Publications by authors named "François Berthoux"

49 Publications

Repeat renal biopsy improves the Oxford classification-based prediction of immunoglobulin A nephropathy outcome.

Nephrol Dial Transplant 2020 07;35(7):1179-1186

Department of Nephrology, Dialysis and Renal Transplantation, HOPITAL NORD, CHU Saint-Etienne, France.

Background: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD).

Methods: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation.

Results: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for-cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2.

Conclusion: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN.
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http://dx.doi.org/10.1093/ndt/gfy341DOI Listing
July 2020

Deletion Variants of and Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy.

J Am Soc Nephrol 2018 02 7;29(2):661-669. Epub 2017 Nov 7.

Department of Nephrology, Dialysis and Renal Transplantation, University North Hospital, Saint-Etienne, France; and

Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H-related genes 1 and 3 () is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of and gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients' medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for We did not detect an association between and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, did not associate with progression to stage 3 CKD or renal death. In conclusion, the genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.
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http://dx.doi.org/10.1681/ASN.2017010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791061PMC
February 2018

Prognostic Value of Serum Biomarkers of Autoimmunity for Recurrence of IgA Nephropathy after Kidney Transplantation.

J Am Soc Nephrol 2017 Jun 2;28(6):1943-1950. Epub 2017 Mar 2.

Microbiology and.

A prognostic biomarker for IgA nephropathy (IgAN) recurrence after renal transplant is lacking. We followed 96 consecutive first renal transplant recipients with native kidney IgAN (79 men; 92 deceased donors; mean age =48.1 years) on calcineurin inhibitor-based immunosuppression over 10 years for death, allograft failure, and clinicopathologic recurrence (CPR; clinically evident and biopsy-proven). Using time-dependent Cox regression analysis and receiver operating characteristic curves, we assessed prognostic significance of levels of galactose-deficient IgA1 (Gd-IgA1; autoantigen) and Gd-IgA1-specific IgG and IgA autoantibodies in serum obtained at time of transplant or native-kidney IgAN diagnosis (30 patients only). Overall, 13 patients died, 34 kidneys failed (17 due to CPR), and 34 patients developed CPR after a mean interval of 5.8 years. Compared with healthy controls (=30), patients had significantly elevated serum Gd-IgA1 levels at diagnosis and transplant, but levels did not associate with any outcome. Patients also had significantly elevated levels of normalized (but not total) serum Gd-IgA1-specific IgG autoantibodies at diagnosis and transplant, and the level at transplant associated with higher risk of CPR (relative risk, 2.68; 95% confidence interval, 1.26 to 5.71; =0.01; area under the receiver operating characteristic curve, 0.62; 95% confidence interval, 0.51 to 0.74; =0.05). Normalized Gd-IgA1-specific IgG autoantibody level remained an independent risk factor for CPR in multivariate analysis. Serum Gd-IgA1-specific IgA autoantibody level did not change between diagnosis and transplant or predict outcome. This study emphasizes post-transplant prognostic value of normalized serum IgG antiglycan autoantibody level in patients with IgAN.
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http://dx.doi.org/10.1681/ASN.2016060670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461789PMC
June 2017

GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.

PLoS Genet 2017 02 10;13(2):e1006609. Epub 2017 Feb 10.

Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.
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http://dx.doi.org/10.1371/journal.pgen.1006609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328405PMC
February 2017

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.

Nat Genet 2014 Nov 12;46(11):1187-96. Epub 2014 Oct 12.

Division of Nephrology, Dialysis and Transplantation, Giannina Gaslini Institute, Genova, Italy.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
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http://dx.doi.org/10.1038/ng.3118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213311PMC
November 2014

Biomarkers in IgA nephropathy: relationship to pathogenetic hits.

Expert Opin Med Diagn 2013 Nov;7(6):615-27

Children's Foundation Research Institute at Le Bonheur Children's Hospital , 50 North Dunlap, Room 520 Research Tower, Memphis, TN 38103-2893 , USA +1 901 287 5366 ; +1 901 287 6337 ;

Introduction: IgA nephropathy, the most prevalent glomerular disease in the world, requires a renal biopsy for diagnosis. Reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate its natural history and risk for progression.

