Armin Goralczyk

Interleukin 2 receptor antagonists for liver transplant recipients: a systematic review and meta-analysis of controlled studies.

Interleukin 2 receptor antagonists (IL‐2Ra) are frequently used as induction therapy in liver transplant recipients to decrease the risk of acute rejection while allowing the reduction of concomitant immunosuppression. We conducted a systematic review of prospective, controlled studies to test the hypothesis that the use of IL‐2Ra is associated with a decrease in acute rejection and/or a decrease in the side effects of concomitant medication. We performed a search of all major databases and secondary sources from inception to December 2010. Random effects models were used to assess the incidence of acute rejection, graft loss, patient death, and adverse side effects, with or without IL‐2Ra. Subgroup analysis and meta‐regression were used to explore differences in effect and sources of heterogeneity. Eighteen studies (13 randomized and 5 nonrandomized) met the inclusion and exclusion criteria. Acute rejection at 12 months or later favored the use of IL‐2Ra (relative risk [RR] 0.83; 95% confidence interval [CI] 0.76‐0.94) and steroid‐resistant rejection was also less frequent in patients receiving IL‐2Ra (RR 0.66; CI 0.48‐0.91). Graft loss and patient death did not differ significantly between treatments. Patients who received IL‐2Ra in addition to reduced or delayed calcineurin inhibitors had better renal function (mean difference of estimated glomerular filtration rate: 6.29 mL/min; CI 1.66‐10.91) and a lower incidence of renal dysfunction (RR 0.46; CI 0.27‐0.78). The use of IL‐2Ra was also associated with a lower incidence of posttransplant diabetes mellitus, whereas the incidence of other adverse events was similar. Conclusion: The use of IL‐2Ra is associated with a lower incidence of acute rejection after transplantation. Concomitant immunosuppression can be reduced, avoiding long‐term side effects of immunosuppression. (HEPATOLOGY 2011;).

Dental care and oral health in solid organ transplant recipients: a single center cross-sectional study and survey of German transplant centers

Aim of this study was to collect information about oral health of patients before and after SOT as well as information about center‐based recommendations for dental care. In a single center cross‐sectional study, the oral situation of 20 patients before and 20 after SOT were examined including dental (DMF‐T), periodontal (PSR®/PSI), and oral hygiene findings (modified QHI). In a second project, a survey among 50 transplant centers in Germany was questioned regarding their recommendations for dental care of SOT recipients. Patients before and after SOT showed similar quality of dental findings (DMF‐T), but worse compared to the general population. In addition, most patients in both groups showed pronounced periodontal treatment need (PSR®/PSI score 3 or 4). Oral hygiene findings (modified QHI) after SOT were significantly worse than in patients on the waiting list (P = 0.032). In a second project, the questionnaire was returned by 28 of 50 centers. Interpretation of data showed that 89% carry out a dental examination before SOT and 67% contacted the patients’ dentists. After SOT, 83% of the transplant centers recommend antibiotic cover before dental measures. The results of our study revealed lacks in the dental care of SOT recipients. Consistent recommendations regarding the dental care of patients before and after SOT should be determined.

High predictability of a sustained virological response (87%) in chronic hepatitis C virus genotype 1 infection treatment by combined IL28B genotype analysis and γ-glutamyltransferase/alanine aminotransferase ratio: a retrospective single-center study.

Background: Chronic hepatitis C virus genotype 1 (HCV-G1) infection is treated with pegylated interferon-α and ribavirin. Predictive factors for treatment success are even more important now as direct-acting antiviral agents are available. Methods: Clinical and laboratory parameters were analyzed by uni- and multivariate statistical means in 264 patients with HCV-G1 infections with regard to treatment outcome. Results: The overall sustained virological response (SVR) rate was 44%. Univariate analyses revealed SVRs to be associated with age, high alanine aminotransferase (ALT) and low γ-glutamyltransferase (γ-GT) serum activities, a low pretreatment γ-GT/ALT ratio, rapid virological response (RVR), and absence of steatosis. Multivariate analyses unveiled IL28B rs12979860 genotype (CC vs. CT: OR = 2.8, CI: 1.5–4.9, p = 0.001; CC vs. TT: OR = 7.1, CI: 3.1–16.7, p < 0.001), low pretreatment γ-GT/ALT ratio (OR = 2.5, CI: 1.7–3.3, p < 0.001), age (OR = 0.96, CI: 0.94–0.98, p = 0.001) and RVR (OR = 4.18, CI: 2.85–8.65, p < 0.001) to be significantly related to treatment outcome. Patients with the IL28B rs12979860 CC genotype and a low pretreatment γ-GT/ALT ratio achieved the highest rate of a SVR with the highest predictive values (OR = 26.7, 95% CI: 10–71.1, p < 0.0001). Conclusion: The pretreatment γ-GT/ALT ratio significantly enhances the predictability of the IL28B genotype. Employing this combination will help to identify patients who will most likely benefit from an interferon-α-based combination therapy in a nontriaged ordinary setting.

