Gerd R. Silberhumer

CC Chemokine and CC Chemokine Receptor Profiles in Visceral and Subcutaneous Adipose Tissue Are Altered in Human Obesity

BACKGROUND/AIMS Obesity is associated with a low-grade inflammation, insulin resistance, and macrophage infiltration of adipose tissue. The role of CC chemokines and their respective receptors in human adipose tissue inflammation remains to be determined. METHODS sc and visceral adipose tissue of obese patients (body mass index 53.1 +/- 11.3 kg/m(2)) compared with lean controls (body mass index 25.9 +/- 3.8 kg/m(2)) was analyzed for alterations in inflammatory gene expression. RESULTS Macrophage infiltration was increased in sc and visceral adipose tissue of obese patients as determined by increased mRNA expression of a macrophage-specific marker (CD68) and by elevated macrophage infiltration. Gene expression of CC chemokines involved in monocyte chemotaxis (CCL2, CCL3, CCL5, CCL7, CCL8, and CCL11) and their receptors (CCR1, CCR2, CCR3, and CCR5) was higher in sc and visceral adipose tissue of obese patients. Serum concentrations of the inflammatory marker IL-6 and C-reactive protein were elevated in obese patients compared with lean controls. Obese patients revealed increased insulin resistance as assessed by the homeostasis model assessment of insulin resistance index and reduced plasma adiponectin concentrations. Adipose tissue expression of many CC chemokines and their receptors in the obese group positively correlated with CD68 expression. CONCLUSION Up-regulation of the CC chemokines and their respective receptors in adipose tissue occurs in human obesity and is associated with increased systemic inflammation.

Combination of extended donor criteria and changes in the Model for End-Stage Liver Disease score predict patient survival and primary dysfunction in liver transplantation: a retrospective analysis.

Background. The purpose of this study was to analyze the impact of extended donor criteria (EDC) and of changes in the Model for End-Stage Liver Disease (MELD) score while waiting for liver-transplantation (&Dgr;-MELD) on patient survival and initial graft function. Methods. We included 386 consecutive patients with end-stage liver disease who underwent orthotopic liver transplantation at the Medical University Vienna between 1997 and 2003. Primary outcome was patient survival and secondary outcome was initial graft function. EDC included: age >60 years, >4 days intensive medical care, cold ischemia time >10 hr, need for noradrenalin >0.2 &mgr;g/kg/min or doputamin >6 &mgr;g/kg/min, a donor peak serum sodium >155 mEq/L, a donor serum creatinine >1.2 mg/100 mL, and a body mass index >30. Results. &Dgr;-MELD was significantly higher in the nonsurvivor population (P=0.01) and EDC showed a significant influence on initial graft function (P=0.01). Worsening in either &Dgr;-MELD or the presence of at least two EDC was not associated with an increased risk of primary graft dysfunction and death. Worsening in &Dgr;-MELD and the presence of at least two EDC was significantly associated with primary graft dysfunction (P=0.01) and death (P=0.008). Conclusion. The combination of a liver recipient with worsening &Dgr;-MELD and a potential donor with at least two EDC should be avoided.

Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.

The appropriate time point for starting immunosuppressive treatment with calcineurin inhibitors after orthotopic liver transplantation (OLT) has been a subject of debate. The aim of the study was to analyze the effects of anti‐thymocyte globulin (ATG) induction therapy on rejection, renal function, infection, tumor rate, and survival. We retrospectively analyzed 391 patients after OLT who had either received calcineurin inhibitors immediately after OLT (n = 129) or after an initial short‐term Thymoglobulin induction therapy (n = 262). The 1‐year acute rejection rate was 14.5% vs. 31.8% in favor of ATG (P = 0.0008). Rejection grades and the need for treatment also differed significantly (7.3% vs. 23.3%; P = 0.001). Serum creatinine at transplantation was similar in both groups (1.14 mg/dL vs.1.18 mg/dL; P = NS). Postoperative hemofiltration was less frequently seen after induction therapy (P < 0.05). Reduced renal function at 1 year was commonly observed, but serum creatinine (1.26 mg/dL vs. 1.37mg/dL; P = 0.015) and glomerular filtration rate (81 mL/min vs. 75 mL/min; P = 0.02) were far better in the ATG group. Undesired side effects occurred at a similar rate in both groups. Five‐year patient survival was also similar in the 2 groups (70.1% and 74.3%; P > 0.05). Short‐term ATG induction therapy with delayed administration of calcineurin inhibitors led to a more favorable rejection rate and an improved clinical course in case of a rejection episode. It has beneficial effects on renal function immediately after OLT as well as later, and no additional harmful effects. Liver Transpl 13:1039–1044, 2007.