Areas Covered: In this review, the authors examine serum levels of galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG and IgA autoantibodies that are integral to pathogenesis of IgA nephropathy. They also explore biomarkers related to alternative and lectin pathways of complement activation and serum and urinary peptide biomarkers detected by mass spectrometric methods. The literature search included review of all publications having IgA nephropathy in the title that were cited in PubMed and Scopus over the past 10 years and a non-systematic review of abstracts published for the annual meetings of the American Society of Nephrology and the International Symposia on IgA Nephropathy.

Expert Opinion: Serum Gd-IgA1 level and glycan-specific autoantibody levels are prime candidates to become diagnostic biomarkers for IgA nephropathy because of their central role in the earliest stages of disease pathogenesis. Assays for serum levels of complement proteins C3 and factor H are readily available in clinical practice and deserve continued study, either alone or in tandem with total serum IgA or serum Gd-IgA1 levels, as prognostic biomarkers for patients with IgA nephropathy. Urinary peptidomic data are also reviewed because this approach can successfully differentiate patients with IgA nephropathy from healthy controls and from patients with other forms of renal disease.
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http://dx.doi.org/10.1517/17530059.2013.856878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557957PMC
November 2013

Overweight/obesity revisited as a predictive risk factor in primary IgA nephropathy.

Nephrol Dial Transplant 2013 Nov 11;28 Suppl 4:iv160-6. Epub 2013 Sep 11.

Nephrology, Dialysis and Renal Transplantation Department, University Hospital of Saint-Etienne, Saint-Etienne, France.

Background: The absolute renal risk (ARR) of dialysis/death in IgA nephropathy (IgAN) was based on three major, independent equipotent risk factors: hypertension, proteinuria ≥1 g/day and severe pathological score at diagnosis. We studied, in our prospective regional cohort of IgAN, the impact of body mass index (BMI) on the ultimate outcome in light of this ARR concept.

Methods: We had information on 331 IgAN patients (233 men). At diagnosis, the BMI was normal (<25 kg/m(2)) in 195 and elevated (≥25) in 136 (44.1%) with 102 overweight (25-29.9) and 34 obese (≥35) defining two groups, normal BMI and elevated BMI, subsequently compared.

Results: At diagnosis, in the overweight/obese group, hypertension and proteinuria ≥1 g/day were more frequent (respectively, P < 0.0001 and P = 0.0006) and the mean global optical score was increased (P = 0.002). This resulted in a worse ARR scoring distribution (P < 0.0001). In addition, these patients with an elevated BMI were ∼10 years older (P < 0.0001), including more obese women and with an eGFR already lower (P = 0.0003). At last follow-up, in the overweight/obese group, progression remained worse with greater prevalence of CKD-3+ (43.4 versus 21.0%; P < 0.0001) and dialysis/death events (21.3 versus 13.9%). Kaplan-Meier survival and Cox regression analyses demonstrated that ARR remained a powerful independent risk factor for prediction of events, but not BMI.

Conclusions: IgAN patients with an elevated BMI at diagnosis had a significantly worse presentation and worse final outcome. Overweight/obesity increased hypertension frequency, proteinuria level and some renal lesions all of which translate into a worse ARR for prediction of CKD-3+ or dialysis alone or dialysis/death, with no apparent direct effect of BMI per se.
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http://dx.doi.org/10.1093/ndt/gft286DOI Listing
November 2013

The podocin mutation R229Q and early recurrence (within the first year) of glomerular disease after renal transplantation.

Ann Transplant 2013 Aug 28;18:436-42. Epub 2013 Aug 28.

Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Saint-Etienne, Saint-Etienne, France.

Background: Podocin is a key protein involved in the pathogenesis of steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis (FSGS) and is characterized by a high rate of early recurrence after renal transplantation (RTx) in children and adults.

