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Competing Interests: S.B. has received lecture fees from Astellas. L.E. has received fees from Astellas, Chiesi, Novartis, and Sanofi. The other authors declare no conflicts of interest.

Background: Patients with HNF1B mutations develop progressive chronic renal failure, diabetes mellitus (40-50%), and liver tests abnormalities (40-70%). In HNF1B patients who reach end-stage renal disease, single kidney transplantation (SKT) or combined kidney-pancreas transplantation can be considered., Methods: A retrospective multicenter study including 18 HNF1B patients receiving SKT or kidney-pancreas transplantation, and in vitro experiments including the characterization of the HNF1B expression after calcineurin inhibitor (CNI) exposure., Results: After SKT, 50% of the HNF1B patients develop early posttransplantation diabetes mellitus, whereas 40% experience new-onset or severe worsening of preexisting abnormalities of liver tests, including severe cholestasis. In liver biopsies, disorders of the cholangiocytes primary cilium and various degrees of bile duct paucity and dysplasia were identified. In vitro studies combining CNI exposure and siRNA-mediated inhibition of NFATc revealed that calcineurin inhibition decreases HNF1B expression in epithelial cells but independent of NFATc., Conclusions: Because HNF1B-related disease is a heterozygous condition, CNIs used to prevent rejection may induce reduced expression of the nonmutated allele of HNF1B leading to a superimposed defect of HNF-1β transcriptional activity. Taking into account the specific risk of posttransplantation diabetes mellitus and liver disorders in HNF1B patients, these findings advocate for in-depth characterization of pathways that regulate HNF1B and plead for considering individually tailored graft management that may include a CNI-free immunosuppressive regimen. Interventional studies will have to confirm this individualized approach.

Background: Ribavirin is efficient at treating chronic hepatitis E virus infection in solid-organ transplant patients. However, the early kinetics of viral replication under therapy and the impact of immunosuppressant regimens on viral replication are unknown: thus, determining the aim of our study., Methods: Thirty-five patients with a solid-organ transplant and chronic hepatitis E virus infection were given ribavirin for 3 months. The hepatitis E virus (HEV) RNA concentrations were determined before treatment, at days 7, 15, and 21 and at months 1, 2, and 3 during therapy and after ribavirin cessation., Results: A sustained virological response (SVR) occurred in 63%. Decreased viral concentration within the first week post-ribavirin therapy was an independent predictive factor for SVR, and a decreased HEV concentration of 0.5 log copies/mL or greater had an 88% positive predictive value. No correlation between ribavirin trough level on day 7 or at month 2 with a virological response or an SVR was observed. Before therapy, HEV RNA concentration was significantly greater in patients receiving mechanistic target of rapamycin inhibitor-based immunosuppression compared to patients given calcineurin inhibitors. The use of mycophenolic acid did not impact on the response to ribavirin., Conclusion: An early response to ribavirin can be used to define the optimal duration of therapy in the setting of HEV infection.

Introduction: The occurrence of de novo anti-human leukocyte antigen (HLA) antibodies and donor-specific antibodies (DSAs) after early graft loss is not well known. The aims of this single-center study were to evaluate the incidence of de novo DSAs and non-DSA anti-HLA antibodies after allograft nephrectomy for early graft loss and to seek the predictive factors for the development of DSAs., Materials and Methods: Thirty-two patients, who experienced an early graft loss (<3 months after transplantation) and required an allograft nephrectomy, and who were considered for retransplantation, were included in the study. Anti-HLA antibodies were assessed, using the Luminex assay, before transplantation, on day 15 and at months 1, 3, 6, and 9 after the nephrectomy, and then every 3 to 6 months until the last follow-up., Results: The median time between transplantation and allograft nephrectomy was 2.5 (0-81) days. The median follow-up was 335 (30-1441) days. At month 9, postallograft nephrectomy, the incidence of DSAs was 56.6% (17/30). Anti-HLA class I and class II DSAs were detected, respectively, in 33.3% (10/30) and 30% (9/30) of patients. The incidence of de novo non-DSA anti-HLA antibodies was 64% (19/30): of these, 83.3% reacted to the donors' epitopes. Induction therapy (type and dose) and the time between transplantation and allograft nephrectomy did not influence the incidence of DSAs. No independent predictive factor for the development of DSAs was identified., Conclusion: Even after a short transplantation period, DSAs and non-DSA anti-HLA antibodies may develop in more than 50% of patients whose immunosuppression has been stopped after an allograft nephrectomy.

