Evaluation of the efficacy of an interdialytic "ethanol 40% v/v - enoxaparin 1000 U/mL" lock solution to prevent tunnelled catheter infections in chronic hemodialysis patients: a multi-centre, randomized, single blind, parallel group study.

BACKGROUND: Tunnelled dialysis catheter (TC) infections are a major health complication and are associated with increased antibiotic consumption, hospital stays, health costs and mortality. Experimental data provide evidence that Ethenox, a mixture of enoxaparine 1000 U/mL in 40% v/v ethanol, could be a promising lock solution. The aim of the study is to compare an interdialytic lock solution of Ethenox with reference lock solutions, unfractionated heparin (UFH) or citrate 4% for the prevention of TCI in hemodialysis patients. METHOD: This study will monitor a multicentre, prospective, single blind, randomized, controlled, parallel group trial. The main inclusion criteria are patients > 18 years old with end-stage renal disease, treated with chronic hemodialysis/hemodiafiltration three times a week, with incident or prevalent non-impregnated internal jugular TCs inserted for at least 2 weeks and able to give informed consent. Exclusion criteria are TCI in the previous 4 weeks and anti-infective treatment for TCI in the previous 2 weeks. Patients will be randomized to receive either study treatment Ethenox in the intervention group or reference solutions in the control group, unfractionated heparin (UFH) or citrate 4% w/v according to usual practice. The primary outcome measure will be time to first TCIs assessed by an endpoint adjudication committee blinded to the study arm according to predefined criteria. Patients will receive the study treatment for up to 12 months. Intention-to-treat analysis of the primary endpoint will be performed with a marginal Cox proportional hazard model. Prospective power calculations indicate that the study will have 90% statistical power to detect a clinical significant two-fold increase in median infection-free survival if 200 patients are recruited into each arm over a period of 24 months. DISCUSSION: Firm evidence of the efficacy of the Ethenox lock in preventing TCI could be of major clinical benefit for patients. The results of this study will allow the development of new guidelines based on a high level of evidence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03083184 , date of registration March 17 2017 and European Clinical Trials Database Identifier: EudraCT 2016-A00180-51), date of registration July 11 2016.

Prophylaxis versus pre-emptive treatment for prevention of cytomegalovirus infection in CMV-seropositive orthotopic liver-transplant recipients.

This study compared the pre-emptive and the prophylactic strategies used to prevent cytomegalovirus (CMV) infection and disease in CMV-seropositive orthotopic liver-transplant recipients and searched for associated predictive factors. Seventy-three orthotopic liver-transplant recipients who had received a transplant before November 2005 were given ganciclovir IV pre-emptively (group I) and 56 recipients who had received a transplant after November 2005 were given prophylactic valganciclovir for 3 months (group II). Demographic and biochemical parameters did not statistically vary between the groups at baseline. Monitoring of CMV DNAemia was similar in both groups. Forty-two (57.5%) patients presented with CMV infection in group I and 18 (32.1%) in group II (P < 0.004). CMV DNAemia was first detected at a median of 33 days post-transplant in group I and at 98.5 days in group II (P < 0.003), but viral loads were not significantly different. The overall incidence of CMV disease was 9.6% in group I versus 7.1% in group II (ns). Thirty-five (47.9%) patients presented with biopsy-proven acute rejection in group I and 13 (23.2%) in group II (P = 0.004). Forty (55%) patients in group I and 25 (44.6%) in group II presented with de novo post-transplant diabetes (P = 0.057). At 1-year post-transplant, global survival curves were not significantly different. Independent factors associated with CMV reactivation were an absence of CMV prophylaxis, CMV serological status of the donor, cold ischemia time, and HLA A + B + DR compatibility. CMV prophylaxis is efficacious and can prevent safely the direct and indirect effects of CMV infection in CMV-seropositive orthotopic liver-transplant recipients.

Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells.

A primary HCMV infection or virus reactivation may cause severe disease in hosts with a deficient immune system. The virus can disturb both innate and adaptive immunity by targeting dendritic cell (DC) functions. Monocytes, the precursors of DCs in vivo (MoDCs), are the primary targets of HCMV; they can also harbor latent virus. The DCs generated from infected monocytes (CMV-MoDCs) have an altered phenotype and functional defects. We have shown that CMV-MoDCs do not secrete IL-12 in response to lipopolysaccharide stimulation, cannot ingest dead cells, induce T(H)1 differentiation, or the proliferation of naive allogeneic CD4(+) T cells. We found that the GM-CSF signaling in an entire population of CMV-MoDCs was impaired, although only half of the cells were productively infected, and that IL-6 secretion and suppressors of cytokine signaling 3 induction contributed to this bystander effect. We also showed that MoDCs derived ex vivo from monocytes of viremic patients had the same altered phenotype as CMV-MoDCs, including decreased STAT5 phosphorylation, indicating defective GM-CSF signaling. We have thus described a new mechanism of HCMV-induced immunosupression, indicated how infection may disturb both GM-CSF-dependent physiologic processes and proposed GM-CSF-based therapeutic approaches.