Material And Methods: We studied 206 RTx adult recipients: 187 with a diagnosis of glomerular nephropathy, GN (biopsy-proven in 149, clinical in 38), plus 19 with unknown diagnosis as original kidney disease (OKD), the NPHS2 gene polymorphism, G755A, and correlated with the presence of early recurrence of OKD within the first year (proteinuria over 1 g/day and graft-biopsy proven).

Results: The A allele podocin gene mutation frequency was 3.4% (14/412) overall - 7.1% (4/56) in FSGS as expected, but surprisingly 5.7% (6/106) in IgA nephropathy. Fifty recipients (24.3%) developed proteinuria >1 g/d, with 12 recipients demonstrating early clinico-pathological recurrence by 1 year (5.8%) with 5/28 in FSGS, 2/53 in IgAN, 2/14 in membranoproliferative GN (with 1 graft loss within the first year), 1/19 in crescentic GN, 1/19 in unknown disease, and 1/38 in clinical GN. Only 2 recurrent patients (both with FSGS) had the R229Q podocin mutation (16.7%).

Conclusions: The podocin mutation R229Q may play a role in the pathogenesis of FSGS and in early recurrence after transplantation, but does not allow accurate prediction of recurrence or the associated potential for prevention.
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http://dx.doi.org/10.12659/AOT.884003DOI Listing
August 2013

Validation of the absolute renal risk of dialysis/death in adults with IgA nephropathy secondary to Henoch-Schönlein purpura: a monocentric cohort study.

BMC Nephrol 2013 Aug 1;14:169. Epub 2013 Aug 1.

University Hospital of Saint-Etienne; Nephrology, Dialysis and Renal Transplantation Department, North Hospital, Saint-Etienne, France.

Background: We established earlier the absolute renal risk (ARR) of dialysis/death (D/D) in primary IgA nephropathy (IgAN) which permitted accurate prospective prediction of final prognosis. This ARR was based on the potential presence at initial diagnosis of three major, independent, and equipotent risk factors such as hypertension, quantitative proteinuria≥1 g per day, and severe pathological lesions appreciated by our local classification scoring≥8 (range 0-20). We studied the validity of this ARR concept in secondary IgAN to predict future outcome and focused on Henoch-Schönlein purpura (HSP) nephritis.

Methods: Our cohort of adults IgAN concerned 1064 patients with 101 secondary IgAN and was focused on 74 HSP (59 men) with a mean age of 38.6 at initial diagnosis and a mean follow-up of 11.8 years. Three major risk factors: hypertension, proteinuria≥1 g/d, and severe pathological lesions appreciated by our global optical score≥8 (GOS integrated all elementary histological lesions), were studied at biopsy-proven diagnosis and their presence defined the ARR scoring: 0 for none present, 3 for all present, 1 or 2 for the presence of any 1 or 2 risk factors. The primary end-point was composite with occurrence of dialysis or death before (D/D). We used classical statistics and both time-dependent Cox regression and Kaplan-Meier survival curve methods.

Results: The cumulative rate of D/D at 10 and 20 years post-onset was respectively 0 and 14% for ARR=0 (23 patients); 10 and 23% for ARR=1 (N=19); 27 and 33% for ARR=2 (N=24); and 81 and 100% (before 20 y) in the 8 patients with ARR=3 (P=0.0007). Prediction at time of diagnosis (time zero) of 10y cumulative rate of D/D event was 0% for ARR=0, 10% for ARR=1, 33% for ARR=2, and 100% by 8.5y for ARR=3 (P=0.0003) in this adequately treated cohort.

Conclusion: This study clearly validates the Absolute Renal Risk of Dialysis/Death concept in a new cohort of HSP-IgAN with utility to individual management and in future clinical trials.
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http://dx.doi.org/10.1186/1471-2369-14-169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733957PMC
August 2013

Renal transplantation outcome in selected recipients with IgA nephropathy as native disease: a bicentric study.

Ann Transplant 2012 Jul-Sep;17(3):45-51

Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Saint-Etienne, CHU of Saint-Etienne, France.

