Publications by authors named "Marie Essig"

84 Publications

The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

Université Paris Saclay, Université Paris-Sud, UVSQ, Villejuif, France.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928708PMC
February 2021

[Therapeutics for acute tubular necrosis in 2020].

Nephrol Ther 2021 Apr 19;17(2):92-100. Epub 2021 Jan 19.

Service de néphrologie, hôpital Ambroise-Paré, AP-HP, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France; Équipe 5, Inserm U-1018, UVSQ, université Paris Saclay, Villejuif, France. Electronic address:

Acute kidney injury is a major cause of in-hospital morbidity and mortality because of the serious nature of the underlying illnesses and the high incidence of complications. The two major causes of acute kidney injury that occur in the hospital are prerenal disease and acute tubular necrosis. Acute tubular necrosis has a histological definition, even if a kidney biopsy is rarely performed. Kidney injuries occurring during acute tubular necrosis are underlined by different pathophysiological mechanisms that emphasize the role of hypoxia on the tubular cells such as apoptosis, cytoskeleton disruption, mitochondrial function and the inflammation mediated by innate immune cells. The microcirculation and the endothelial cells are also the targets of hypoxia-mediated impairment. Repair mechanisms are sometimes inadequate because of pro-fibrotic factors that will lead to chronic kidney disease. Despite all the potential therapeutic targets highlighted by the pathophysiological knowledge, further works remain necessary to find a way to prevent these injuries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2020.11.002DOI Listing
April 2021

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

World J Hepatol 2020 Dec;12(12):1326-1340

U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France.

Background: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.

Aim: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated untreated hepatitis B virus (HBV)-monoinfected patients.

Methods: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.

Results: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% 30.7%, 0.42 and 50.0% 30.7%, = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group the naïve group (hazard ratio: 2.283, = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.

Conclusion: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v12.i12.1326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772739PMC
December 2020

Severe acute respiratory syndrome coronavirus 2 indirectly damages kidney structures.

Clin Kidney J 2020 Dec 14;13(6):1101-1104. Epub 2020 Dec 14.

Service de Néphrologie et Dialyse, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France.

Background: The objectives were to characterize Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) in patients with acute kidney injury (AKI).

Methods: Kidney biopsy samples in two Caucasian patients and one African with COVID-19 AKI were investigated.

Results: All patients had a high-level non-selective glomerular proteinuria. SARS-CoV-2 samples by real-time polymerase chain reaction (RT- PCR) assay were all-negative, as well as for virus particles in the kidney by electron microscopy. The three patients and patients with other AKI did not differ significantly with regard to angiotensin-converting enzyme 2 and transmembrane protease serine 2 kidney staining.

Conclusions: The kidney damage particularly in Caucasians in COVID-19 seems to be an AKI, possibly by the systemic inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769537PMC
December 2020

Sofosbuvir and the risk of kidney dysfunction.

J Hepatol 2021 Jan 16;74(1):256-257. Epub 2020 Oct 16.

Hepatology and Gastroenterology Unit, Limoges Dupuytren Hospital, Avenue Martin Luther King, 87042 Limoges, France; INSERM U-1248, Limoges Faculty of Pharmacy, 2, Rue du Docteur Marcland, 87042 Limoges, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.08.019DOI Listing
January 2021

Urinary Protein Biomarker Panel for the Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Recipients.

Kidney Int Rep 2020 Sep 29;5(9):1448-1458. Epub 2020 Jun 29.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Introduction: Antibody-mediated rejection (ABMR) impacts kidney allograft outcome. The diagnosis is made based on findings from invasive kidney transplant biopsy specimens. The aim of this study was to identify a noninvasive urinary protein biomarker for ABMR after kidney transplantation.

Methods: We performed a multicenter case-control study to identify a urinary biomarker for ABMR (training cohort,  = 249) and an independent, prospective multicenter cohort study for validation ( = 391). We used concomitant biopsies to classify the samples according to the Banff classification. After untargeted protein identification and quantification, we used a support vector machine to train the model in the training cohort. The primary endpoint was the diagnostic accuracy of the urinary biomarker for ABMR in the validation cohort.