Decreased prevalence and incidence of HCV markers in haemodialysis units: a multicentric French survey.

BACKGROUND: A variety of epidemiological data provide evidence for the nosocomial transmission of hepatitis C virus (HCV) infections to haemodialysis patients. We conducted a multicentric study to determine the prevalence and incidence of HCV infection in French haemodialysis units. METHODS: Patients undergoing chronic haemodialysis in 56 French units (4718 patients) were systematically screened for anti-HCV antibodies using third-generation tests. The incidence was estimated by detecting HCV RNA in seronegative patients using a standardized real-time PCR assay on pooled samples. RESULTS: Testing for HCV antibodies identified 361 patients with anti-HCV antibodies, giving a prevalence of 7.7%. Multivariate analysis demonstrated that anti-HCV status was linked to the time on haemodialysis, previous kidney transplantation and the presence of anti-HBc antibodies, whereas erythropoietin therapy and carrying out dialysis in dedicated spaces seem to protect against HCV infection. Only two of the 4357 patients without anti-HCV antibodies tested positive for HCV RNA, giving an estimated incidence of 0.05% new HCV infections/year. Molecular analyses indicated that the two patients probably acquired HCV outside the haemodialysis unit. CONCLUSION: This decreased prevalence and incidence emphasizes the importance of adhering to the recommended universal infection-control precautions. Virological follow-up based on detecting anti-HCV antibodies with sensitive, specific new-generation serological tests could be adequate for dialysis units with few HCV infections. However, new infections in haemodialysis units should be identified by determining the HCV RNA status of seronegative patients. Standardized real-time PCR assays, plus pooling serum samples, make this a promising method for large-scale epidemiological studies.

Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient.

Hepatitis E virus (HEV) can induce chronic hepatitis in immunosuppressed patients. There is no established treatment for HEV infection. Pegylated interferon-alpha-2a (Peg-IFN-alpha-2a) has been successfully used for treating HEV infection in liver transplant patients with chronic hepatitis. A kidney transplant patient with chronic HEV infection evolved to end-stage kidney disease and started haemodialysis. Three months after immunosuppressive therapy was stopped, HEV RNA was still detected both in serum and in stools. Before considering a retransplantation, we decided to initiate Peg-IFN-alpha-2a therapy to eradicate the virus. A 3-month course of Peg-IFN-alpha-2a was scheduled, and the latter was started at the weekly dose of 135 microg. Serum HEV RNA became negative by Week 3 of Peg-IFN-alpha-2a therapy, and remained negative until the last follow-up, i.e. 6 months after anti-viral therapy was stopped. Hence, we report the first known case of a 3-month course of Peg-IFN-alpha-2a inducing a sustained virological response in this HEV-positive and RNA-positive haemodialysis patient who had failed to be cleared of the virus after immunosuppressant withdrawal.

Impact of very early high doses of recombinant erythropoietin on anemia and allograft function in de novo kidney-transplant patients.

After kidney transplantation, occurrence of anemia in the early post-transplant period (<1 month) is high and arises out of issues that are multifactorial. We performed a retrospective single-center study to assess whether delivery of high doses of erythropoietin-stimulating agents (ESA) within the first week of kidney transplantation, translates at 1 month post-transplant, in to causing less anemia and whether it has an impact on allograft function. Ninety-nine patients were not given ESA (group I), whereas 82 were (250 IU/kg/week; group II). All patients had similar pretransplant and baseline (day 0) variables. Similar numbers of group II patients were still receiving ESA by day 14 (97.5%) and day 30 (89%). Respective figures for group I were 27% and 27%. Independent factors for anemia at 1 month post-transplant included: being male subject, treatment for hypertension at pretransplant, anemia at transplant, a higher mean corpuscular volume at transplant, and an induction therapy using antithymocyte globulins. Independent predictive factors for lower creatinine clearance included being female subjects, having a donor aged >50 years, being a recipient aged >50 years, not treated for hypertension at pretransplant, and no post-transplant ESA therapy. High doses of ESA within the first month of kidney transplantation have no impact on anemia or renal function by 1 month post-transplant.

