA4Ig failed to prevent the development of transplant arteriosclerosis. By contrast, IL-10 suppressed the development of transplant arteriosclerosis effectively. The suppressive effects of IL-10 in preventing the development of chronic allograft deterioration were associated with lower transcript levels of transforming tumor growth factor beta 1 and macrophage migration inhibitory factor in the graft. In addition, higher transcript levels of heme oxygenase-1 were found in IL-10-transduced allograft. CONCLUSIONS: Targeting on IL-10 is superior to CTLA4Ig or IDO for the treatment of chronic allograft deterioration.
Abstract: A 51-year-old renal transplant recipient presented with marked renal function deterioration 13 months after renal transplantation. After exclusion of ureteral obstruction, transplant artery stenosis and acute rejection, the diagnosis of a severe renal vein stenosis was made by an MR scan. After angiographic confirmation of the stenosis, treatment was attempted with percutaneous stent angioplasty. The long-term clinical course was favorable, with marked improvement in renal function. Transplant renal vein stenosis is a rare, but potentially curable, cause of renal allograft functional deterioration.
Abstract: BACKGROUND/AIMS: The critical issue before major hepatic resection is to evaluate and detect patients with a potentially increased risk of hepatic failure. In this study the prognostic value of the monoethylglycinexylidide (MEGX)- liver function test was evaluated with regards to clinical course and survival after partial liver resection. METHODOLOGY: Between 1995 and 2000 a total of 55 patients (29 male, 26 female) underwent a partial liver resection at the Georg-August University of Göttingen. Forty-two patients were treated for malignant, and 13 for benign, disease. MEGX-testing was performed 15 and 30 minutes after a single-dose of 1mg/kg BW Lidocaine i.v. was applied. RESULTS: MEGX-test results after 30 minutes had significant influence on hospital mortality. Patients who died during the hospital stay showed median MEGX-30 minutes results of 32 microg/L in (4-107 microg/L) in comparison to the surviving patients with a median 68 microg/L (16-176 microg/L) (p = 0.026). Furthermore, patients with MEGX scaled categories of 3 and 4 had a significantly lower surivial at 150 days (p = 0.008) and overall (p = 0.0002). There was an indirect impact of MEGX on hospital stay, costs and mortality reflecting high fluid loss: patients with lower loss of fluid over drainages had a significantly lower mortality at 150 days (p = 0.00046) and overall (p = 0.00008), than did patients with higher fluid loss. Low MEGX-values significantly influenced long hospital stay (p = 0.00001) and high costs (p = 0.00001). Pathologic MEGX in combination with increased age, increased BMI and extensive surgical procedures including resection of over 50% volume of the liver had a significant influence on complications (p = 0.015). CONCLUSION: The preoperative MEGX-test, especially the 30 minutes value, is a useful medium to estimate the liver reserve in non-cirrhotic patients prior to liver resection. In combination with the resection volume it may be very useful to identify patients with a high risk of developing a postoperative liver failure.
Abstract: BACKGROUND: Chronic allograft nephropathy (CAN) is, among others, caused by nephrotoxic side effects of calcineurin inhibitors (CNI), which are to date still the mainstay of immunosuppressive therapy. Sirolimus (SIR), an immunosuppressive compound without effects on glomerular perfusion, has been used in CNI-sparing immunosuppressive protocols. We report the 5-year follow-up of a prospective, controlled conversion study from CNI to SIR in patients with moderately to severely impaired renal function. METHODS: Twelve renal transplant recipients with moderately to severely impaired renal function (estimated glomerular filtration rate of 17 to 35 mL/min according to the MDRD formula), enrolled in a prospective, controlled 1-year pilot study were followed for 5 years. RESULTS: Three renal grafts (25%) were lost during the 5-year follow-up. Graft loss was due to noncompliance in one patient and to CAN in the other two patients. These two patients returned to dialysis 43 and 59 months after conversion, corresponding to 86 and 75 months after transplantation, respectively. Six of nine patients had a stable or even better renal function compared to the baseline. The lipid profile increased initially, but then remained stable over time. CONCLUSION: Conversion of immunosuppressive therapy from CNI to SIR in patients with impaired renal function more than 1 year after transplantation is feasible and safe yielding improved renal function in the majority of patients, which was sustained at 5 years follow-up.
Abstract: AIM: To assess the outcome of patients, who underwent transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and subsequently liver transplantation (OLT) irrespective of tumor size when no tumor progression was observed. METHODS: Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included. RESULTS: The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 mo. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria. CONCLUSION: Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy.
Abstract: Heme oxygenase 1 (HO-1) enhances cellular antioxidative capability by increasing the cleavage of the endogenous and exogenous heme. Besides the biochemical activities of HO, the products of heme degradation significantly contribute to the cytoprotective effects of HO. Here, we show that HO-1 deficiency significantly increases the susceptibility of mice to apoptotic insults, whereas expression of HO-1 significantly increased the resistance of primary hepatocyte to apoptosis. This phenomenon was correlated with the production of one of its catalytic products-carbon monoxide (CO). Surprisingly, exposing the primary mouse hepatocyte to CO could improve the cellular energy metabolism in a soluble guanylyl cyclase-dependent manner. One-hour inhalation of low-dose CO enhanced the hepatic soluble guanylyl cyclase activities in mice. In parallel, the levels of hepatic adenosine triphosphate increased significantly and were associated with a marked reduction of TNF-alpha-induced apoptosis in the liver of D-galactosamine-sensitized mice. In addition, CO inhalation for 1 h significantly improved the survival of mice after initiation of fulminant hepatitis. Up to 90% of mice given CO survived for more than 7 days, whereas control mice died within 12 h. The data provide novel insight of CO-mediated cytoprotection.