Results: We identified a set of 10 urinary proteins that accurately discriminated patients with ( = 60) and without ( = 189) ABMR in the training cohort with an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.96-1.00). The diagnostic accuracy was maintained in the validation cohort (AUC, 0.88; 95% CI, 0.8-0.93) for discriminating the presence ( = 43) from the absence ( = 348) of ABMR. The negative predictive value of the 10-protein marker set for exclusion of ABMR was 0.99, and the positive predictive value was 0.33. The diagnostic accuracy was independent of the reason for performing the biopsy, time after transplantation, and better than the accuracy of gross proteinuria (AUC, 0.76).

Conclusions: We identified and validated a urinary protein biomarker set that can be used to exclude ABMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2020.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486186PMC
September 2020

Ifosfamide nephrotoxicity in adult patients.

Clin Kidney J 2020 Aug 31;13(4):660-665. Epub 2019 Dec 31.

Department of Nephrology, Dialysis, Transplantation, Georges Pompidou European Hospital, Paris, France.

Background: Ifosfamide, a widely prescribed antineoplasic agent, is frequently associated with kidney dysfunction. Its nephrotoxicity is well documented in children, but data are lacking in adult patients.

Methods: The aim of this retrospective study was to describe the clinical, biological and histological characteristics of ifosfamide nephrotoxicity.

Results: We report 34 patients (median age: 41 years) admitted in six French nephrology departments for kidney failure and/or tubular dysfunction. Fifteen patients (44.1%) received cisplatin as part of their chemotherapy. In 6 patients (17.7%), ifosfamide nephrotoxicity was revealed by a proximal tubular dysfunction (PTD), in 5 patients (14.4%) by an acute kidney injury (AKI), in 6 patients (17.7%) by a chronic kidney disease (CKD) and in 17 patients (49.7%) by an association of PTD and AKI. Fourteen renal biopsies (41.2%) were performed and revealed acute tubular necrosis (85.7%), vacuolation (78.6%) and nuclear atypias (71.4%) of renal epithelial cells, interstitial inflammation (71.4%) and fibrosis (57.1%). Electron microscopy showed mitochondrial enlargement and dysmorphic changes suggestive of mitochondrial toxicity. Ten patients (29.4%) progressed to Stage 5 CKD, six (17.6%) required haemodialysis and six patients died during a median follow-up period of 31 months. Risk factors for Stage 5 CKD were age and cisplatin co-administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfz183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467602PMC
August 2020

Renal involvement in eosinophilic granulomatosis with polyangiitis (EGPA): a multicentric retrospective study of 63 biopsy-proven cases.

Rheumatology (Oxford) 2021 01;60(1):359-365

Department of Nephrology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort.

Methods: We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy.

Results: Sixty-three patients [27 women, median age 60 years (18-83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1-296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation.

Conclusion: Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa416DOI Listing
January 2021

Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients.

Clin Kidney J 2020 Jun 22;13(3):347-353. Epub 2020 May 22.

Service de Néphrologie et Dialyse, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France.

Among patients hospitalized for novel coronavirus disease (COVID-19), between 10 and 14% develop an acute kidney injury and around half display marked proteinuria and haematuria. Post-mortem analyses of COVID-19 kidney tissue suggest that renal tubular cells and podocytes are affected. Here we report two cases of collapsing glomerulopathy and tubulointerstitial lesions in living COVID-19 patients. Despite our use of sensitive reverse transcription polymerase chain reaction techniques in this study, we failed to detect the virus in blood, urine and kidney tissues. Our observations suggest that these kidney lesions are probably not due to direct infection of the kidney by severe acute respiratory syndrome coronavirus 2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314263PMC
June 2020

Viral metagenomics analysis of kidney donors and recipients: Torque teno virus genotyping and prevalence.

J Med Virol 2020 Jul 13. Epub 2020 Jul 13.

INSERM UMR 1092, Université Limoges, Limoges, France.

