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Background: Minimal data are available regarding the prevalence and incidence of anemia among patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) in France., Methods: This was a retrospective non-interventional study of patients with a record of NDD-CKD in the Echantillon Généraliste des Bénéficiaires (EGB) database between January 01, 2012, and December 31, 2017. The primary objective was to estimate the annual incidence and prevalence of anemia of NDD-CKD. Secondary objectives included description of the demographics and clinical characteristics of patients with NDD-CKD-related anemia. An exploratory objective was to use machine learning to identify patients from the general population that might have NDD-CKD but without a recorded ICD-10 diagnosis of CKD., Results: During 2012-2017, 9865 adult patients in the EGB database had confirmed NDD-CKD; of these, 49.1% (4848/9865) had anemia. From 2015 to 2017, estimates of incidence (108.7-114.7 per 1000 population) and prevalence (435.7-449.5 per 1000 population) of NDD-CKD-related anemia were stable. Less than half of patients with anemia of NDD-CKD were treated with oral iron, and approximately 15% were treated with erythropoiesis-stimulating agents. Based on adult French population projections in 2020 and an estimated prevalence rate in 2017 of 42.2 per 1000 population for confirmed plus possible NDD-CKD (as a proportion of the general French population), the estimated number of patients with possible NDD-CKD in France was 2,256,274, approximately five-fold greater than the number identified by diagnostic codes and hospitalizations., Conclusions: Anemia of NDD-CKD was shown to be a constant long-term burden in France, and its apparent prevalence may still be significantly underestimated. Given the potential treatment gap, additional initiatives to better identify and treat NDD-CKD anemia may improve patient management and treatment outcomes., Competing Interests: The authors have read the journal’s policy and have the following competing interests: AP, JB and AS are paid employees of Heva (https://hevaweb.com/en). LD is a paid employee of Astellas Pharma Inc. (https://www.astellas.com/en/). JW and LT are paid employees of Astellas Pharma Europe (https://www.astellas.com/eu/) outside of the current study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2023 Dardim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Limited real-world data are available in Europe, especially France, regarding the therapeutic management of anaemia in patients with dialysis-dependent chronic kidney disease (DD CKD)., Methods: This retrospective, longitudinal, observational study was based on medical records from the MEDIAL database of not-for-profit dialysis units in France. From January to December 2016, we included eligible patients (≥18 years), with a diagnosis of CKD and receiving maintenance dialysis. Patients with anaemia were followed up for 2 years after inclusion. Patient demographic data, anaemia status, CKD-related anaemia treatments, and treatment outcomes including laboratory test results were evaluated., Results: Of 1632 DD CKD patients identified from the MEDIAL database, 1286 had anaemia; 98.2% of patients with anaemia were receiving haemodialysis at index date (ID). Of patients with anaemia, 29.9% had haemoglobin (Hb) levels of 10-11 g/dL and 36.2% had levels of 11-12 g/dL at ID. Furthermore, 21.3% had functional iron deficiency and 11.7% had absolute iron deficiency. The most commonly prescribed treatments at ID for patients with DD CKD-related anaemia were intravenous (IV) iron with erythropoietin-stimulating agents (ESAs) (65.1%). Among patients initiating ESA treatment at ID or during follow-up, 347 (95.3%) reached the Hb target of 10-13 g/dL and maintained response within the target Hb range for a median duration of 113 days., Conclusions: Despite combined use of ESAs and IV iron, duration within the Hb target range was short, suggesting that anaemia management can be further improved., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