Background: IgA nephropathy (IgAN) is the causative disease of at most 10% of patients on dialysis and waiting for kidney transplantation. The disease can recur on the graft and it is important to know the exact impact of such recurrence on overall results of transplantation in this subgroup of young recipients.

Material/methods: This is a retrospective study done in two closed centers over three decades with a final number of 142 recipients (111 men; median age of 42.2 years at surgery) with biopsy-proven IgAN among 1979 transplanted patients (7.2%). The mean follow-up time was 6.6 years. Recurrence was defined clinically as proteinuria over 1 g/day ± haematuria and associated with ≥1+ IgA mesangial deposits on the graft biopsy. We used Cox regression and Kaplan-Meier survival curves to study the event.

Results: Patient survival was excellent: 92% at 10 y; graft survival was 53% at 10y and similar to other recipients. The clinico-pathological (full) recurrence (CPR) was observed overall in 25 cases (17.6%) leading to graft loss in 10 cases (7%). The cumulative rate at 10 y of full recurrence and graft loss due to CPR was 21% and 13% respectively. We could not demonstrate any major influence of immunosuppression (induction or maintenance) or other factors on full recurrence. In addition, 10.5% of recipients disclosed only pathological recurrence without significant clinical consequences.

Conclusions: Despite significant prevalence of full recurrence after grafting, the overall good results observed still validate renal transplantation in this subgroup of IgAN recipients.
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http://dx.doi.org/10.12659/aot.883457DOI Listing
March 2013

Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy.

J Am Soc Nephrol 2012 Sep 16;23(9):1579-87. Epub 2012 Aug 16.

Nephrology, Dialysis, and Renal Transplantation Department, University North Hospital, 42055 Saint-Etienne Cedex 2, France.

Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. Here, we analyzed serum samples obtained at diagnosis for autoantigen and autoantibodies from 97 patients with IgAN selected from our prospective cohort according to their absolute renal risk for progression to dialysis or death (0, very low; 1, low; 2, high; 3, very high). We also analyzed samples from controls comprising 30 healthy volunteers and 30 patients with non-IgAN disease. The mean follow-up was 13.8 years. We found that mean serum levels of total autoantigen, normalized IgG autoantibody, and total IgA autoantibody were significantly higher in patients than in the combined controls (all P≤0.01). Furthermore, increasing levels correlated with worse clinical outcomes. In Cox regression and Kaplan-Meier analyses, IgG autoantibody levels ≥1.33 predicted dialysis or death (both P≤0.01). In conclusion, these data suggest that serum levels of IgG and IgA autoantibodies strongly associate with the progression of IgAN nephropathy.
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http://dx.doi.org/10.1681/ASN.2012010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431415PMC
September 2012

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

PLoS Genet 2012 21;8(6):e1002765. Epub 2012 Jun 21.

Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹⁰), with heterogeneity detected only at the PSMB9/TAP1 locus (I² = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻⁴). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²⁸). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.
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http://dx.doi.org/10.1371/journal.pgen.1002765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380840PMC
September 2012

Mycophenolate sodium dosing in combination with tacrolimus: pharmacokinetic evaluation of a novel regimen in de novo tacrolimus-treated kidney transplant patients.

Clin Nephrol 2012 Jun;77(6):425-31

Université Jean MONNET, Saint-Etienne, France.

Background: There are no clear guidelines concerning the appropriate dose of mycophenolate acid (MPA) to be used in association with tacrolimus. When MPA is given at an approved fixed dose in cyclosporine-treated patients, initial systemic under exposure is frequent and associated with the occurrence of acute rejection. We pharmacologically evaluated in tacrolimus-treated recipients a novel dosing regimen of MPA with an initial high dose followed by a gradual decrease over time.

Methods: 15 de novo tacrolimus-treated kidney transplant patients were administered mycophenolate sodium at the dose of 720 mg b.i.d. for the first week post-transplant, 540 mg b.i.d. until Day 30, and then 360 mg b.i.d. until Day 90. MPA exposure was evaluated by the 12 h area under MPA concentration versus time curve (AUC) determined at Days 2, 7, 15, 30 and 90 post-transplant.