Calcineurin Inhibitor Sparing With Mycophenolate Mofetil in Liver Transplantion: A Systematic Review of Randomized Controlled Trials

Liver transplant recipients are at high risk of developing acute and chronic renal failure. Moreover, introduction of the model for end‐stage liver disease (MELD) score for primary allocation of liver grafts favors patients with pretransplant kidney dysfunction, which in turn have a higher risk of posttransplant renal failure. Calcineurin inhibitors (CNI) further increase the risk of renal failure and therefore sparing CNI with the use of mycophenolate mofetil (MMF) may improve renal function. MMF may either be used de novo in the immediate posttransplant period in combination with low‐dose CNI (scenario 1) or patients that receive immunosuppression based on CNI may be converted to MMF in combination with minimization or elimination of CNI (scenario 2). Although many retrospective cohort studies and nonrandomized trials have implicated efficacy of this approach the evidence from randomized controlled studies has not been summarized. In the current review we report the results of a systematic review and meta‐analysis of randomized controlled trials.

Adult Living Donor Liver Transplantation with ABO-Incompatible Grafts: A German Single Center Experience

Adult living donor liver transplantations (ALDLTs) across the ABO blood group barrier have been reported in Asia, North Americas, and Europe, but not yet in Germany. Several strategies have been established to overcome the detrimental effects that are attached with such a disparity between donor and host, but no gold standard has yet emerged. Here, we present the first experiences with three ABO-incompatible adult living donor liver transplantations in Germany applying different immunosuppressive strategies. Four patient-donor couples were considered for ABO-incompatible ALDLT. In these patients, resident ABO blood group antibodies (isoagglutinins) were depleted by plasmapheresis or immunoadsorption and replenishment was inhibited by splenectomy and/or B-cell-targeted immunosuppression. Despite different treatments ALDLT could safely be performed in three patients and all patients had good initial graft function without signs for antibody-mediated rejection (AMR). Two patients had long-term graft survival with stable graft function. We thus propose the feasibility of ABO-incompatible ALDLT with these protocols and advocate further expansion of ABO incompatible ALDLT in multicenter trials to improve efficacy and safety.

Vitamin D status and serum ferritin concentration in chronic hepatitis C virus type 1 infection.

The circulating 25‐hydroxylated form of vitamin D3, 25(OH)D, and serum ferritin concentrations have been described to be associated with disease progression in chronic hepatitis C. Both parameters also have been assessed with regard to treatment outcome, however, with divergent results. This study examined both the pre‐ and posttreatment serum concentrations of 25(OH)D and ferritin in 191 patients infected chronically with hepatitis C virus (HCV) type 1 with regard to liver inflammatory activity (grading), disease progression in terms of fibrosis (staging) and an antiviral treatment outcome. Mean pretreatment serum 25(OH)D and ferritin concentrations were 18 ± 10 ng/ml and 280 ± 225 µg/L, respectively. Multivariate analysis revealed lower pretreatment serum 25(OH)D and higher ferritin concentrations to be significantly related to both severity of inflammatory activity and of fibrotic alterations. Pretreatment serum ferritin concentration, furthermore, unlike 25(OH)D concentration, was found to be associated with a sustained virological response by uni‐ and multivariate analyses. A sustained virological response was featured by a significant increase in serum 25(OH)D levels (18 ± 10 ng/ml vs. 22 ± 11 ng/ml; P < 0.01), a reduction of serum ferritin concentration (191 ± 156 µg/L vs. 103 ± 63 µg/L; P < 0.001) and a normalization of serum alanine aminotransferase (ALT) and γ‐glutamyl‐transferase (γ‐GT) activities. Taken together, decreased 25(OH)D and increased ferritin serum levels indicate the severity of hepatic inflammation and fibrosis in patients infected chronically with HCV type 1. Elevated ferritin, furthermore, was found to be an independent predictor for standard IFN‐based therapy responsiveness. J. Med. Virol. 85:1534–1541, 2013.

Posterior cavoplasty: a new approach to avoid venous outflow obstruction and symptoms for small-for-size syndrome in right lobe living donor liver transplantation

PurposeA common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV.MethodIn this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty.ResultsIn patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different.ConclusionWe recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

BackgroundImmunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation.Methods/DesignA 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, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT.DiscussionThis prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial.Trial registration numberNCT00890253 (clinicaltrials.gov)

Fourteen-year survival of a renal graft reused 2 years after initial transplantation: a case report

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.

Liver transplantation in patients with liver cirrhosis and active pneumonia: an observational study

Patients with chronic liver disease are at high risk for severe infection because of increased bacterial translocation and immune suppression associated with liver dysfunction. Patients presenting with severe pneumonia and acute decompensation of cirrhosis are generally not considered for liver transplantation because it is unknown if these patients can recover from infection while under immunosuppression. We performed an observational study where patients with cirrhosis of the liver remained on the waiting list, although suffering from active pneumonia. Nine patients were included, but only six patients improved under goal‐directed therapy and subsequently underwent liver transplantation. All six patients recovered quickly from infection; five patients recovered without sequelae and one patient died because of late complications. We propose that in patients with chronic liver disease and active pneumonia transplantation is a treatment option that should not hastily be abandoned.