BACKGROUND Potential benefits of once-daily, prolonged-release tacrolimus over the immediate-release formulation include improved adherence to immunosuppressives post transplantation. An observational study was performed to characterize real-world practice surrounding conversion from immediate- to prolonged-release tacrolimus in kidney transplant recipients. MATERIAL AND METHODS We performed a prospective, observational study of renal transplant recipients converted from immediate- to prolonged-release tacrolimus capsules. Conversion took place at the baseline visit, within the first 6 months of transplantation (early conversion group) or between 6 and 12 months of transplantation (late conversion group). Data collection was performed at routine follow-up at 6 and 12 months. Endpoints included conversion ratio from immediate- to prolonged-release tacrolimus, reasons for conversion, additional visits due to conversion, safety, and tolerability. RESULTS The analysis population comprised 591 patients. Baseline characteristics were similar between the 2 groups. The mean conversion ratio of the daily dose of tacrolimus was 0.98±0.17 in the early group and 0.99±0.09 in the late group. Time from conversion (mean ±SD) to first measurement of trough tacrolimus blood concentration was 12.1±11.6 and 27.6±26.7 days in the early and late groups, respectively. The highest number of additional visits required was 6 in the early conversion group, in 3 patients (0.7%), and 3 in the late conversion group, in 2 patients (1.6%). Conversion from immediate- to prolonged-release tacrolimus was associated with a very low rate of graft rejection. CONCLUSIONS Favorable clinical outcomes and safety profiles were observed with conversion from immediate- to prolonged-release tacrolimus over 1 year following renal transplantation, with no marked differences between the early and late conversion groups.

BACKGROUND In adult liver transplant patients, the use of prolonged-release tacrolimus may have treatment adherence benefits over the immediate-release formulation. The aim of this study was to characterise real-world practice data on conversion of liver transplant recipients from immediate- to prolonged-release tacrolimus in France. MATERIAL AND METHODS A prospective, observational study (NCT02143479) was conducted in 18 transplant centers in France between June 2014 and March 2016. Liver transplant recipients (n=398) included patients who changed from immediate-release to prolonged-release tacrolimus within the first three months (early conversion group) (n=205) or between three and 12 months after transplantation (late conversion group) (n=184). Clinical data were collected at an initial baseline outpatient visit and six-month and 12-month follow-up visits. Endpoints included the dose conversion ratio from immediate-release to prolonged-release tacrolimus, number of and reasons for additional visits due to conversion, safety, and tolerability. RESULTS Baseline clinical and demographic characteristics were similar between the two cohorts. The mean ±SD ratio of conversion of tacrolimus dose was 1.04±0.28; 1.01±0.28 (early) and 1.08±0.28 (late) (p=0.0247). The mean ±SD time from conversion to the first tacrolimus trough blood concentration was 30.8±42.8 days; 24.8±45.4 days (early) and 37.5±38.7 days (late). Only one patient required an additional visit due to conversion. Reasons for conversion included the physician's preference (56.3%), center practice (38.6%), and the dosing frequency (36.0%). Conversion was associated with a low rate of graft rejection, and no new safety issues were reported. CONCLUSIONS Conversion of liver transplant recipients from immediate-release to prolonged-release tacrolimus within three to 12 months of transplantation was easy to manage and associated with favorable clinical outcomes and safety profiles.

BACKGROUND Different pharmaceutical forms of oral tacrolimus allow tailored administration. The granular formulation facilitates accurate dose adjustment of tacrolimus according to patient characteristics, such as weight, or potential concomitant drug interactions. Currently, there are no data describing the use of tacrolimus granules in transplant recipients in France. MATERIAL AND METHODS OPTIMOD was a 6-month prospective, observational multicenter study that aimed to describe patient characteristics and conditions of use of tacrolimus granules. The 25 participating centers enrolled patients at time of tacrolimus granules initiation and were to collect patient and treatment data at initiation and after 6 months of follow-up. All analyses were descriptive. RESULTS Of 61 patients included, 55.7% were children (mainly kidney graft recipients) and 44.3% were adults (mostly lung graft recipients). Overall, 24.6% of patients (all children) initiated tacrolimus granules immediately post-transplant; the remaining 75.4% converted to tacrolimus granules from ciclosporin or immediate-release tacrolimus hard capsules. The main reasons for initiating tacrolimus granules, irrespective of whether first- or second-line therapy, were to offset potential drug-drug interactions in adults by adjusting dose, and to adapt to the particular needs of children as patients. Most patients (78.7%) underwent ≥1 dose modification during follow-up. Eleven rejection episodes occurred during follow-up, of which none led to graft loss. The adverse-event profile of the tacrolimus granules was similar to that of other tacrolimus formulations and 7 treatment-related adverse events were recorded. CONCLUSIONS Results suggest that tacrolimus granules are well tolerated and effective in preventing transplant rejection when administered in routine practice in France.