Pre-emptive intravenous ganciclovir versus valganciclovir prophylaxis for de novo cytomegalovirus-seropositive kidney-transplant recipients.

This sequential study evaluated two strategies regarding human cytomegalovirus (HCMV) infection/disease in HCMV-seropositive de novo kidney-transplant patients. The first cohort of patients (group 1; n = 132) was monitored sequentially for HCMV DNAemia; if it was positive (a cut-off at 3 log(10) copies/ml), the patient was given pre-emptive IV ganciclovir therapy (10 mg/kg/day for 3 weeks). The second cohort consisted of 150 patients (group 2) who were given valganciclovir (VGC) prophylaxis (900 mg/day) for the first 3 months posttransplantation. During the mean follow-up of at least 2 years for both cohorts, VGC prophylaxis resulted in a significant decrease in both CMV infection (68.9% vs. 33.3%; P < 0.001) and disease (9.8% vs. 2.68%, P = 0.021). Factors associated with HCMV reactivation in multivariate analysis were (i) no HCMV prophylaxis; (ii) recipient's age; (iii) being placed on ciclosporine A and mycophenolic acid from the beginning of transplantation (iv) donor HCMV-seropositivity; and (v) being a male recipient. No cases of ganciclovir resistance were detected in the prophylactic group. HCMV prophylaxis had no impact on 2-year patient/graft survival or on kidney-allograft function. We conclude that VGC-prophylaxis can be reasonably used to treat HCMV-seropositive kidney-transplant recipients.

[Efficiency of rituximab treatment for recurrence of membranous glomerulopathy after renal transplantation]. / Rémission prolongée induite par le rituximab d'une récidive de glomérulonéphrite extramembraneuse.

Idiopathic membranous glomerulonephritis (MGN) is a rare cause of end-stage renal failure, which can lead to chronic hemodialysis. This glomerulopathy can recur after renal transplantation despite immunosuppressive therapy. To date, there is no confirmed therapy for treatment of renal grafts after recurrence of MGN. Herein, we report on a 27-year-old man who underwent cadaveric renal transplantation for MGN in September 2001. At 2 months posttransplant, a renal biopsy showed membranous deposition on immunofluorescence staining evocative of recurrence of MGN. Proteinuria developed progressively and, at one year, was estimated at 7.65 g/24 h, with hypoalbuminemia of 24 g/l. This persisted despite symptomatic treatment with anti-proteinuric agents (enalapril 20 mg/day and irbesartan 75 mg/day) and atorvastatin (10 mg/day). By March 2004, his proteinuria was 11 g/day; therefore, therapy with rituximab (monoclonal anti-CD20) at 375 mg/m(2) weekly was initiated for four consecutive weeks, followed by the same dosage every four months for one year. Biological controls performed two weeks after the fourth infusion of rituximab showed a fall in proteinuria, assessed at 1 g/24 h, with albuminemia of 29 g/l and normalized lipidic results. A renal biopsy performed 6 months after the first infusion was unchanged. Follow-up at 30 months showed consistent remission of membranous nephropathy, demonstrated by a serum creatinine level of 150 mumol/L, microalbuminuria of 107 mg/24 h and normal albuminemia of 43.7 g/l. There were no side effects; in particular, no infectious complications occurred, despite CD19 lymphocytes being still negative after 30 months. Monoclonal CD-20 antibodies have shown efficacy against MGN compared to conventional therapies in native kidneys. It has recently been shown that CD20 mRNA is overexpressed in the renal interstitium in patients suffering from MGN and that the interstitial infiltrates is mainly composed of B-cell lymphocytes in these patients. These data may explain the efficiency of rituximab in these circumstances.

Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates.

Few studies have reported the use of double-filtration plasmapheresis (DFPP) in antibody-incompatible kidney transplantation. To assess the efficiency and tolerability of DFPP, we prospectively studied four chronic hemodialysis patients from two centers undergoing antibody-incompatible kidney transplantation. DFPP was used for ABO-incompatible transplantation (n = 1), for high human leukocyte antigen (HLA) immunization levels (n = 2) or for the presence of a donor-specific antibody (DSA) against a potential living donor (n = 1). In all the patients, the DFPP program was discontinued because of the adverse effects. Low blood pressure occurred during the first hour of the session in all the patients. A significant loss of plasma proteins, clotting factors and immunoglobulins also occurred during this treatment. In addition, fistula thrombosis was diagnosed in two patients. Three patients experienced gastrointestinal symptoms. The DFPP reduced the titers of the anti-B antibodies and reduced the levels of DSA in one patient, but had no effect on anti-HLA antibodies in the remaining two patients. Our study highlights the non-tolerability and poor efficacy of DFPP prior to antibody-incompatible kidney transplantation that limit its extensive use in the desensitization protocols.

