The Association of IL28B Polymorphism and Graft Survival in Patients with Hepatitis C Undergoing Liver Transplantation

<div><p>Hepatitis C virus (HCV) infection is the leading cause of liver transplantation (LT) in Western countries. Polymorphism in the IL28B gene region has a major impact on the natural history and response to antiviral treatment in HCV. We investigated whether IL28B polymorphism was associated with graft survival in patients with or without HCV undergoing LT. 1,060 adult patients (age >18 years) underwent LT between years 2000 and 2008. Patients with previous LT, living donor LT and patients dying or requiring retransplants within 30 days of LT were excluded. DNA samples of 620 (84%) recipients and 377 (51%) donors were available for genotyping of IL28B rs12979860C>T. Donor IL28B genotypes had no significant differences in graft survival irrespective of HCV status. There was no difference in graft outcome in the non-HCV cohort (n = 293) based on recipient IL28B genotype. In the HCV group (n = 327), recipients with CC or CT genotype had better graft survival compared to TT genotype (62% vs. 48%, p = 0.02). HCV recipients with CC or CT genotype had delayed time to clinically relevant HCV recurrence compared to TT (10.4 vs. 6.7 months, p = 0.002). The beneficial effect of the CC/CT genotype on HCV recurrence and graft survival was independent of antiviral treatment. In conclusion, our study demonstrated that in contrast to donor IL28B genotype recipient IL28B was associated with graft survival and clinically relevant HCV recurrence in HCV infected recipients. No effect of IL28B genotype was manifest in non-HCV LT recipients.</p> </div

Recipient IL28B genotype and graft survival by HCV status.

<p>Kaplan-Meier curves for liver graft survival in HCV infected (A) and non-HCV recipients (B).</p

Donor IL28B genotype and graft survival by HCV status.

<p>Kaplan-Meier curves for liver graft survival in HCV infected (A) and non-HCV recipients (B).</p

Frequencies of donor and recipient IL28B rs12979860 genotypes in patients with or without HCV.

<p>Frequencies of donor and recipient IL28B rs12979860 genotypes in patients with or without HCV.</p

Relative expression of IL28 mRNA based on IL28B genotypes.

<p>There was no effect of IL28B genotypes on IL 28 mRNA expression. Median expression and range were shown.</p

Kaplan-Meier curves for survival free from HCV recurrence according to recipient IL28B genotypes.

<p>Only patients with a liver biopsy were included in the analysis. Percentage of patients without histological HCV recurrence on clinically indicated biopsies within first year after LT was higher in CC/CT compared to TT genotype (p = 0.002).</p

Flow diagram of study participants with available genotyping data.

<p>LT = liver transplantation.</p

Donor and recipient characteristics based on recipient IL28B rs12979860 genotypes.

<p>LT = liver transplant; HCC = hepatocellular carcinoma; VL = viral load at the time of LT.</p

Effect of Cholecalciferol Supplementation on Inflammation and Cellular Alloimmunity in Hemodialysis Patients: Data from a Randomized Controlled Pilot Trial

<div><p>Background</p><p>Memory T-cells are mediators of transplant injury, and no therapy is known to prevent the development of cross-reactive memory alloimmunity. Activated vitamin D is immunomodulatory, and vitamin D deficiency, common in hemodialysis patients awaiting transplantation, is associated with a heightened alloimmune response. Thus, we tested the hypothesis that vitamin D₃ supplementation would prevent alloreactive T-cell memory formation in vitamin D-deficient hemodialysis patients.</p><p>Methods and Findings</p><p>We performed a 12-month single-center pilot randomized, controlled trial of 50,000 IU/week of cholecalciferol (D₃) versus no supplementation in 96 hemodialysis patients with serum 25(OH)D<25 ng/mL, measuring effects on serum 25(OH)D and phenotypic and functional properties of T-cells. Participants were randomized 2∶1 to active treatment versus control. D₃ supplementation increased serum 25(OH)D at 6 weeks (13.5 [11.2] ng/mL to 42.5 [18.5] ng/mL, p<0.001) and for the duration of the study. No episodes of sustained hypercalcemia occurred in either group. Results of IFNγ ELISPOT-based panel of reactive T-cell assays (PRT), quantifying alloreactive memory, demonstrated greater increases in the controls over 1 year compared to the treatment group (delta PRT in treatment 104.8+/−330.8 vs 252.9+/−431.3 in control), but these changes in PRT between groups did not reach statistical significance (p = 0.25).</p><p>Conclusions</p><p>D₃ supplements are safe, effective at treating vitamin D deficiency, and may prevent time-dependent increases in T-cell alloimmunity in hemodialysis patients, but their effects on alloimmunity need to be confirmed in larger studies. These findings support the routine supplementation of vitamin D-deficient transplant candidates on hemodialysis and highlight the need for large-scale prospective studies of vitamin D supplementation in transplant candidates and recipients.</p><p>Trial Registration</p><p><a href="http://clinicaltrials.gov/show/NCT01175798" target="_blank">Clinicaltrials.gov NCT01175798</a></p></div

Laboratory parameters of bone and mineral metabolism and activated Vitamin D requirements.

<p>Mean (SD) unless otherwise specified.</p><p>*p-values for comparison of change from baseline to 12 months between groups (treatment vs control).</p><p><b>**</b>n = 41 in treatment group and 27 in control group.</p><p>Laboratory parameters of bone and mineral metabolism and activated Vitamin D requirements.</p