The viral load of the ubiquitous and nonpathogenic torque teno virus (TTV) is associated with the grade of immunosuppression of its host. The development of next-generation sequencing (NGS) allowed to describe the human virome of the blood compartment in transplanted patients, and showed that TTV is the most important part of the virome. This study is a descriptive retrospective pilot study of sequencing plasma samples from 15 matched donors and recipients. After sample processing, nucleic acids were amplified by rolling circle amplification and submitted to NGS by ion proton sequencing technology. Results were analyzed after mapping of reads on the 29 TTV reference genomes and de novo assembling of the reads with MIRA software. The number of TTV species present in donors and recipients was, on average, 12 in donors and 33 in recipients. TTV species predominantly present in donors were TTV-13 and TTV-18; and in recipients were TTV-P15-2, TTV-27, TTV-HD14a, and TTV-22. We highlighted a significant variability in abundance and composition in sequential samples from recipients. Temporal evolution of TTV populations was clearly observed in recipients, but no preferential transmission of a species from donor to recipient was evidenced. Diversity and population expansion were observed in kidney recipients. Further study of TTV species could help assess the potential impact of each species of this virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.26298DOI Listing
July 2020

Transcriptional Changes in Kidney Allografts with Histology of Antibody-Mediated Rejection without Anti-HLA Donor-Specific Antibodies.

J Am Soc Nephrol 2020 09 8;31(9):2168-2183. Epub 2020 Jul 8.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium

Background: Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype.

Methods: In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status.

Results: Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFN-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences.

Conclusions: ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020030306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461663PMC
September 2020

Evaluation of Longitudinal Exposure to Tacrolimus as a Risk Factor of Chronic Kidney Disease Occurrence Within the First Year Post-Liver Transplantation.

Transplantation 2020 Jun 29. Epub 2020 Jun 29.

Hepatology and Gastroenterology Unit, University Hospital of Limoges, 2 avenue Martin Luther King, 87042 Limoges, France. INSERM UMR850, Pharmacology and Transplantation, Rue du Pr. Bernard Descottes, 87025 LIMOGES, France. FHU SUPORT: University Hospital Federation SUrvival oPtimization in ORgan Transplantation, Limoges, 87000, Tours, 30000, Poitiers 86000, France. Department of Digestive Surgery and Liver Transplantation, Trousseau University Hospital, Avenue de la République, 37170 Chambray-lès-Tours, France. Hepatology and Gastroenterology Unit, University Hospital of Poitiers, 2 rue de la Milétrie, 86000 Poitiers, France. Hepatology and Gastroenterology Unit, Regional Hospital Center of Orléans, 14 avenue de l'hôpital, 45100 Orléans La Source, France.

Background: Renal failure is predictive of mortality in the early post liver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim was to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on CKD-free 1-year-survival.

Methods: Retrospective data of consecutive patients transplanted between 2011 and 2016, and treated with tacrolimus were collected. TLE and all relevant pre- and post-LT predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated GFR (eGFR) values below 60ml/min/1.73m² at least for the last three months before M12 post-LT.

Results: Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at one-month post-LT (eGFRM1) <60 ml/min/1.73m² were significant predictors of CKD. By distinguishing two situations within AKI (i.e. with or without hepatorenal syndrome (HRS)), only HRS-AKI remained associated to CKD. HRS-AKI and eGFRM1 <60 ml/min/1.73m² increased the risk of CKD (HR= 2.5; 95% CI: 1.2-4.9 and HR=4.8; 95% CI: 2.6-8.8, respectively).

Conclusions: In our study, TLE, unlike HRS AKI and eGFRM1, was not predictive of CKD-free survival at one year post-LT. Our results once again question the reversibility of HRS-AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000003384DOI Listing
June 2020

Antibody-mediated rejection with and without donor-specific anti-human leucocyte antigen antibodies: performance of the peripheral blood 8-gene expression assay.

Nephrol Dial Transplant 2020 08;35(8):1328-1337

KU Leuven Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium.