Abstract: BACKGROUND: Living kidney donation helps to avoid or reduce the time period of dialysis and on waiting lists in patients requiring a new organ. Mini-incision donor nephrectomy (MIDN) shows to result in better clinical outcome in comparison with traditional open donor nephrectomy (ODN). This study was performed to evaluate the impact of different surgical procedures on the quality of life (QoL) in patients that underwent donor nephrectomy. METHODS: The aim of the study was to detect differences in QoL assessed with the Short Form-36 Version 2 (SF-36v2) questionnaire between MIDN (n = 34) and ODN (n = 36). Furthermore, the development of QoL from prior to surgery until one yr afterwards, as well as outcomes of QoL in comparison with norm-based scores was investigated. RESULTS: Sixty-one of 70 patients, which is 87% (MIDN: 86%, ODN: 88%) resent a whole set questionnaires. QoL was similar at all time-points (prior to surgery, one wk, three months and one yr) in both groups. A tendency of better QoL in MIDN (Bodily Pain) after one wk was detectable (p = 0.075). Physical Component Summaries (PCS) significantly decreased from prior to surgery until one wk after surgery (p = 0.001) and improved significantly until three months (MIDN: p = 0.006, ODN: p = 0.001) and also until one yr after surgery (p = 0.002). Mental Component Summaries (MCS) were stable throughout the whole investigated time period. In comparison with norm-based scores, MIDN (p = 0.005) and ODN (p = 0.001) showed significantly higher PCS prior to, lower scores one wk after (p = 0.001), similar scores three months after and better scores (MIDN: p = 0.023, ODN: 0.015) one yr after surgery. Mental Component Scores were similar in both prior to and one wk after surgery. After three months and one yr scores were significantly better in MIDN (three months: p = 0.049, one yr: p = 0.037) and ODN (three months: 0.020, one yr: 0.073). CONCLUSION: Quality of life after living donor nephrectomy is not influenced by the surgical technique. Nevertheless the standardized instrument of the SF-36v2 Health Survey is a useful, practicable and universally interpretable tool to gain and estimate recovery from surgical procedures in the perioperative period and its development thereafter.
Abstract: BACKGROUND: The chemokine system plays an important role in the pathogenesis of acute rejection or atherosclerosis. Three polymorphisms in the promoter region of the chemokine RANTES (-403G/A, -28G/C, In1.1T/C) are associated with a different expression of this chemokine as well as the occurrence of cardiovascular disease. Therefore, we investigated the impact of these three polymorphisms on the outcome after renal transplantation. METHODS: In 261 patients receiving their first kidney transplant, we genotyped the RANTES promoter polymorphisms (-403G/A, -28G/C, In1.1T/C) by real-time PCR. RESULTS: For the RANTES -403G/A and for the intronic polymorphism In1.1T/C, we found a significantly higher rate of recurrent acute rejection episodes (-403G/A: 11.1 vs. 31.0%, In1.1T/C: 11.8 vs. 33.0%). For the overall rate of acute rejection, we observed no significant differences according to the RANTES promoter polymorphisms. The other tested variables (DGF, graft survival, renal function) were not associated with one of the three polymorphisms. CONCLUSION: Our data indicate a relevant role of RANTES in kidney transplantation, particularly for the occurrence of recurrent acute rejection. To clarify the role of the analysed polymorphisms for long-term survival, especially for the occurrence of cardiovascular events, larger studies in the future are needed.
Abstract: BACKGROUND: While early surgical success made organ transplantation possible in the 1950s and 1960s, the breakthrough in clinical organ transplantation was achieved through the discovery and invention of modern immunosuppressive agents in the early/mid-1980s. Especially during the 1990 s, a large array of immunosuppressants has expanded the armamentarium used to prevent and treat allograft rejection, resulting in an excellent short-term and an acceptable long-term outcome. However, these drugs have potent but still non-specific immunosuppressive properties and frequently show severe acute and chronic side effects, sometimes questioning the overall success. CONCEPTS/TRENDS: As the "Holy-Grail" of the transplant community, the induction of "true donor-specific tolerance" has not been achieved yet; current immunosuppressive strategies, in particular in Europe, include "individually tailored immunosuppressive" protocols, mostly based on specific immunologic and non-immunologic risk factors. These protocols allow for optimal immunosuppressive protocols for each patient group according to their needs by choosing the most suitable, well-tolerated combination of agents and the most effective doses to avoid acute rejection episodes (incidence and severity) and minimise drug-related toxicity to reduce long-term drug-related morbidity and mortality. Nevertheless, transplant recipient are still being forced to take a life-long course of chemical immunosuppressive agents to keep their graft, knowing about the possible life-threatening side effects. SUMMARY: We review current trends of immunosuppressive protocols in liver and kidney transplantation, focusing on calcineurin-inhibitor-sparing protocols, mammalian-target-of-rapamycin (mTOR) inhibitor based-protocols and corticosteroid-avoidance protocols, being aware of the fact, that most of these strategies could be applicable for other transplanted organs, too. Finally, we describe future trends and new developments that are rising on the horizon.
Abstract: We describe the first case of sirolimus-induced drug fever in a female liver transplant recipient, with a history of hepatitis C-induced end-stage liver cirrhosis in 1999. In 2005, six years after transplantation, she developed calcineurin inhibitor-induced renal function impairment. Immunosuppression was switched from tacrolimus to sirolimus. Two days after the intake of sirolimus, she developed daily fever spikes, but no infectious focus was found. Antibiotic therapy had no influence on the fever. After fourteen days, sirolimus was switched back to tacrolimus and the fever disappeared. In history, the patient developed ciclosporin-induced generalized seizures eleven days after liver transplantation, followed by the development of a motoric speech disorder. Magnetic resonance imaging (MRI) findings were consistent with leucoencephalopathy, therefore immunosuppressive therapy was changed from ciclosporin to tacrolimus and the neurologic symptoms improved significantly. Our case is the first reported case of sirolimus-induced drug fever. In addition, the patient showed the rare occurrence of ciclosporin-induced leukencephalopathy with seizures.