Results: Median MPA AUC was constantly within the therapeutic window of 30 - 60 mg/l × h throughout the three months of evaluation. More than 75% of patients had a MPA AUC above 30 mg/l × h at Day 2 and Day 7 post-transplant.

Conclusion: This exploratory study suggests that such a dosing regimen of mycophenolate sodium might quickly offer and sustain an optimal exposure to MPA in tacrolimus-treated kidney transplant patients.
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http://dx.doi.org/10.5414/cn107360DOI Listing
June 2012

Impact of mycophenolic acid and tacrolimus on Th17-related immune response.

Transplantation 2011 Aug;92(4):396-403

Laboratoire de Néphrologie, Université Jean Monnet, and Service de Néphrologie, Dialyse et Transplantation rénale, Hôpital Nord, CHU de Saint-Etienne, France.

Background: Little is known on the impact of immunosuppressive drugs on the development of the different T-cell subsets that compose the immune balance. We have explored the influence of mycophenolic acid (MPA) and tacrolimus on T cells response with a special focus on the Th17-cell subset.

Methods: In an in vitro model of human CD4 cells activation, we first compared the influence of MPA and tacrolimus on the transcription of different set of genes related to each of the main T-cell subsets and then investigated how these two drugs interfere with interleukin (IL)-17 production. We also studied, in stable kidney transplant patients, the relation between IL-17 serum concentration and systemic drug exposure.

Results: MPA and tacrolimus exhibited a comparable impact on T-cell response, dampening most Th1-related genes transcription and preserving regulatory T cells/Th2 molecular phenotypes. Although both MPA and tacrolimus decreased Th17-related transcripts after T-cell activation, MPA exerted a stronger inhibitory effect on IL-17 production than tacrolimus. Accordingly, renal transplant patients treated with MPA in combination with minimized dose of tacrolimus tended to have lower circulating IL-17 levels than patients treated with tacrolimus alone given at conventional dose.

Conclusions: A treatment combining MPA and tacrolimus is susceptible to favorably tip the immune balance and might confer optimal allograft immunoprotection. Because of its ability to profoundly inhibit IL-17 production, MPA may help to better overcome Th17-related alloreactivity in the context of calcineurin inhibitor-minimizing protocol.
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http://dx.doi.org/10.1097/TP.0b013e3182247b5fDOI Listing
August 2011

Single nucleotidic polymorphism 844 A->G of FCAR is not associated with IgA nephropathy in Caucasians.

Nephrol Dial Transplant 2012 Feb 12;27(2):656-60. Epub 2011 Jul 12.

EA3064, GIMAP, Université Jean Monnet, Saint Etienne, France.

Background: IgA nephropathy is characterized by a high heterogeneity of clinical expression with 10-30% of patients progressing to end-stage renal failure. The gene of the FcαRI or CD89 presents a single-nucleotide polymorphism responsible for a proinflammatory phenotype of neutrophils in vitro and ex vivo. The aim of our study was to assess whether this CD89 polymorphism 844 A->G is (i) a marker of disease susceptibility and/or (ii) associated with a more severe prognosis.

Methods: All patients diagnosed with IgA nephropathy and for whom DNA frozen sample was available were included in this European monocentric retrospective analysis and compared to a cohort of healthy volunteers. Allelic discrimination was performed by real-time quantitative polymerase chain reaction (Applied Biosystems™). We first compared the distribution of A and G alleles between patients and volunteers and then studied the relationships between alleles and renal survival, histological score, proteinuria and renal function at diagnosis.

Results: Seven hundred and twenty-six patients were analyzed for the study of susceptibility and 425 in the association study. The presence of the G allele was not associated with the occurrence of IgA nephropathy (χ(2) test 0.57, ns). Likewise, renal survival and the criteria for disease activity at time of diagnosis were not affected by the presence of the G allele.

Conclusions: No significant association between 844 A->G CD89 polymorphism and the expression of the IgA nephropathy in Caucasians exists. This result does, however, not preclude the implication of other CD89 polymorphisms neither the possibility for a role of CD89 in the pathogenesis of IgA nephropathy.
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http://dx.doi.org/10.1093/ndt/gfr246DOI Listing
February 2012

Predicting the risk for dialysis or death in IgA nephropathy.