Although immunosuppressive therapy after organ transplantation is paramount for long-term outcomes, patients do not comply with their immunosuppressive treatment as much as might be expected. In this observational study, patients having undergone a kidney or liver transplantation were enrolled. Adherence was evaluated by patients using the compliance evaluation test and by physicians using a visual analogic scale. A linear regression was performed to identify determinants of adherence. Less patients having undergone kidney transplantation (27%) described themselves as good compliers than liver transplanted patients (40%). Discrepancy was noted between the physician and patient assessments. Rates of good adherence were significantly different depending on gender, age at transplantation, retransplantation, and time elapsed since transplantation, in at least one of the groups evaluated (whole cohort, kidney liver transplantation groups). In all three groups, adherence decreased with the number of immunosuppressants prescribed. In the whole cohort, the rate of good adherence was significantly higher in patients taking lower number of immunosuppressive drugs (45% for 1 vs. 24% for 3 immunosuppressants; p = 0.02). In this study, which is the first study of this scale in France, we confirmed that adherence with immunosuppressant treatment was low and that simpler treatment regimens may favor adherence., (© 2012 John Wiley & Sons A/S.)

Background: Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection., Methods: This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months., Results: The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time., Conclusions: Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Objectives: The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-alpha therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-alpha therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-alpha therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis., Methods: Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-alpha treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96)., Results: In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-alpha therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls., Conclusions: The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-alpha therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.

The diagnosis of autoimmune liver disease (primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis) can be made by assaying specific autoantibodies in the serum. A review is presented of these antibodies, the methods used to detect them, and the antigens identified to date. Hepatitis C is the most common cause of autoantibody production in liver diseases and is also discussed.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of antimitochondrial antibodies (AMA) directed primarily against the E2 subunits of the pyruvate dehydrogenase complex, the branched chain 2-oxo-acid dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, as well as the dihydrolipoamide dehydrogenase-binding protein (E3BP) of pyruvate dehydrogenase complex. The autoantibody response to each E2 subunit is directed to the lipoic acid binding domain. However, hitherto, the epitope recognized by autoantibodies to E3BP has not been mapped. In this study, we have taken advantage of the recently available full-length human E3BP complementary DNA (cDNA) to map this epitope. In addition, another lipoic binding protein, the H-protein of the glycine cleavage complex, was also studied as a potential autoantigen recognized by AMA. Firstly, the sequence corresponding to the lipoic domain of E3BP (E3BP-LD) was amplified by polymerase chain reaction and recombinant protein and then purified. Immunoreactivity of 45 PBC sera (and 52 control sera) against the purified recombinant E3BP-LD was analyzed by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Secondly, reactivity of PBC sera was similarly analyzed by immunoblotting against H-protein. It is interesting that preabsorption of patient sera with the lipoic acid binding domain of E3BP completely removed all reactivity with the entire protein by immunoblotting analysis, suggesting that autoantibodies to E3BP are directed solely to its lipoic acid binding domain. Fifty-three percent of PBC sera reacted with E3BP-LD, with the majority of the response being of the immunoglobulin G (IgG) isotype (95%). Surprisingly, there was little IgM response to the E3BP-LD suggesting that the immune response was secondary because of determinant spreading. In contrast, H-protein does not appear to possess (or expose) autoepitopes recognized by PBC sera. This observation is consistent with structural data on this moiety.

Background: Recurrence of primary biliary cirrhosis (PBC) within liver allografts remains a controversial issue. The aims of this study were to evaluate this risk and to determine the presence, if any, of a predictive histological feature., Methods: We reviewed the most recent and the 1-year protocol liver biopsies of 69 patients who received transplants for PBC and of 53 control patients. Histological features consistent with PBC recurrence included nonsuppurative destructive cholangitis, mixed portal infiltrate, fibrosis, and ductopenia. A complete evaluation was undertaken in each patient with these histological features., Results: These histological features were present in six patients who received transplants for PBC (8.7% vs. 0% in the control group) and occurred between 1 and 8 years after transplant. In five of the six patients, anti-mitochondrial antibody-2 (anti-M2) antibodies remained at high titers. Cholestasis was present in four patients, and clinical symptoms in two patients. All six patients were negative for hepatitis C antibodies and hepatitis C RNA in their serum. None had bile duct obstruction. The presence of plasma cells in the portal infiltrate at 1 year after transplant was predictive of this risk of recurrence., Conclusion: The risk of PBC recurrence is real (8.7%). The presence of plasma cells in the portal infiltrate seems to be an early marker of recurrence of PBC in patients transplanted for this indication.