Background: Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries. Few data regarding genotype 3 HEV extrahepatic manifestations exist., Methods: We assessed kidney function and histology in solid-organ transplant patients during HEV infection. In all, 51 cases of genotype 3 HEV infections were diagnosed (34 kidney, 14 liver, and 3 kidney-pancreas transplant patients). Of these, 43.2% were cleared of the virus spontaneously within 6 months of infection, whereas 56.8% evolved to chronic hepatitis. Twelve of these patients completed a 3-month antiviral therapy and were followed up for 6 months posttreatment. Kidney function (estimated glomerular filtration rate [eGFR] obtained by the Modification of Diet in Renal Disease equation) and proteinuria were assessed before infection, during HEV infection and during follow-up. Kidney biopsies were obtained from patients with high proteinuria and decreased eGFR levels., Results: During HEV infection, there was a significant decrease in eGFR in both kidney- and liver-transplant patients. Glomerular diseases were observed in kidney biopsies obtained during the acute and chronic phases. This included membranoproliferative glomerulonephritis and relapses in IgA nephropathy. The majority of patients had cryoglobulinemia that became negative after HEV clearance. Kidney function improved and proteinuria decreased after HEV clearance., Conclusion: HEV-associated glomerulonephritis seems to be an HEV-related extrahepatic manifestation. Further studies are required to confirm these observations.

Background: Tenofovir therapy has been found to be efficient in treating hepatitis B virus (HBV) in nontransplant patients. However, in the setting of solid-organ transplantation, the efficacy of tenofovir has not been tested. The aim of this pilot study was to assess the clinical and biologic response and tolerance to tenofovir therapy in HBV-positive organ transplant recipients., Methods: Seven patients, three kidney, three liver, and one cardiac transplant recipients, with chronic HBV infection were partial responders to adefovir (n=7), lamivudine (n=7), or entecavir (n=5) therapy. Consequently, they were placed on tenofovir therapy (245 mg daily, which was adapted to renal function) alone (n=4) or in combination with lamivudine (n=3). Tenofovir therapy was assessed at 1, 3, 6, and 12 months postinitiation or at the last follow-up., Results: HBV DNA viral load (4.16 [2.03-5.56] log10 copies/mL at baseline) became significantly decreased to 3.15 (1.08-5.17), 2.88 (1.3-4.3), 3.53 (1.3-5.75), 3.33 (1.3-7.57), and 2.31 (1.3-4.81) log copies/mL at 1, 3, 6, and 12 months posttenofovir initiation and at last follow-up, respectively (P=0.02). Three patients were HBV DNA negative at the last follow-up. Liver enzyme levels did not change significantly throughout the follow-up period. Clinical and biologic tolerance was excellent., Conclusions: Even though HBV DNA clearance was not achieved in all patients, the results of this pilot study are encouraging and demonstrate that tenofovir therapy is safe and efficacious in treating HBV-positive organ transplant patients. However, a larger trial is needed to confirm these preliminary results., (© 2011 by Lippincott Williams & Wilkins)

Background: Hepatitis-E virus (HEV) infection can be responsible for chronic hepatitis in solid-organ transplant patients., Methods: We identified 33 cases of autochthonous acute HEV infection in solid-organ transplant patients., Results: Among 27 HEV-positive patients, who had a follow-up of more than 6 months, 16 (59.25%) evolved to chronic HEV infection, defined by persisting elevated liver-enzyme levels and positive serum HEV RNA 6 months after diagnosis. Serial liver biopsies showed progression in liver activity and liver fibrosis. Three patients developed liver cirrhosis. The proportion of patients receiving tacrolimus compared with cyclosporine A was significantly higher in patients who evolved to chronic disease. Immunosuppressive therapy was reduced in patients with chronic hepatitis; however, those who had a dramatic decrease in tacrolimus trough levels were more likely to clear the virus. Four chronic liver transplant patients were cleared off the virus at 14, 16, 22, and 23 months after diagnosis. At last follow-up, their tacrolimus trough levels and daily steroid doses were significantly lower than those who remained viremic. These four patients had lower liver-enzyme levels and lower activity scores on liver biopsies, and their peripheral blood CD3- and CD4-positive cell counts were also significantly higher., Conclusions: The rate of chronic HEV-related hepatitis is approximately 60% in solid-organ transplant patients. When possible, the reduction of immunosuppressive drugs targeting T cells should be considered as a first-line therapeutic option.