Abstract: Chronic allograft nephropathy and (cardiovascular) death with functioning graft are major causes of late graft loss. NOD2/CARD15 (nucleotide oligomerization domain-2/caspase-recruiting activating domain-15), an intracellular receptor that is part of the innate immunity repertoire, has convincingly been shown to be involved in infection/inflammation-associated diseases. Specifically, NOD2/CARD15 polymorphisms are clearly associated with Crohn's disease and transplant-associated mortality after bone marrow transplantation. The aim of this study was to clarify the relevance of NOD2/CARD15-haplotypes in kidney transplantation. Three hundred fifty-two patients receiving their first kidney transplant were genotyped for the three major NOD2/CARD15 polymorphisms, R702W, G908R, and 1007fs with subsequent reconstruction of the different haplotypes. Four different NOD2/CARD15 haplotypes were observed in our population [CG(-): 89.8%, CGC: 3.5%, CC(-): 1.6%, TG(-): 5.1%]. After stratifying the different haplotypes into diplotypes (wild type: CG(-)/CG(-), n=284, mutated haplotype, n=68) we found a significant association with all-cause and cardiovascular mortality, also after adjusting to different covariates, and (only) in univariate analysis with graft survival. In conclusion, we found different effects of the NOD2/CARD15 haplotypes on disorders, like cardiovascular and all-cause mortality,which may be considered at least in part as chronic inflammation-driven. Further studies are needed to confirm and work out the association between these disorders and the NOD2/CARD15 haplotypes.
Abstract: BACKGROUND: Disorders of calcium homeostasis are one of the most common problems in patients with end-stage renal disease (ESRD). Elevated calcium levels increase the incidence of cardiovascular mortality in ESRD patients, and appear to be a risk factor for the occurrence of delayed graft function (DGF) after kidney transplantation. Therefore, we investigated the impact of pretransplant serum calcium levels on outcomes after kidney transplantation: DGF, acute rejection, graft function, and survival, as well as the incidence of cardiovascular events. METHODS: We studied 285 patients (96.9% of all transplanted patients) who underwent their first transplantation between 1995 and 2004. Demographic data were extracted from hospital records or were documented during follow-up; serum samples were collected at the time of transplantation. RESULTS: In our cohort the incidence of DGF was 16.5% and 35.4% of acute rejection episodes (ARE). However, pretransplant calcium levels were not related to DGF or ARE in our patient cohort. Furthermore, there was no correlation between pretransplant serum calcium level with the incidence of cardiovascular events or mortality, as well as graft function or survival. CONCLUSION: In our study population pretransplant calcium levels showed no effect on DGF, ARE rate, the occurrence of cardiovascular events or death, renal graft function, or survival. Therefore, pretransplant calcium level is not a helpful marker for risk stratification at the time of transplantation.
Abstract: PURPOSE: In this study we present the technique of a strictly retroperitoneal donor nephrectomy via a pararectal mini-incision. MATERIAL AND METHODS: Data of 34 living kidney donations were analyzed. All donors underwent a pararectal mini-incision and strictly retroperitoneal nephrectomy (MIDN). RESULTS: Total operation time, perioperative use of pain medication, length of hospital stay after successful mobilization, and return to full enteral nutrition and regular digestion were evaluated retrospectively. Total operation time for MIDN was 132+/-26 min. The total average application was 22.2+/-19.4 mg of opioid in morphine equivalent dosage (MED), 7.7+/-6.1 g metamizol, and 512+/-325 mg NSAR during hospital stay, which was 4.9+/-1.4 days. Patients were mobilized primarily 2.9+/-8.0 h after surgery. Mobility was achieved 33.8+/-15.8 h after surgery. Enteral nutrition with fluids was started after 1.9+/-7.0 h, full enteral nutrition was accomplished after 37.4+/-19.0 h, and normal digestion returned 58.6+/-23.0 h after the procedure. CONCLUSIONS: The strictly retroperitoneal nephrectomy via a mini-incision is an elegant, minimally traumatic, safe, and quickly learnable method, resulting in short hospital stays, good cosmetic results, and a low grade of complications.
Abstract: AIM: To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCl(4)-induced micronodular cirrhosis model. METHODS: Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1x 10(12) vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis. RESULTS: Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/HO-1-transduced livers. CONCLUSION: Enhancement of HO activity in the livers suppresses the development of cirrhosis.
Abstract: Severe infections are the most dangerous complications in liver transplantation and their prevention is one of the major goals. A 60-year-old Saudi-Arabian female with decompensated hepatitis C liver cirrhosis received a right-lobe liver graft from her healthy daughter. After 9 days, the patient developed a rapidly progressive necrotizing pneumonia that was fatal in spite of extracorporal lung assist. The pneumonia was due to a Panton-Valentine Leucocidine-positive (PVL) methicillin-resistant Staphylococcus aureus (MRSA), or "community-acquired" MRSA, that had not been detectable in the patient preoperatively. The same strain of PVL-MRSA could be demonstrated in the nares of the asymptomatic donor, but not of other relatives, patients, or medical staff. These findings strongly suggest transmission of PVL-MRSA from the donor to the recipient. This case demonstrates a previously unknown, and potentially fatal, risk in living-donor liver transplantation: transmission of a severe infection from a healthy donor to the recipient.
Abstract: Cyclooxygenases (COX) are known to be involved in inflammatory kidney diseases. However, there are no data available about the expression of COX-1 and only preliminary reports about the expression of COX-2 in biopsies of patients undergoing acute renal allograft rejection. We conducted this prospective study to analyze the expression, distribution, and cellular localization of COX-1 and -2 and thus to elucidate the role of COX in human kidney transplantation. One hundred forty-four biopsies were included from patients without rejection and unaltered morphology (n = 60), with acute interstitial rejection (n = 7), with acute vascular rejection (n = 21), with chronic allograft nephropathy (n = 16), without rejection but with various other lesions (n = 40). COX-1 and -2 expression was localized in each biopsy by immunohistochemistry. We found a highly significant up-regulation of COX-1 in vessels and in infiltrating interstitial cells of patients with acute allograft rejection compared with biopsies with well-preserved tissue. Also, COX-2 expression was significantly elevated in infiltrating interstitial cells of biopsies with acute rejection. This is the first prospective study demonstrating a significant induction of both COX-1 and -2 in human allograft biopsies with acute rejection after renal transplantation.