Prospective monitoring of cytomegalovirus, Epstein-Barr virus, BK virus, and JC virus infections on belatacept therapy after a kidney transplant.

OBJECTIVES: Few data regarding viral replication in patients receiving belatacept are available. The aim of this single-center study was to compare the incidence of viral infections (cytomegalovirus, Epstein Barr virus, BK virus, and JC virus), in 62 de novo kidney transplant patients enrolled in the BENEFIT studies, receiving either belatacept (n=42) or cyclosporine (n=20). MATERIALS AND METHODS: By means of polymerase chain reaction, belatacept-treated patients were tested for cytomegalovirus, Epstein-Barr virus, BK virus, and JC virus infections monthly for 36 months, monthly for the first 6 months, and then quarterly for 36 months in cyclosporine-treated patients. Additional samples were obtained when a viral infection was suspected. RESULTS: The number of positive cytomegalovirus, BK virus, or JC virus viremias over the number of polymerase chain reactions performed through all 3 years was similar in both groups. Conversely, over the 3-year study, the number of positive Epstein-Barr virus viremias over the number of Epstein-Barr virus polymerase chain reactions performed was significantly higher in the belatacept group (76% vs 50%; P = .047). The number of Epstein-Barr virus primary infection was similar in both groups, while the number of Epstein-Barr virus reactivation was higher in the belatacept group. CONCLUSIONS: Epstein-Barr virus replication occurs more often in patients receiving belatacept, than it does in those receiving cyclosporine.

Treatment of hepatitis C virus infection after kidney transplantation.

The prevalence of chronic hepatitis C virus (HCV) infection after kidney transplantation (KT) varies a lot from one country to another. In the setting of (powerful) immunosuppression, HCV replication can sharply increase, thereby leading to potential severe HCV-related liver damage such cirrhosis or fibrosing cholestatic hepatitis. In the setting of KT, α-interferon (α-IFN) therapy alone has been associated with a very low sustained virological response (SVR), and a poor tolerance, particularly with regard to the kidney allograft, i.e. it induces acute rejection. The combined use of α-IFN plus ribavirin leads to a greater rate of SVR, but randomized clinical trials are missing in order to evaluate its safety with respect to the allograft function. Ribavirin monotherapy, or ribavirin plus amantadine therapy are not able to induce SVR; ribavirin may have an effect upon HCV-related proteinuria. Finally, it seems advisable to try and eradicate HCV infection prior to KT, i.e. while the patient is on dialysis therapy. After KT, α-IFN plus ribavirin therapy could be attempted only in those patients developing rapid cirrhosis or in those developing fibrosing cholestatic hepatitis or in those having de novo cryoglobulinemic glomerulonephritis within the allograft.

Hepatitis E virus and the kidney in solid-organ transplant patients.

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.

Biological agents in kidney transplantation: belatacept is entering the field.

IMPORTANCE OF THE FIELD: Kidney transplantation is the best treatment for end-stage kidney-disease patients. However, despite major breakthroughs in the last decades, and the progresses made with immunosuppressants, the long-term results still need to be improved. This is related to the increased risk of cardiovascular mortality, de novo post-transplant malignancies, and chronic kidney disease within the allograft. The last is multifactorial and includes immunological and non-immunological factors. Amongst the last is the calcineurin inhibitor (CNI) (cyclosporine A (CsA) and tacrolimus)-related nephrotoxicity. Kidney-allograft function at 1-year post-transplantation is a good surrogate marker of long-term allograft survival. AREAS COVERED IN THIS REVIEW: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig, a fusion protein, presents as abatacept, which conserves the natural structure of CTLA4, and belatacept, which has enhanced activity thanks to two amino-acid substitutions. Abatacept and belatacept block CD86-CD28 interaction, but belatacept blocks them more powerfully. Abatacept is already approved for the treatment of rheumatoid arthritis and is marketed as Orencia(®) (Bristol-Myers Squibb, Princeton, NJ, USA), whereas belatacept is not yet approved. Herein, we review the current data available on the use of belatacept in Phase II and III kidney-transplantation trials. Note, though, that data from belatacept Phase II liver transplantation trials are not yet available. WHAT THE READER WILL GAIN: The results show in de novo kidney transplant patients that as compared to CsA-treated patients, belatacept-treated patients showed: i) a significant better allograft function both at 1- and 2- year post-transplantation and ii) better cardiovascular and metabolic profiles. Regarding the safety data, Epstein-Barr virus (EBV) seronegative belatacept-treated patients experience more post-transplant lymphoproliferative disorders than the EBV seropositive belatacept-treated patients and the CsA-treated patients. TAKE HOME MESSAGE: CNIs are potent immunosuppressants but have some degree of nephrotoxicity. Therefore, it is important to have strong data showing that belatacept-based therapy is as efficient as CsA-based therapy, but displaying at both 1- and 2-year post-transplantation a better allograft function, which might translate in the long-term into longer allograft survival.