J Am Soc Nephrol 2011 Apr 21;22(4):752-61. Epub 2011 Jan 21.

Nephrology, Dialysis, and Renal Transplantation Department, University North Hospital, 42055 Saint-Étienne Cedex 2, France.

For the individual patient with primary IgA nephropathy (IgAN), it remains a challenge to predict long-term outcomes for patients receiving standard treatment. We studied a prospective cohort of 332 patients with biopsy-proven IgAN patients followed over an average of 13 years. We calculated an absolute renal risk (ARR) of dialysis or death by counting the number of risk factors present at diagnosis: hypertension, proteinuria ≥1 g/d, and severe pathologic lesions (global optical score, ≥8). Overall, the ARR score allowed significant risk stratification (P < 0.0001). The cumulative incidence of death or dialysis at 10 and 20 years was 2 and 4%, respectively, for ARR=0; 2 and 9% for ARR=1; 7 and 18% for ARR=2; and 29 and 64% for ARR=3, in adequately treated patients. When achieved, control of hypertension and reduction of proteinuria reduced the risk for death or dialysis. In conclusion, the absolute renal risk score, determined at diagnosis, associates with risk for dialysis or death.
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http://dx.doi.org/10.1681/ASN.2010040355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065230PMC
April 2011

Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial.

Transpl Int 2010 Nov 19;23(11):1084-93. Epub 2010 Aug 19.

Service de Néphrologie et Transplantation Rénale, Hôpital Hôtel Dieu, Nantes, France.

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12-month, prospective, multicenter, open-label study. Deceased-donor kidney transplant patients at protocol-specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy-proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow-up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m(2) and 49 ml/min/1.73 m(2) in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF-risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.
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http://dx.doi.org/10.1111/j.1432-2277.2010.01094.xDOI Listing
November 2010

Thymoglobulin induction and sirolimus versus tacrolimus in kidney transplant recipients receiving mycophenolate mofetil and steroids.

Transplantation 2010 Jun;89(12):1511-7

Department of Nephrology, Saint-Louis Hospital, Paris, France.

Background: To define the role of mammalian target of rapamycin inhibitors in kidney transplantation, we compared efficacy and safety of two immunosuppressive regimens-a calcineurin inhibitor-free regimen with depletive induction versus a calcineurin inhibitor-based regimen.

Methods: De novo renal allograft recipients were randomized before transplantation to receive sirolimus (SRL; n=71, group A) or tacrolimus (n=70, group B). All patients received mycophenolate mofetil and corticosteroids. In group A, patients received rabbit antithymocyte globulin induction. In group B, antithymocyte globulin therapy could be given in case of delayed graft function. The estimated glomerular filtration rate (GFR) (Nankivell's formula) at month 12 was the primary endpoint.

Results: GFR showed no significant difference at month 12, with 56.1 in group A versus 58.4 mL/min/1.73 m in group B. In functioning grafts, renal function was significantly better in the SRL group, with higher GFR values at months 1, 2, 3, 6, and 9 (P<0.05). At month 12, patient survival and incidence of biopsy-proven rejection were not different between groups (95.8% vs. 97.1%, and 16.9% vs. 12.9%, respectively). However, proportion of graft loss was higher with SRL at months 6 and 12 (11.3% vs. 0.0%, P=0.004; 14.1% vs. 4.3%, P=0.044, respectively). Adverse events and premature withdrawals were more frequent with SRL (P<0.001 and P<0.05, respectively), whereas cytomegalovirus infections were more frequent with tacrolimus (P<0.001).

Conclusion: Patients treated with induction plus SRL, mycophenolate mofetil, and corticosteroids may obtain good renal function but have a higher risk of adverse events, drug withdrawal, and graft loss.
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http://dx.doi.org/10.1097/TP.0b013e3181db09e4DOI Listing
June 2010

Creatinine-based GFR predicting equations in renal transplantation: reassessing the tubular secretion effect.