Abstract: Percutaneous endoscopic catheter gastrostomy (PEG) is a convenient way to supply enteral nutrition for patients with swallowing disorders. One rare complication of PEG is the buried bumper syndrome where gastric mucosa overgrows the internal bumper and prevents free flow of the feeding solution. As a consequence, the application of enteral feeding has to be stopped until a free outflow is re-established. We report a case of buried bumper where symptoms were misinterpreted for several months as PEG stoma infection by the homecare service. This led to a vastly delayed diagnosis and treatment. As endoscopic intervention was unsuccessful, surgical PEG removal was required. In consequence, we recommend early endoscopic exploration in cases with prolonged inflammatory signs at the PEG stoma site in order to avoid misdiagnosis of buried bumper syndrome and to allow timely endoscopic intervention.
Abstract: BACKGROUND: Shortage of donor organs is one of the major problems for liver transplant programmes. Living liver donation is a possible alternative, which could increase the amount of donor organs available in the short term. OBJECTIVE: To assess the attitude towards living organ donation in the general population to have an overview of the overall attitude within Germany. METHODS: A representative quota of people was evaluated by a mail questionnaire (n = 250). This questionnaire had 24 questions assessing the willingness to be a living liver donor for different potential recipients. Factors for and against living liver donation were assessed. RESULTS: Donating a part of the liver was almost as accepted as donating a kidney. The readiness to donate was highest when participants were asked to donate for children. In an urgent life-threatening situation the will to donate was especially high, whereas it was lower in the case of recipient substance misuse. More women than men expressed a higher disposition to donate for their children. Sex, religion, state of health and age of the donor, however, did not influence other questions on the readiness to consider living organ donation. The will for postmortem organ donation positively correlated with the will to be a living organ donor. CONCLUSIONS: The motivation in different demographic subgroups to participate in living liver transplantation is described. Differences in donation readiness resulting from the situation of every donor and recipient are thoroughly outlined. The acceptance for a living liver donation was found to be high - and comparable to that of living kidney donation.
Abstract: The exact mechanism of acute and chronic allograft rejection still remains unclear. The chemokine SDF-1 as mediator of allograft rejection has been under intensive investigation in liver, cardiac and bone marrow transplantation, whereas in renal transplantation, there are no reports about SDF-1 to date. This study was performed to evaluate if SDF-1 might also play an important role in human renal graft biopsies. One hundred and ninety formalin-fixed, paraffin-embedded renal allograft biopsies were included in the analysis from patients with normal renal graft morphology (according to Banff 97 classification grade 1, n = 84), with acute interstitial rejection (Banff grade 4 type I, n = 10), with acute vascular rejection (Banff grade 4 type II, n = 21), with chronic allograft nephropathy (CAN, Banff grade 5, n = 23), and without rejection but with various other lesions (Banff grade 6, n = 42). SDF-1 was localized by immunohistochemistry. In biopsies with CAN, SDF-1 expression was significantly elevated in interstitial infiltrates and infiltrating neointimal cells of arteries compared with biopsies with normal renal graft morphology. This is the first study describing a role of SDF-1 in human renal allograft rejection. We were able to demonstrate in a large number of biopsies an upregulation of SDF-1 in patients with CAN. Whether SDF-1 has pro-inflammatory or protective properties in this setting has to be evaluated in further trials.
Abstract: ANAMNESIS: A 18-year-old woman suffered from severe multi-trauma in combination with acute brain injury (Glasgow Coma Scale Score = 4) after road accident. After prolonged rescue measures and emergency stabilisation the patient was transferred by helicopter to the emergency department of our clinic. INVESTIGATIONS: Cranial computer tomography showed a severe general cerebral edema and a marked reduction in cerebral perfusion. Additionally, blunt abdominal injury, severe chest injury and multiple fractures were seen. Due to the severe and diffuse brain injury, a neurosurgical intervention was not possible. The patient was transferred to the intensive care unit. THERAPY AND COURSE: Intensive supportive therapy was started (artificial ventilation, massive transfusion, volume replacement, insertion of a chest tube, renal replacement therapy). Control cerebral computer tomography indicated a complete destruction of the cerebral parenchyma and infarction. Sedation was stopped. After 48-hours of intensive care therapy brain death was stated and the approval for organ donation was given by the next of kin. Heart and kidneys were explanted and transplanted successfully. CONCLUSION: Even under conditions of limited organ functions early identification and maximal supportive therapy may help to supply organ donation. Under certain condition, multiorgan failure may be reversible in possible organ donors.
Abstract: AIM: To evaluate survival in patients undergoing palliative resection versus non-resection surgery for primary colorectal cancer in a retrospective analysis. METHODS: Demographics, TNM status, operating details and survival were reviewed for 67 patients undergoing surgery for incurable colorectal cancer. Palliative resection of the primary tumor was performed in 46 cases in contrast to 21 patients with non-resection of the primary tumor and bypass surgery. Risk factors for postoperative mortality and poor survival were analyzed with univariate and multivariate analyses. RESULTS: The two groups were comparable in terms of age, gender, preoperative presence of ileus and tumor stage. Multivariate analysis showed that median survival was significantly higher in patients with palliative resection surgery (544 vs 233 d). Differentiation of the tumor and tumor size were additional independent factors that were associated with a significantly poorer survival rate. CONCLUSION: Palliative resection surgery for primary colorectal cancer is associated with a higher median survival rate. Also, the presence of liver metastasis and tumor size are associated with poor survival. Therefore, resection of the primary tumor should be considered in patients with non-curable colon cancer.