Risk factors for capillary C4d deposition in kidney allografts: evaluation of a large study cohort.

Background. Capillary deposition of the complement split product C4d has turned out to be a valuable marker of antibody-mediated rejection. The impact of pre- and posttransplant variables including particular immunosuppressive regimens on the frequency of C4d deposition has not yet been systematically investigated in a large multivariate analysis. Methods. In this retrospective study, the authors evaluated the incidence of C4d deposition in 388 kidney transplant recipients subjected to diagnostic biopsy within the first 6 months and analyzed the influence of potential confounders on the rate of C4d-positive graft dysfunction by applying multivariate logistic regression. Results. Sixty-six recipients (17%) developed linear C4d deposits in at least a quarter of peritubular capillaries, a finding associated with inferior 1-year allograft survival (73% vs. 88% in C4d-negative patients, P=0.0003). A 50% reduction in the odds of C4d-positive graft dysfunction was found if calcineurin inhibitor or mycophenolate mofetil (MMF) therapy was started 2 to 4 hr before transplantation when compared with initiation after surgery (adjusted odds ratio [OR], 0.5; P=0.03). No differences with respect to C4d staining results were found for the use of tacrolimus, MMF, or sirolimus, or for cyclosporine C2 monitoring. Retransplantation (OR, 3.6; P<0.001) and presensitization (OR, 3.1; P=0.002) turned out to be strong independent risk factors for C4d deposition. Conclusions. The authors’ results suggest a reduced risk of C4d-positive graft dysfunction for patients receiving immunosuppression before transplantation. Apart from first dose timing, no influence of particular immunosuppressive strategies on C4d staining results was found.

Is MELD score sufficient to predict not only death on waiting list, but also post-transplant survival?

Model for end‐stage liver disease (MELD) score has emerged as a useful tool in predicting mortality in patients awaiting liver transplantation. There is still, however, discussion as to whether further parameters could improve the sensitivity and specificity of the MELD score. From 1997 to 2003, 621 adult patients with end‐stage liver disease were listed for orthotopic liver transplantation (OLT). Patients suffering from hepatoma were excluded from analysis (113 patients). The MELD score was investigated at the time of listing (MELD ON) and of coming off the list (MELD OFF). Patients who died while on the waiting list showed a significant increase in their MELD score during the waiting time (MELD ON: 21 ± 7 vs. MELD OFF: 28 ± 9) as well as a significantly higher MELD ON compared with patients who were transplanted (MELD ON: 16 ± 5 vs. MELD OFF: 17 ± 7) or removed from the waiting list (MELD ON: 16 ± 6 vs. MELD OFF: 12 ± 3). Multivariate analysis identified MELD ON, ascites and recurrent infection as independent risk factors for death on the waiting list (P < 0.01). MELD score was not identified as a predictor for the post‐transplant survival rate. MELD score is a strong predictor for death on the waiting list, but refractory ascites and recurrent infection are independent risk factors, too.

Prophylactic Bisphosphonate Treatment Prevents Bone Fractures After Liver Transplantation

A randomized controlled prospective open‐label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention‐to‐treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/‐SD BMD ZOL: 0.80 ± 0.19 g/cm2 vs. CON: 0.73 ± 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.

Bariatric surgery in morbidly obese adolescents: long-term follow-up

OBJECTIVE Morbid obesity is an increasingly common disease in the industrialized world and poses a great challenge to the medical community. Many obese adolescents have undergone various conservative treatment methods without adequate success so that a surgical approach became necessary. We report on 18 patients who underwent bariatric surgery as well as a long-term follow-up program. METHODS Eight patients received a laparoscopic adjustable gastric banding (LAGB). Four of these had to undergo a gastric bypass surgery (GByp) as second procedure due to insufficient weight loss. Nine patients primarily received a gastric bypass. RESULTS LAGB: Mean weight loss after 24 months was 20 ± 6.3 kg. Four of the patients showed a regain in weight leading to a mean weight loss of 9 kg compared to initial weight after 53.3 months mean in this group. These patients had to undergo an additional gastric bypass procedure and lost 31 ± 18.3 kg after 18 months. GByp: Mean weight loss in nine patients after gastric bypass (primary procedure) was 31 ± 10.2 kg after 12 months and 36 ± 30.1 kg at the end of the observation time. Sleeve: Initial weight in this patient was 232 kg with a weight loss of 38 kg after 24 months. DISCUSSION AND CONCLUSION It is remarkable that in four of eight patients who underwent LAGB had to undergo a second surgical procedure (GByp). No previous indicator, neither from a psychological nor from a medical point of view, could be detected. More long-term studies including psychological aspects seem to be necessary.