Nephrol Dial Transplant 2010 Sep 24;25(9):3076-82. Epub 2010 Mar 24.

Service de Néphrologie, Dialyse, Transplantation Rénale, Laboratoires d'Explorations Fonctionnelles Rénales, EA 3065 Hôpital NORD, CHU de Saint-Etienne, Université Jean MONNET, Saint-Etienne, France.

Background: The real utility of blocking the tubular secretion of creatinine with cimetidine in order to ameliorate the prediction of renal graft function is questionable, particularly in the context of an increasing diffusion of the Modification of Diet in Renal Disease (MDRD) study equation. We have compared the impact of cimetidine on the performances of the Cockcroft-Gault (C-G) and MDRD equations in 56 renal transplant patients with an estimated glomerular filter rate (GFR) >30 mL/min/1.73 m(2) for whom true GFR was directly measured by inulin clearance.

Methods: Serum creatinine concentration (SCr) was measured [isotope dilution mass spectrometry (IDMS) traceable enzymatic assay] at the beginning of the inulin clearance procedure and 2 days later, after three oral cimetidine doses of 800 mg every 12 h. Predictive and diagnostic performances of the re-expressed MDRD and C-G formulas were compared before and after cimetidine intake.

Results: Mean SCr (+/-SD) increased from 120 micromol/L (+/-34) before to 154 micromol/L (+/-47) after cimetidine. The beneficial effect of cimetidine was significant only on the accuracy of the C-G formula (accuracy 30% post-cimetidine of 93 and 79% for the C-G and MDRD equations, respectively). Likewise, while a higher proportion of patients were correctly staged using the chronic kidney disease classification after cimetidine with the C-G equation (59% before and 68% after), no improvement was seen with the MDRD formula (59 vs 57%). For both equations, receiver operating characteristic curves analysis showed only a marginal gain in GFR prediction.

Conclusion: Our data do not support the use of a cimetidine-based strategy for the evaluation of renal graft function in the clinic, particularly when the GFR is estimated by the MDRD equation.
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http://dx.doi.org/10.1093/ndt/gfq123DOI Listing
September 2010

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.

Kidney Int 2010 May 3;77(10):921-7. Epub 2010 Mar 3.

Regina Margherita Children's Hospital, Turin, Italy.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.
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http://dx.doi.org/10.1038/ki.2010.43DOI Listing
May 2010

Cardiovascular death after renal transplantation remains the first cause despite significant quantitative and qualitative changes.

Transplantation 2010 Apr;89(7):806

Service de Néphrologie, Dialyse et Transplantation rénale, Hôpital Nord, CHU de Saint-Etienne, France.

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http://dx.doi.org/10.1097/TP.0b013e3181caeeceDOI Listing
April 2010

Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus.

Transplantation 2009 Jul;88(1):69-76

Service de Néphrologie et Transplantation Rénale, Hôpital Pasteur, Nice, France.

Background: Concerns about delayed graft function (DGF) and wound healing complications with sirolimus has led to suggestions that everolimus introduction could be delayed after transplantation.

Methods: In a prospective, multicenter, open-label study, deceased-donor kidney transplant recipients at protocol-specified risk of DGF (defined as > or =1 dialysis session during the first week posttransplant excluding day 1) were randomized to start everolimus therapy on day 1 posttransplant (immediate everolimus [IE]), or from week 5 (delayed everolimus [DE]) with mycophenolic acid until everolimus was initiated. All patients received anti-interleukin-2 receptor antibodies, cyclosporine A, and corticosteroids. A planned 3-month analysis from this 12-month study is presented here.

Results: One hundred and thirty-nine patients were randomized (IE 65, DE 74). The primary composite endpoint: biopsy-proven acute rejection, graft loss, death, DGF, wound healing events, or lost to follow-up at month 3, occurred in 36 IE patients (55.4%) and 47 DE patients (63.5%, P=0.387). The incidence of DGF was similar between groups (IE 24.6%, DE 24.3%; n.s.). Wound healing events of any type occurred in 40.0% and 41.9% of IE and DE patients (n.s.); events relating to initial transplant surgery occurred in 36.9% IE patients and 37.8% DE patients (n.s.), most of which were fluid collections. Study drug was discontinued due to adverse events or graft loss in 13 IE (20.0%) and 17 DE patients (23.0%).