Abstract: BACKGROUND: Mini-incision donor nephrectomies (MIDNs) were established during the last decade, as an alternative to traditional open donor nephrectomy (ODN) via flank incision. In this study, we investigated intra-operative and post-operative data on outcome following MIDN in comparison with ODN data. METHODS: Data of 70 living kidney donations, performed at the University of Regensburg Medical Center since 1996, were evaluated. Donor operation was performed as either strictly retroperitoneal MIDN (n = 34) or as traditional ODN (n = 36) via flank incision. Total operation time, warm ischaemia time (WIT), perioperative pain-medication usage and creatinine levels as well as length of hospital stay, return to complete enteral nutrition and regular digestion were evaluated retrospectively. RESULTS: Total operation times were similar in MIDN, n = 34 (132 +/- 26 min) and in ODN, n = 36 (140 +/- 37 min) (P = 0.424). WIT was also similar in both: MIDN (0.9 +/- 0.4 min) and ODN (0.9 +/- 0.4 min) (P = 0.568). The requirement for post-operative opioids in morphine equivalent doses was significantly lower in MIDN (8.4 +/- 16 mg) compared with ODN (44 +/- 57 mg) (P = 0.001). Additional application of non-opioids (metamizole) (MIDN: 4.8 +/- 6.3 g, ODN: 3.4 +/- 3.9 g) and non-steroidal antirheumatic (NSAR) (diclofenac) (MIDN: 322 +/- 361 mg, ODN: 247 +/- 474 mg) revealed no significant differences between the groups. The hospital stay was 4.9 +/- 1.4 days in MIDN which was significantly shorter than that in ODN (9.3 +/- 3.3 days) (P = 0.001). Patients achieved fully independent mobility earlier in MIDN than in ODN (P = 0.934). Start of enteral nutrition with fluids was significantly quicker in MIDN (1.9 +/- 7 h) compared with ODN (12 +/- 13 h) (P = 0.05). Full enteral nutrition was accomplished significantly earlier in MIDN (1.6 +/- 0.8 days) (P = 0.023). Return to normal digestion revealed no significant differences between groups. Serum creatinine levels of all kidney donors were in the normal range (66 +/- 18 micromol/l) one day before nephrectomy, increased on day 1 after surgery (119 micromol/l +/- 31 micromol/l) and were stable on day 3 (115 micromol/l +/- 30 micromol/l) without significant differences. CONCLUSION: Strictly, retroperitoneal MIDN in living kidney donation is a fast and safe method for the procurement of a living donor graft, giving the patient a significantly shorter period of recovery, and thus is an attractive and recommendable alternative to traditional ODN procedures.
Abstract: INTRODUCTION: Conditioning of liver grafts by bolus pretreatment with prostaglandins has been previously demonstrated to improve hepatic bile flow. However, the underlying mechanisms have not been investigated. To elucidate whether improved bile flow after prolonged ischemia is due to maintained bile acid secretion or due to increased paracellular permeability, we performed a study using increasing doses of the marker acid taurocholate in the isolated perfused rat liver system. METHODS: Livers were harvested from adult Lewis rats and stored for 24 hours in UW solution. Pretreatment of livers was performed 1 minute before preservation. One group received prostaglandin I2, the second group received prostaglandin E1, and the control group was treated with saline. After 24 hours of cold storage the grafts were investigated in the isolated perfused rat liver system by perfusion with an oxygenated Krebs-Ringer-Henseleit buffer. Increasing doses of the radiolabeled marker bile acid taurocholate were infused to investigate bile acid transport. RESULTS: Bile flow and bile acid output were increased by pretreatment of the livers with prostaglandin I2 and prostaglandin E1, as compared to the control group. More specifically, the maximum transport rate was tripled by prostaglandin I2 and by prostaglandin E1 preconditioning of liver grafts, in comparison to the control group (P < .01 vs prostaglanin I2 and E1). CONCLUSION: The results clearly demonstrate that increased bile flow after conditioning of liver grafts with prostaglandins is not due to increased paracellular permeability but is based on markedly improved bile acid output.
Abstract: Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.
Abstract: BACKGROUND: Primary graft dysfunction due to ischemia and reperfusion injury represents a major problem in liver transplantation. The related cell stress may induce apoptosis, which can be suppressed by bcl-2. The purpose of the study was to investigate the effect of adenoviral bcl-2 gene transfer on early graft function and survival in rat liver transplantation. METHODS: An adenoviral construct that transfers bcl-2 under the control of a tetracycline inducible promoter was generated (advTetOn bcl-2) and used with a second adenovirus that transfers the repressor protein (advCMV Rep). Forty-eight hours before explantation, donor rats were treated with advTetOn bcl-2/ advCMV Rep (n=7) and doxycyclin, with the control adenoviral construct advCMV GFP (n=8) or with doxycyclin alone (n=8). Liver transplantation was performed following 16 hours of cold storage (UW). Bcl-2 expression and intrahepatic apoptosis was assessed. Bile flow was monitored 90 min posttransplantation. The endpoint for survival was 7 days. RESULTS: Bcl-2 was expressed in hepatocytes and sinusoidal lining cells. This was associated with a significant reduction of apoptotic sinusoidal lining cells and hepatocytes after 24 hours and 7 days. Bile production was significantly higher following bcl-2 pretreatment. Furthermore, bcl-2 transfer resulted in significantly improved survival (100% vs. 50% both control groups). CONCLUSIONS: Adenoviral bcl-2 transfer results in protein expression in hepatocytes and sinusoidal lining cells resulting in early graft function and survival enhancement after prolonged ischemia and reperfusion injury. The inhibition of apoptosis in the context of liver transplantation might be a reasonable approach in the treatment of graft dysfunction.
Abstract: Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.
Abstract: This study analyzes the course of 62 patients aged over 60 years (i.e., 7% of all recipients) which were liver transplanted over the last 10 years. The data show that the results of transplantation in patients with malignant tumors (n = 25) are unfavorable (20% 5-year survival), while good results could be obtained in patients with benign indications (n = 37), including mainly posthepatitic cirrhosis, but also three fulminant liver failures (75% 5-year survival). Causes of death were mainly septic complications in the early phase and tumor recurrence in patients with malignant disease.