The difficulty in defining extended donor criteria for liver grafts: The Eurotransplant experience

Donor criteria for liver grafts have been expanded because of organ shortage. Currently, no exact definitions for extended donor grafts have been established. The aim of this study was to analyze the impact of donor‐specific risk factors, independent of recipient characteristics. In collaboration with Eurotransplant and European Liver Transplant Register, solely donor‐specific parameters were correlated with 1‐year survival following liver transplantation. Analyses of 4701 donors between 2000 and 2005 resulted in the development of a nomogram to estimate graft survival for available grafts. Predictions by nomogram were compared to those by Donor Risk Index (DRI). In the multivariate analysis, cold ischemic time (CIT), highest sodium, cause of donor death, γ‐glutamyl transferase (γ‐GT), and donor sex (female) were statistically significant factors for 3 months; CIT, γ‐GT, and cause of donor death for 12‐month survival. The median DRI of this study population was 1.45 (Q1: 1.17; Q3: 1.67). The agreement between the nomogram and DRI was weak (kappa = 0.23). Several donor‐specific risk factors were identified for early survival after liver transplantation. The provided nomogram will support quick organ quality assessment. Nevertheless, this study showed the difficulties of determining an exact definition of extended criteria donors.

Dynamic changes in MELD score not only predict survival on the waiting list but also overall survival after liver transplantation

The predictive value of MELD score for post‐transplant survival has been under constant debate since its implementation in 2001. Aim of this study was to assess the impact of alterations in MELD score throughout waiting time (WT) on post‐transplant survival. A single‐centre retrospective analysis of 1125 consecutive patients listed for liver transplantation between 1997 and 2009 was performed. The impact of MELD score and dynamic changes in MELD score (DeltaMELD), as well as age, sex, year of listing and WT were evaluated on waiting list mortality and post‐transplant survival. In this cohort, 539 (60%) patients were transplanted, 223 (25%) died on list and 142 (15%) were removed from the waiting list during WT. One‐, three‐ and five‐year survival after liver transplantation were 83%, 78% and 76% respectively. DeltaMELD as a continuous variable proved to be the only significant risk factor for overall survival after liver transplantation (hazard ratio (HR): 1.06, 95% confidence interval (CI) 1.02–1.1, P = 0.013). The highest risk of post‐transplant death could be defined for patients with a DeltaMELD > 10 (HR: 4.87, 95% CI 2.09–11.35, P < 0.0001). In addition, DeltaMELD as well as MELD at listing showed a significant impact on waiting list mortality. DeltaMELD may provide an easy evaluation tool to identify patients on the liver transplant waiting list with a high mortality risk after transplantation in the current setting. Temporarily withholding and re‐evaluating these patients might improve overall outcome after liver transplantation.

Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.

T‐cell depletion is an essential aspect of clinical immunosuppression. The aim of the present study was to compare the efficacy of two dosage regimens in this setting. We retrospectively compared 246 patients (group 1) who received a 10‐day antithymocyte globulin (ATG) induction protocol with 226 patients (group 2) who received a 3‐day protocol. The 6‐month rejection rate was 22.3% in group 1 and 12.7% in group 2 (P = 0.03). The sub‐analysis showed a higher rejection rate in patients with cholestatic disease (P = 0.01), who were more numerous in group 1. This resulted in an overall difference between the groups. Rates of de novo malignancies and recurrent hepatocellular carcinoma were identical. Viral infection rates were 16% and 18%, respectively (P > 0.5). The rates of bacterial and fungal infection were also similar (37% vs. 42%, P > 0.1). However, infection and ATG administration are independent risk factors for survival. A lower rate of fatal infection was observed in group 2 (P = 0.01), while the 10‐day ATG regimen had a detrimental effect on patients who had infection (P < 0.0001). Our results strongly support the application of 3‐day ATG induction therapy regimen after orthotopic liver transplantation, as it is associated with the same rejection rate as long‐term ATG induction therapy, without the negative survival effect of the latter due to lethal infection.