Background: Recently a peripheral blood 8-gene expression assay was developed for non-invasive detection of antibody-mediated rejection (ABMR) after kidney transplantation. Its value has not yet been evaluated in detail in clinical scenarios with different baseline disease probability [human leucocyte antigen donor-specific antibodies (HLA-DSA)-positive versus HLA-DSA-negative cases at the time of stable graft function versus graft dysfunction].

Methods: Here we investigated the diagnostic accuracy of the 8-gene expression assay for histology of ABMR (ABMRh) with or without HLA-DSA in a cross-sectional cohort study of 387 blood samples with a concomitant graft biopsy.

Results: In patients with HLA-DSA (n = 64), the 8-gene expression assay discriminated DSA-positive ABMRh (DSAposABMRh) cases (n = 16) with good diagnostic performance {area under the receiver operating characteristic curve [AUROC] 83.1% [95% confidence interval (CI) 70.8-95.3]}. Also, in HLA-DSA-negative samples (n = 323), a clinically relevant diagnostic performance for DSAnegABMRh cases was found (n = 30) with an AUROC of 75.8% (95% CI 67.4-84.4). The 8-gene assay did not discriminate DSAposABMRh cases from DSAnegABMRh cases. There was a net benefit for clinical decision-making when adding the 8-gene expression assay to a clinical model consisting of estimated glomerular filtration rate, proteinuria, HLA-DSA and age.

Conclusion: The 8-gene expression assay shows great potential for implementation in the clinical follow-up of high-risk HLA-DSA-positive patients and clinical relevance in HLA-DSA-negative cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa096DOI Listing
August 2020

Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations.

Eur J Clin Pharmacol 2020 Jul 1;76(7):947-955. Epub 2020 May 1.

INSERM, IPPRITT, U1248, F-87000, Limoges, France.

Purpose: The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations.

Methods: In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L.

Results: A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively.

Conclusion: The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8 mg/kg/day just before dialysis, taking into account the type of infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-020-02867-3DOI Listing
July 2020

The COVID-19 outbreak and the angiotensin-converting enzyme 2: too little or too much?

Nephrol Dial Transplant 2020 06;35(6):1073-1075

APHP University Paris Saclay, Ambroise Paré Hospital, Division of Nephrology, Boulogne Billancourt, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197558PMC
June 2020

Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection.

Am J Transplant 2020 12 27;20(12):3462-3476. Epub 2020 Jun 27.

Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

The urinary chemokines CXCL9 and CXCL10 are promising noninvasive diagnostic markers of acute rejection (AR) in kidney recipients, but their levels might be confounded by urinary tract infection (UTI) and BK virus (BKV) reactivation. Multiparametric model development and validation addressed these confounding factors in a training set of 391 samples, optimizing the diagnostic performance of urinary chemokines. CXCL9/creatinine increased in UTI and BKV viremia with or without nephropathy (BKVN) (no UTI/leukocyturia/UTI: -0.10/1.61/2.09, P = .0001 and no BKV/viremia/BKVN: -0.10/1.90/2.29, P < .001) as well as CXCL10/creatinine (1.17/2.09/1.98, P < .0001 and 1.13/2.21/2.51, P < .001, respectively). An optimized 8-parameter model (recipient age, sex, estimated glomerular filtration rate, donor specific antibodies, UTI, BKV blood viral load, CXCL9, and CXCL10) diagnosed AR with high accuracy (area under the curve [AUC]: 0.85, 95% confidence interval [CI]: 0.80-0.89) and remained highly accurate at the time of screening (AUC: 0.81, 95% CI: 0.48-1) or indication biopsies (AUC: 0.85, 95% CI: 0.81-0.90) and within the first year (AUC: 0.86, 95% CI: 0.80-0.91) or later (AUC: 0.90, 95% CI: 0.84-0.96), achieving AR diagnosis with an AUC of 0.85 and 0.92 (P < .0001) in 2 external validation cohorts. Decision curve analyses demonstrated the clinical utility of the model. Considering confounding factors rather than excluding them, we optimized a noninvasive multiparametric diagnostic model for AR of kidney allografts with unprecedented accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15959DOI Listing
December 2020

The FcγRIIIA-158 VV genotype increased the risk of post-transplant lymphoproliferative disorder in T-cell-depleted kidney transplant recipients - a retrospective study.