Abstract: Purpose: Acute renal dysfunction has been observed in up to 50% of all patients after orthotopic liver transplantation (OLT). More than 90% of patients receive calcineurin inhibitors (CNIs) for immunosuppression after OLT, and nephrotoxicity of CNIs contributes to renal impairement. Early renal dysfunction significantly increases the risk of chronic renal failure und subsequently the risk of premature death. Multiple trials investigated the effect of delayed CNI and reduced-dose CNI regimens or early withdrawal of CNI in patients with renal dysfunction after OLT. Generally, avoidance of CNIs improves kidney function and does not result in higher rate of rejection when an adequate level of immunosuppression is maintained. Based on the aforementioned data this study protocol was designed to evaluate the efficacy and safety of CNI-free de-novo immunosuppression after liver transplantation. Methods and Design: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, everolimus, and prednisolone. The primary endpoint is the rate of steroid resistant reject. Secondary endpoints are the incidence of acute rejection, kidney function, liver allograft function (assessed by measurement of AST, ALT, total bilirubine, AP, GGT), treatment failure (reintroduction of CNI), incidence of adverse events, and mortality up to one year after OLT. Discussion: The ongoing clinical trial represents an intermediate element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a prospective therapeutic exploratory study. If the data of this ongoing research project confirms feasibility of de-novo CNI-free immunosuppression, this should be confirmed in a randomized, prospective, controlled double-blinded clinical.
Abstract: Einleitung: Die ABO-inkompatible Leberlebendtransplantation (ABOi-LDLT) ist mittlerweile ein in Japan und den USA, etabliertes Verfahren, um den Donorpool zu erweitern. ABO-inkompatible Lebertransplantationen sind auch in Europa durchgef 252;hrt worden, Publikationen aus Deutschland gibt es jedoch bisher nicht. Die besonderen Risiken der ABOi-LTX sind a) die humorale Absto 223;ung durch blutgruppenspezifische Isoh 228;magglutinine, b) vaskul 228;re und c) bili 228;re Komplikationen. Ein allgemein etabliertes Protokoll zur Verringerung dieser Risiken existiert nicht. Dies ist ein erster Bericht 252;ber Erfahrungen mit der ABOi-LDLT in Deutschland. Methoden: Wegen fortgeschrittener Lebercirrhose (N=2) oder nicht-resektablen cholangiocellul 228;ren Carcinoms (CCC; N=1) erhielten drei Patienten in unserer Klinik eine ABOi-LDLT. Zur Reduktion der Isoh 228;magglutinine f 252;hrten wir bei allen Patienten pr 228;operativ Plasmapheresen durch. Um die Menge der residenten B-Zellen zu verringern, wurde bei zwei Patienten die Transplantation mit einer Splenektomie kombiniert. Die Induktionsimmunsuppression wurde mit Methylprednisolon durchgef 252;hrt, beim letzten Patienten zus 228;tzlich mit Antithymozytenglobulin (ATG). Die Basisimmunsuppression beinhaltete Tacrolimus und Prednisolon in Kombination mit Sirolimus oder Mycophenols 228;ure. Ergebnisse: Bei allen drei Patienten bestand eine gute Prim 228;rfunktion des Transplantats und eine akute Absto 223;ung konnte histologisch bei allen Patienten ausgeschlossen werden. Zwei Patienten wurden am 49. bzw. 55. postoperativen Tag nach Hause entlassen; ein Patient verstarb an einem Multiorganversagen infolge einer Sepsis. Schlussfolgerung: Die drei Falldarstellungen demonstrieren die Durchf 252;hrbarkeit der blutgruppen-inkompatiblen Lebertransplantation. Eine humorale Absto 223;ung oder andere f 252;r die ABOi-LDLT typische Komplikationen trat bei keinem Patienten auf. Da die Splenektomie in publizierten gr 246; 223;eren Fallzahlen zu einer erh 246;hten Morbidit 228;t und Mortalit 228;t durch postoperative Infektionen f 252;hrt, wurde, analog zu aktuellen Protokollen, beim letzten Patienten darauf verzichtet. Statt dessen wird zur Depletion der B-Zellen h 228;ufig der anti-CD20-Antik 246;rper Rituximab eingesetzt. Wir entschieden uns beim letzten Patienten die Induktionsimmunsuppression mit ATG durchzuf 252;hren, denn zus 228;tzlich zur Depletion von T-Zellen induziert ATG eine Apoptose in B- und Plasmazellen, welche umfassender sein k 246;nnte als durch Rituximab alleine. Es zeigt sich, da 223; auch dieses alternative Vorgehen die humorale Absto 223;ung verhindern kann. Die M 246;glichkeit der ABOi-LDLT sollte auch in Europa weiter exploriert werden und die Ergebnisse in einem Register der multizentrischen Auswertung zug 228;nglich gemacht werden.