Treatment of chronic hepatitis C virus infection in dialysis patients: an update.

Hepatitis C virus (HCV) infection is a blood-borne infection and its prevalence used to be elevated in hemodialysis (HD) patients. Its main mode of contamination relies on nosocomial transmission. HCV infection is frequently associated in HD patients with normal liver enzymes whereas liver histology can display some degree of HCV-related lesions. The assessment of HCV-related lesions, even in HD dialysis patients, can be done via noninvasive tests. After kidney transplantation, HCV-related lesions can worsen; however, in this setting antiviral treatment harbors the risk of acute rejection. Therefore, it is recommended to implement antiviral treatment while the patient is receiving dialysis therapy. In this setting, the rate of viral clearance is usually high. In case of sustained virological response, no relapse occurs after kidney transplantation, despite heavy immunosuppression.

[Cytomegalovirus effects in solid organ transplantation and the role of antiviral prophylaxis]. / Effets du cytomégalovirus en transplantation et place de la prophylaxie antivirale.

Cytomegalovirus (CMV) belongs to ß-Herpesviridae family. Morbidity related to this infectious agent remains a serious concern in the context of immunosuppression. Occurence of CMV infection within the first 3 months post-renal transplantation without any antiviral prophylaxis is about 70% of patients. Direct and indirect effects of CMV infection in the setting of organ transplantation are described in this review. A 3 to 6 months course of prophylaxis with valganciclovir is advised concerning high-risk transplant recipients (D+/R-) but recommendation regarding intermediate-risk transplant recipients (CMV-seropositive patients) is still unclear. Recent studies highlight a benefit of long time prophylaxis (until 6 months) in terms of CMV disease occurence among D+/R- patients. News assays that measures IFNγ responses to a variety of CMV epitopes (Quantiferon(®) and Elispot IFNγ) are developped to predict CMV disease onset after discontinuation of antiviral prophylaxis. These assays could contribute to adapt prophylaxis to each recipient.

Cytomegalovirus prophylaxis with valganciclovir in cytomegalovirus-seropositive kidney-transplant patients.

The aims of this prospective, open-label, single-center pilot study were to assess the efficacy and safety of human cytomegalovirus (HCMV) prophylaxis using valganciclovir in HCMV- seropositive kidney-transplant patients to prevent HCMV infection and disease. Fifty-one HCMV seropositive kidney-transplant patients recipients who received transplants between 1 December 2005 and 30 November 2006 were included in the study. Valganciclovir was given from transplantation up to 114 (37-329) days, and was adapted to renal function, i.e., 900 mg/d if calculated creatinine clearance was >60 ml/min, or 450 mg/day if it was <60 ml/min. HCMV DNAemia was assessed every 2 weeks during prophylaxis, and on the same basis for 3 months post-prophylaxis. Immunosuppression was based on calcineurin inhibitors (ciclosporine A=22; tacrolimus=11), with mycophenolate mofetil (n=51), and low-dose steroids. Eighteen patients received no calcineurin-inhibitors, but Belatacept instead. During valganciclovir prophylaxis, asymptomatic HCMV DNAemia was observed in one patient, and no case of HCMV disease occurred. Within 252 days (45-425) post-valganciclovir prophylaxis, HCMV DNAemia was detected in 23.5% (n=12) of patients, of whom two had two or more consecutive HCMV DNAemias. Valganciclovir prophylaxis in HCMV-seropositive kidney-transplant patients is effective for preventing cytomegalovirus disease.