Transpl Int 2020 08 14;33(8):936-947. Epub 2020 May 14.

EA7501 « Groupe Innovation et Ciblage Cellulaire » team « Fc Receptors, Antibodies and Microenvironment », University of Tours, Tours, France.

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration-effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case-control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery: HR = 2.22 [1.03-4.76], P = 0.043, validation: HR = 1.75 [1.01-3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.13624DOI Listing
August 2020

Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results.

Nephrol Dial Transplant 2021 01;36(1):176-184

Division of Nephrology, Ambroise Paré University Medical Center, APHP, Boulogne Billancourt, F-92100 Paris, France.

Background: Although kidney transplantation prolongs survival relative to dialysis, it is associated with a higher death rate than in the general population. The objective of the present study was to assess and compare the risk of mortality and frequency of non-lethal cardiovascular (CV) events in kidney transplant recipients (KTRs) beyond 1 year after successful transplantation versus patients with chronic kidney disease (CKD) using propensity score-matched analysis of estimated glomerular filtration rate (eGFR) and other parameters.

Methods: After propensity score matching, we studied 340 KTRs from the French Données Informatisées et Validées en Transplantation cohort and 605 non-transplant patients with CKD (CKDps) from the French Chronic Kidney Disease-Renal Epidemiology and Information Network cohort. The mean ± standard deviation eGFR was 42 ± 13 and 41 ± 12 mL/min/  1.73 m2, respectively (P = 0.649). Descriptive data were completed by a survival analysis with Cox regression models.

Results: After a median follow-up period of 2.8 years (KTRs 2.0 years, CKDp 2.9 years), 71 deaths were recorded (31 and 40 in the KTR and CKD groups, respectively). Univariate analysis showed that KTRs had a significantly greater risk of mortality than CKDps. In multivariable analysis, KTRs were found to have a 2.7-fold greater risk of mortality [hazard ratio 2.7 (95% confidence interval 1.6-4.7); P = 0.005]. There was no between-group difference concerning the risk of CV events (P = 0.448). CV death rates in KTRs (29.0%) approximated those of CKDps (22.5%), whereas death rates due to infections were higher in KTRs (19.4% versus 10.0%).

Conclusion: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa026DOI Listing
January 2021

Severe Infection in Anti-Glomerular Basement Membrane Disease: A Retrospective Multicenter French Study.

J Clin Med 2020 Mar 4;9(3). Epub 2020 Mar 4.

Department of Nephrology, Dialysis, and Transplantation, University of Picardie Jules Verne, Amiens University Hospital, F-80054 Amiens, France.

In patients presenting with anti-glomerular basement membrane (GBM) disease with advanced isolated kidney involvement, the benefit of intensive therapy remains controversial due to adverse events, particularly infection. We aim to describe the burden of severe infections (SI) (requiring hospitalization or intravenous antibiotics) and identify predictive factors of SI in a large cohort of patients with anti-GBM disease. Among the 201 patients (median [IQR] age, 53 [30-71] years) included, 74 had pulmonary involvement and 127 isolated glomerulonephritis. A total of 161 SI occurred in 116 patients during the first year after diagnosis. These infections occurred during the early stage of care (median [IQR] time, 13 [8-19] days after diagnosis) with mainly pulmonary (45%), catheter-associated bacteremia (22%) and urinary tract (21%) infections. In multivariable analysis, positive ANCA (HR [95\% CI] 1.62 [1.07--2.44]; = 0.02) and age at diagnosis (HR [95% CI] 1.10 [1.00-1.21]; = 0.047) remained independently associated with SI. Age-adjusted severe infection during the first three months was associated with an increased three-year mortality rate (HR [95% CI] 3.13 [1.24-7.88]; = 0.01). Thus, SI is a common early complication in anti-GBM disease, particularly in the elderly and those with positive anti-neutrophil cytoplasmic antibodies (ANCA). No significant association was observed between immunosuppressive strategy and occurrence of SI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9030698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141378PMC
March 2020

Cyclosporine A inhibits MRTF-SRF signaling through Na/K ATPase inhibition and actin remodeling.