Abstract: Einf 252;hrung: Akute Nierenfunktionsst 246;rungen werden in bis zu 50% der Patienten nach Lebertransplantation (Ltx) beobachtet. Mehr als 90% der Patienten erhalten eine Immunsuppression basierend auf Calcineurininhibitoren (CNI) und deren Neprotoxizit 228;t tr 228;gt wesentlich zur Nierensch 228;digung bei. Nierenfunktionsst 246;rungen in der Fr 252;hphase nach Ltx erh 246;hen das Risiko einer chronischen Niereninsuffizienz und subsequent das Risiko fr 252;hzeitig zu versterben. In mehreren klinischen Studien wurde der Effekt einer versp 228;teten oder reduzierten Gabe von Calcineurininhibitoren nach Lebertransplantation untersucht. Generell f 252;hrt die Vermeidung von CNI zu einer verbesserten Nierenfunktion ohne Kompromittierung der Sicherheit, wenn ein ad 228;quates Niveau der Immunsuppression erhalten wird mittels nicht-nephrotoxischer Immunuppressiva, z. B. mTOR-Inhibitoren oder Antimetabolite. Basierend auf diesen Erkenntnissen wurde ein Studienprotokoll entwickelt, um die Wirksamkeit und Sicherheit einerCNI-freien de-novo Immunsuppression nach Lebertransplantation zu untersuchen. Methoden und Design: Eine prospektive, therapeutisch-explorative, nicht-Plazebokontrollierte, zweistufige, monozentrische Studie in 29 Patienten nach Lebertransplantation wurde entwickelt, um die Sicherheit und Wirksamkeit einer de-novo CNI-freien Immunsuppression mit Basiliximab, Mycophenolat-Natrium, Everolimus und Prednisolon zu untersuchen. Der prim 228;re Endpunkt ist die Rate steroid-resistente Absto 223;ungen ein Jahr nach Ltx. Sekund 228;re Endpunkte sind die Inzidenz akuter Rejektionen, Nierenfunktion (gemessen an der glomerul 228;ren Filtrationsrate und der Rate und L 228;nge der Nierenersatztherapie), Leberfunktion, die Rate von Nebenwirkungen und Mortalit 228;t bis ein Jahr nach Ltx. Diskussion: Die vorliegende therapeutisch-explorative Studie repr 228;sentiert ein intermedi 228;res Element auf dem Weg zu einer CNI-freien Immunsuppression nach Lebertransplantation. Wenn die Sicherheit des hier beschriebenen Immunsuppressiven Regimes gezeigt werden kann, sollte die Wirksamkeit in einer prospektiven, kontrollierten klinischen Studie best 228;tigt werden.
Abstract: Einf 252;hrung: Lebermetastasen neuroendkriner Tumoren (NET) repr 228;sentieren circa 10% aller sekund 228;ren Lebertumoren und treten in 25-90% aller Patienten mit NET auf. H 228;ufig treten sie multifokal und bilateral auf, so da 223; eine kurative Resektion schwierig ist. Tumor bulk-Syndrom und Hormonsyndrom sind h 228;ufige Symptome. Lebertransplantation (Ltx) wird als Mittel der letzten Wahl in Patienten durchgef 252;hrt welche konventioneller Therapie nicht mehr zug 228;nglich sind. Jedoch ist die Ltx als Therapieoption weiterhin umstritten, da in einigen retrospektive Kohortenanalysen ein vergleichsweise schlechtes gesamt- und rezidivfreies 220;berleben gezeigt werden konnte. Daher werden werder von UNOS noch ET Patienten mit Lebermetastasen eines NET bei der Allokation bevorzugt behandelt und sind somit auf eine Allokation nach dem MELD-System angewiesen. Methoden: Ziel dieser retrospektiven Auswertung unseres Kollektivs von Patienten mit Lebermetastasen eines NET welche einer Ltx zugef 252;hrt worden sind ist es einerseits die Aussicht einer Allokation nach MELD zu analysieren und andererseits die 220;berlebenszeit diese Kollektivs zu vergleichen mit einem repr 228;sentativen Vergleichskollektivs. Ergebnnisse: Sieben Patienten mit Lebermetastasen eines NET sind in unserem Zentrum transplantiert worden. Nach MELD-Allokation h 228;tte keiner der Patienten zeitnah ein Organ erhalten. Das 5-Jahres- 220;berleben ist 71% und damit vergleichbar mit der Referenzkohorte. Diskussion: Patienten mit Lebermetastasen eines NET k 246;nnen von einer Ltx profitieren. Eine prospektive Prognosestudie ist notwendig, um ggf. eine eine 196;nderung der Allokation zu erreichen.
Abstract: Purpose: After liver transplantation more than 90% of the patients receive an immunosuppressive regimen based on calcineurin inhibitors. Aim of this study was to establish estimators of the safety and efficacy of calcineurin inhibitors for de-novo immunosuppression after liver transplantation. These may then be used as reference in therapeutic exploratory studies of calcineurin inhibitor free de-novo immunosuppression. Methods: A systematic review of studies comparing the safety and efficacy of tacrolimus and cyclosporine has been published. But the overall common effects of calcineurin inhibitors have not been reported. The data of 16 controlled clinical trials was used as source data for the meta-analysis. Several methods to estimate the overall common effects and their appropriate confidence interval were evaluated: weighted average with exact confidence interval, a fixed and random effects model with logit transformed rates, estimation of the marginal mean proportion as described by Fleiss, and weighted average with a confidence interval obtained by bootstrap. In a simulation with 10 studies, with variable true common rate, variable sample size, and variable between study variance weighted average with a confidence interval obtained by bootstrap was the most robust method to infer the common true rate and its confidence interval. Results: The following estimates were obtained by weighted average with 95% bootstrap confidence interval: mortality 14.58% [11.52; 17.12], graft loss 18.25% [14.3; 21.57], acute rejection 42.38% [29.56; 52.1], steroid resistant rejection 12.61% [6.36; 18.65], post transplant de-novo dialysis 2.06% [0.25; 6.95], post transplant de-novo diabetes 18% [5.72; 37.2], and post transplant lymphoproliferative disease 1.08% [0.35; 2.56]. Conclusion: A robust estimation of the overall common effects of calcineurin inhibitors in liver transplant patients has been obtained by weighted average with a bootstrap confidence interval.