In France as well as in most of the other European countries, the prevalence of coeliac disease is underestimated. In order to point out a good screening test, we have determined the most sensitive combination (technique-marker) for the diagnosis of the disease among 81 individuals (50 with coeliac disease and 31 controls). Serum anti-gliadin antibodies were measured using three methods: the qualitative dot-blot (Gliastick-Eurospital) and two quantitative methods Elisa (homemade-Saint-Antoine Hospital and alpha-Gliatest-Eurospital); serum anti-endomysium antibodies (EmA) and anti-reticulin antibodies (ARA) were detected using an indirect immunofluorescence assay. We have shown that the simple and fast Gliastick test can fulfil the selected criterion with a sensitivity of 0.90. Nevertheless, uncertain and positives results have to be confirmed by one of the two more specific quantitative tests. The two other markers (ARA and EmA) have shown a better specificity (1) but they were less sensitive (0.54 and 0.56 for ARA and EmA respectively). Thus, they have both to be used as confirmation tests and for follow-up with supervision of the compliance to recommended diet. In conclusion, the Gliastick can be considered as a good screening test for the detection of anti-gliadin antibodies and it would represent the expected help to determine the prevalence of coeliac disease on a large-scale map.

A recently commercialized dot-blot (Cyto-Dot, BMD) offered a new method for the detection of three autoantibodies (Ab) anti-Jo-1, anti-M2, and anti-ribosomal protein although their only common point is the cytoplasmic localisation of their respective antigen. These Ab are detected by indirect immunofluorescence (IF) (anti-M2, anti-ribosomal protein), double immunodiffusion (ID) (anti-Jo-1) and western blotting (WB) (anti-M2). The aim of the study was to compare results obtained by the Cyto-Dot with those obtained by our reference technique. One hundred and seventy-seven sera were analysed, divided into four groups: group I (n = 15) with anti-Jo-1 Ab detected by ID, group II (n = 70) with anti-M2 Ab by WB, group III (n = 33) with anti-ribosomal protein Ab by IF (of which, 19 are precipitating by ID), group IV (control group, n = 59) with 31 sera of healthy individuals, six sera of patients with liver diseases resembling primary biliary cirrhosis and 22 with a particular serological profile. Cyto-Dot is very sensitive and specific for the detection of anti-Jo-1 Ab. Also, it represents a reliable method (sensitivity 0.99) for the screening of anti-M2 Ab and for the confirmation of an atypic immunofluorescence pattern. Equivalent to ID for the detection of anti-ribosomal protein Ab, the Cyto-Dot represents a good alternative technique. However, although this new diagnostic method represents a sensitive technique for the detection of the three auto-Ab, unfortunately, it can not be applied for large series.

About 94% of patients with typical features of primary biliary cirrhosis (PBC) have been shown to be anti-M2 positive. Today the relevance of anti-M2 antibodies as a diagnostic marker of PBC is well established. The usual method of detection is by indirect immunofluorescence with cryostat sections of rat organs. In our laboratory we have developed a second identification technique for these antibodies: Western-blotting. To compare immunofluorescence and immunoblotting results, we selected sera from 252 patients: 142 sera from patients with documented PBC, 50 from patients with another hepatic disease, 10 from patients with haematological lupus and 50 from healthy blood donors. We characterized antimitochondrial antibody M2 by the presence of one or more of five antigenic determinants: 65-70 kDa (a), 52-54 kDa (b), 44 kDa (c), 23-26 kDa (d) and 16-20 kDa (e). This technique is especially useful as a backup method intention for identifying a very slight or atypical fluorescence pattern.