Conclusions: Findings from this randomized, multicenter trial indicate that kidney function recovery, wound healing, efficacy, and tolerance are similar at 3 months posttransplant with immediate or DE in patients at protocol-specified risk of DGF.
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http://dx.doi.org/10.1097/TP.0b013e3181aa7d87DOI Listing
July 2009

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.

Kidney Int 2009 Sep 1;76(5):534-45. Epub 2009 Jul 1.

University Health Network, Toronto General Research Institute, Toronto, Ontario, Canada.

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.
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http://dx.doi.org/10.1038/ki.2009.243DOI Listing
September 2009

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.

Kidney Int 2009 Sep 1;76(5):546-56. Epub 2009 Jul 1.

Department of Cellular Pathology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.
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http://dx.doi.org/10.1038/ki.2009.168DOI Listing
September 2009

Transplantation: Tackling inactivity on the waiting list for transplantation.

Nat Rev Nephrol 2009 Jun;5(6):308-9

An analysis of the US kidney transplant waiting list suggests that recording a potential recipient as 'inactive', during which time he or she cannot be offered a donor organ, is becoming increasingly common and is not in patients' best interests.
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http://dx.doi.org/10.1038/nrneph.2009.53DOI Listing
June 2009

Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients.

J Am Soc Nephrol 2009 Jun 21;20(6):1385-92. Epub 2009 May 21.

Service de Néphrologie, Hôpital Calmette, Lille, France.

Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.
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http://dx.doi.org/10.1681/ASN.2008101037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689909PMC
June 2009

How to improve quality of life in patients with chronic kidney disease: a personal view.

J Nephrol 2008 Mar-Apr;21 Suppl 13:S7-8

Department of Nephrology, Dialysis and Renal Transplantation, Hopital Nord, CHU de Saint-Etienne, Saint-Etienne Cedex 2, France.

The quality of life (QoL) of patients affected with chronic kidney disease (CKD) is clearly diminished, especially at the dialysis or renal transplantation stage. To find an equilibrium and improve his/her QoL, the patient should be active and positive regarding his/her own disease. The patient's disease profoundly affects the QoL of spouse and family. The patient and his family are in permanent need of more knowledge and information about the disease. Health professionals should be aware of all these consequences and try to help/advise the patient to reach the goal of a better daily life in his/her own environment.
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September 2008

Cystatin C-based equations in renal transplantation: moving toward a better glomerular filtration rate prediction?

Transplantation 2008 Jun;85(12):1855-8

Service de Néphrologie, Dialyse, Transplantation Rénale, Laboratoires d'Explorations Fonctionnelles Rénales, Saint-Etienne, France.

Creatinine-based glomerular filtration rate (GFR) estimators perform poorly in renal transplant recipients. Cystatin C might be a better alternative to serum creatinine in assessing renal graft function. We compared several cystatin C-based equations with the modification diet renal disease (MDRD) equation in 120 adult renal transplant recipients for whom the GFR was measured by the gold standard inulin clearance. Mean inulin-measured GFR was 52.6 mL/min/1.73 m (range, 13-119). The Hoek, Rule, Le Bricon, and Filler cystatin C-based formulas showed significantly better performances (accuracy 30% of 82%, 81%, 78%, and 71%), than the MDRD equation (58%, Mac Nemar test, P<0.01). Sensitivity to detect a GFR below 60 mL/min/1.73 m was significantly higher for the Hoek and the Rule equations (0.95, 95% CI 0.91-1) than for the MDRD equation (0.76, 95% CI 0.67-0.85). These data confirm that cystatin C as a GFR marker offers significant advantages over creatinine in renal transplantation.
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http://dx.doi.org/10.1097/TP.0b013e3181744225DOI Listing
June 2008