Abstract: Background: Elevated portal pressure (EPP) might be a result of impaired outflow and is a central problem after adult living donor liver transplantation (ALDLT). EPP results in graft dysfunction indicated by hyperbilirubinemia, coagulopathy, and poor graft outcome. Therefore we modified the caval anastomosis to improve hepatic outflow. Methods: The modified technique is based on the latero-dorsal enlargement of the caval orifice. We have assessed the modified technique in a study cohort of 22 patients between March 2000 and May 2007: 7 received a common end-to-end anastomosis of the right hepatic vein (group I) and 15 patients the modified surgical technique (group II). Portal vein pressure was measured intraoperative, before and after ALDLT. Hyperbilirubinemia, coagulopathy, and graft function were monitored in the first 20 days. Graft outcome was evaluated for 5 years. Results: Overall portal vein pressure (PVP) was reduced by 4 mmHg (P value 60; 0.001) in patients of group II (median PVP 14 mmHg) compared to patients in group I (median PVP 18 mmHg). Patients of group II had less bilirubinemia in the first 20 days after ALDLT (P value 60; 0.001). In particular, patients with small grafts profit from this surgical procedure (P value = 0.04). Other liver function tests were not significantly altered and long term outcome was comparable. Conclusion: The modified surgical procedure facilitates hepatic outflow, prevents elevated PVP after ALDLT, which is associated with improved liver function. Patients with a small graft may benefit from latero-dorsal enlargement of the caval orifice.
Abstract: Einleitung: Ein erh 246;hter portalven 246;ser Druck in der fr 252;hen Phase nach Leberlebendspende ist mit einer schlechten Prognose vergesellschaftet. Dabei sind das Transplantat/Gewichtsverh 228;ltnis und der ven 246;se Abfluss Faktoren, die den portalen Druck beeinflussen. Weiterhin kann eine Rotation des Organs bei der anterioren Implantation der Lebervene des Spenders in die V. cava eine Abflussbehinderung bedingen. Folglich k 246;nnte eine rechtslaterale Implantation der Spendervene den Abfluss entsprechend verbessern. Material und Methoden: Bei 22 Patienten wurde eine Leberlebendspende-Transplantation des rechten Leberlappens durchgef 252;hrt. Bei 7 Patienten wurde herk 246;mmliche anteriore Implantation der Spendervene durchgef 252;hrt und bei 15 Patienten eine rechtslaterale Implantation. Neben den demographischen Daten wurden beide Gruppen bez 252;glich des Transplantat/Gewichtsverh 228;ltnisses verglichen. Intraoperativ wurde der portalven 246;se Druck und der zentrale Venendruck erfasst. Postoperativ wurden neben Bilirubin und Quick, die Transaminasen f 252;r 14 Tage t 228;glich zweimal gemessen. Ergebnisse: Beide Gruppen waren bez 252;glich der demographischen Daten und des Transplantat/Gewichtsverh 228;ltnisses vergleichbar. Der intraoperative zentrale Venendruck war statistisch nicht unterschiedlich (7,7+/-2,6 vs. 9,1+/-4,1). Im Gegensatz zu den anterior Implantierten konnte bei den rechtslaterale Implantierten ein signifikant niedrigerer portalven 246;ser Druck (18,6+/-2,0 vs. 13,1+/-1,9) gemessen werden. Postoperative zeigten die rechtslaterale implantierten Patienten signifikant niedrigere Bilirubin- (max. Unterschied Tag 12) und Transaminasen-Werte (max. Unterschied Tag 3). Der statistische Unterschied war ab dem 15. Tag f 252;r Bilirubin und am dem 7. Tag f 252;r die Transaminasen nicht mehr zu erfassen. Schlussfolgerung: Durch die Anwendung der hier erstmals vorgestellten Anastomosentechnik f 252;r die Implantation der Spendervene in die V. cava bei der Leberlebendspende k 246;nnen intraoperativ niedrigere portalven 246;se Druckverh 228;ltnisse erreicht werden. Dies ist mit einer besseren Organfunktion in der fr 252;hen postoperativen Phase vergesellschaftet.
Abstract: Einf 252;hrung: Nach Lebertransplantation erhalten derzeit mehr als 90% der Patienten ein immunsuppressives Regime, welches auf Calcineurininhibitoren basiert. Ziel dieser Meta-Analyse ist es Sch 228;tzer f 252;r die Wirksamkeit und Sicherheit von Calcineurininhibitoren in der de-novo Immunsuppression nach Lebertransplantation zu etablieren. Diese k 246;nnen dann als Referenzwert f 252;r therapeutisch explorative Studien zur Calcuneurininhibitor-freien de-novo Immunsuppression herangezogen werden Methoden: Meta-Analysen von Studien in welchen die Wirksamkeit und Sicherheit von Tacrolimus und Cyclosporin verglichen wurden sind bereits ver 246;ffentlicht worden. Aber 252;ber den Gesamteffekt beider Substanzen ist bisher nicht berichtet worden. F 252;r die vorliegende Meta-Analyse wurden die Sch 228;tzer von 16 kontrollierten klinischen Studien als Quelldaten herangezogen. Mehrere Methoden zur Sch 228;tzung des Gesamteffektes wurden evaluiert: fixed effects models und random effects models mit studien-spezifischen und populations-spezifischen Varianzen, estimation of the marginal mean proportion und gewichtetes Mittel mit bootstrap-Konfidenzintervall. In einer Simulationsstudie wurden bootstrap-Konfidenzintervall, estimation of the marginal mean und random effects model mit populations-spezifischer Varianz als beste Methoden identifiziert, um eine reliable Sch 228;tzung zu erhalten. Ergebnisse: Gesamtsch 228;tzer f 252;r die Wirksamkeit und Sicherheit der de-novo Immunsuppression mit Calcineurininhibitoren ein Jahr nach Lebertransplantation wurden anhand des gewichteten Mittels mit 95% bootstrap-Konfidenzintervall ermittelt: Mortalit 228;t 14,5% [11,29; 17,26], Organverlust 17,32% [12,76; 21,88], akute Absto 223;ung 41,47% [29,17; 53,77], steroid-resistente Absto 223;ung 12,79% [6,45; 18,8], de-novo Dialysepflichtigkeit 2,18% [0,24; 7,44], de-novo Diabetes 17,12% [5,32; 36,44], lymphoproliferative Erkrankungen 1,06% [0,22; 2,9]. Konklusion: Eine robuste Sch 228;tzung der Gesamteffekte von Calcineurininhibitoren als de-novo Immunsuppression bei Patienten nach Lebertransplantation konnte mittels boostrap-Methode erreicht werden.