Introduction: The aims of our single-center study were to identify whether pretransplant diabetes had an impact on patient survival and, secondly, the predictive factors for development of new-onset diabetes mellitus (NODM) (as defined by American Diabetes Association/World Health Organization)., Patients and Methods: One hundred seventy-nine consecutive adult orthotopic liver-transplant patients were included in this study. Immunosuppression was based on calcineurin inhibitors with steroids, with or without mycophenolate mofetil, and with or without induction therapy. To evaluate the predictive factors for NODM, donor and recipient pre- and posttransplant data were included., Results: At transplantation, 38 patients had diabetes (group I), and the 141 nondiabetic patients constituted group II. In group I, paternal history of diabetes was more frequent (P=0.03), as was length of exposure to smoking (P=0.03), higher pretransplant glycemia (P<0.001), and shorter cold-ischemia (P=0.027) compared with group II. Pretransplant diabetes in group I resulted in a mortality rate of 39.5% at 1 year compared with 19.1% in group II (P=0.009). In group II, in multivariate analysis, independent predictive factors for NODM at M12 were pretransplant glycemia (P=0.037), alcohol-induced end-stage liver disease (P=0.04), and cumulative steroid dose within 1-year posttransplant (P=0.05)., Conclusion: Of the independent predictive risk factors for NODM, only steroid dose is modifiable, emphasizing the need for individualized immunosuppression.

Background: The aim of our study was to determine the prevalence and predictive factors for post-transplant anemia (PTA) at 6 (M6) and 12 (M12) months after orthotopic liver-transplant (OLT) in a cohort of 97 consecutive patients., Methods: Anemia was defined at M6 and M12 according to the World Health Organization criteria, i.e., a hemoglobin level of <12 g/dL for women and <13 g/dL for men. Immunosuppression relied on tacrolimus and steroids with or without mycophenolate mofetil., Results: Anemia was present in 64.5%, 50%, and 52.8% of patients before OLT and at M6 and M12, respectively. Of the anemic patients, 33% (M6) and 30.3% (M12) received recombinant erythropoietin therapy. In multivariate analysis, the independent predictive factors for anemia at M6 were mean corpuscular volume (<85 fl) at day 7, daily steroid dosage (<0.3 mg/kg), serum creatinine (>130 micromol/L), and hemoglobin level (<11 g/dL) 1 month after OLT (M1). Independent predictive factors for anemia at M12 were daily steroid dosage at M1 (<0.3 mg/kg), hematocrit at M1 (<33%), red blood cell count at M6 (<3.75 T/L), daily dosage at M1 of cyclosporine and tacrolimus, and OLT for causes other than alcohol abuse., Conclusion: Anemia is highly prevalent within the first year post-OLT. This deserves further investigation and appropriate treatment.

Background: Type II or III cryoglobulins are fairly prevalent in renal-transplant (RT) patients, and are often related to chronic hepatitis C virus (HCV) infection. However, they rarely result in graft dysfunction. They are sustained by proliferation of oligoclonal B-cells. Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have been achieved in HCV-positive immunocompetent patients with a human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (i.e., rituximab). Thus, this provides the rationale to use rituximab for cryoglobulin-related graft dysfunction in RT patients., Methods: Three RT patients, of whom one was HCV-positive, developed renal-function impairment long after transplantation, as well as de novo nephrotic syndrome (n=2) and severe hypertension (n=2). This latter case was related to type III cryoglobulinemia and was associated with membranoproliferative glomerulonephritis. In addition to their baseline standard immunosuppression, the patients were given weekly rituximab infusions of 375 mg/m (two infusions in patient and four infusions for the other two cases)., Results: This treatment resulted in a dramatic improvement in renal parameters, particularly in a sustained remittence of nephrotic syndrome, a sustained clearance of cryoglobulins in two cases, but also in severe infectious complications in two cases., Conclusion: We conclude that rituximab therapy is highly effective in cryoglobulin-related renal dysfunction in RT patients; however, due to chronic immunosuppression, this is at the expense of infectious complications.

Background: The aim of our study was to identify the independent factors that might predict anemia at 6 (M6) and 12 (M12) months posttransplantation., Methods: Postrenal transplant anemia (PTA) was defined as having a hemoglobin (Hb) level below 13 g/dl for men and below 12 g/dL for women. In this study, we included all the recipients who received a renal transplant in 2001 at our department, and for whom the graft was still functioning 1 year later (n=92)., Results: Anemia was observed in 78%, 35.5% and 25% of patients at day (D)0 and at M6 and M12, respectively. Iron deficiency was found in 14% of patients at D0 and in 13% of patients at M12. A total of 59.8% of patients had received at least one blood transfusion in the postoperative period, whereas 41.3% of patients had received recombinant erythropoietin (rEpo) therapy within the first months posttransplantation. In multivariate analysis, the independent predictive factors of anemia at M6 were Epo level at D0, initial nephropathy (polycystic kidney disease vs. others), posttransplantation rEpo therapy, hematocrit at M3, platelets at D7, and sirolimus therapy. The independent predictive factors of anemia at M12 were Epo level at D0, platelets at D7, delayed graft function (DGF), creatinine clearance at M12, serum creatinine at M12, and Hb level at M6., Conclusions: The prevalence of PTA was 25% at M12. DGF, renal function at M12, and anemia at M6 were independent risk factors for still having anemia at M12.