FASEB Bioadv 2019 Sep 24;1(9):561-578. Epub 2019 Aug 24.

Centre for Biology & Health Research, UMR INSERM 1248 IPPRIT (Individual Profiling and Prevention of RIsks in Transplantation) Limoges University Limoges France.

Calcineurin inhibitors (CNI) are the pillars of immunosuppression in transplantation. However, they display a potent nephrotoxicity whose mechanisms remained widely unsolved. We used an untargeted quantitative proteomic approach (iTRAQ technology) to highlight new targets of CNI in renal proximal tubular cells (RPTCs). CNI-treated RPTCs proteome displayed an over-representation of actin-binding proteins with a CNI-specific expression profile. Cyclosporine A (CsA) induced F-actin remodeling and depolymerization, decreased F-actin-stabilizing, polymerization-promoting cofilin (CFL) oligomers, and inhibited the G-actin-regulated serum response factor (SRF) pathway. Inhibition of CFL canonical phosphorylation pathway reproduced CsA effects; however, S3-R, an analogue of the phosphorylation site of CFL prevented the effects of CsA which suggests that CsA acted independently from the canonical CFL regulation. CFL is known to be regulated by the Na/K-ATPase. Molecular docking calculations identified two inhibiting sites of CsA on Na/K-ATPase and a 23% decrease in Na/K-ATPase activity of RPTCs was observed with CsA. Ouabain, a specific inhibitor of Na/K-ATPase also reproduced CsA effects on actin organization and SRF activity. Altogether, these results described a new original pathway explaining CsA nephrotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fba.2019-00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996406PMC
September 2019

First-in-human use of a marine oxygen carrier (M101) for organ preservation: A safety and proof-of-principle study.

Am J Transplant 2020 06 21;20(6):1729-1738. Epub 2020 Feb 21.

Département D'urologie, Néphrologie et Transplantation, Sorbonne Université, Assistance Publique - Hôpitaux de Paris AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Paris, France.

The medical device M101 is an extracellular hemoglobin featuring high oxygen-carrying capabilities. Preclinical studies demonstrated its safety as an additive to organ preservation solutions and its beneficial effect on ischemia/reperfusion injuries. OXYgen carrier for Organ Preservation (OXYOP) is a multicenter open-label study evaluating for the first time the safety of M101 added (1 g/L) to the preservation solution of one of two kidneys from the same donor. All adverse events (AEs) were analyzed by an independent data and safety monitoring board. Among the 58 donors, 38% were extended criteria donors. Grafts were preserved in cold storage (64%) or machine perfusion (36%) with a mean cold ischemia time (CIT) of 740 minutes. At 3 months, 490 AEs (41 serious) were reported, including two graft losses and two acute rejections (3.4%). No immunological, allergic, or prothrombotic effects were reported. Preimplantation and 3-month biopsies did not show thrombosis or altered microcirculation. Secondary efficacy end points showed less delayed graft function (DGF) and better renal function in the M101 group than in the contralateral kidneys. In the subgroup of grafts preserved in cold storage, Kaplan-Meier survival and Cox regression analysis showed beneficial effects on DGF independent of CIT (P = .048). This study confirms that M101 is safe and shows promising efficacy data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15798DOI Listing
June 2020

[End stage kidney disease in Maghreb and Africa: Overview of transplant programs in Maghreb and Africa].

Nephrol Ther 2020 May 24;16(3):171-176. Epub 2020 Jan 24.

Service de néphrologie, Hôpital Ambroise-Paré, 9, avenue Charles-de-Gaulle, 92100 Boulogne-Billancourt, France; Inserm U-1018, Équipe 5, 16, avenue Paul-Vaillant-Couturier, 94807 Villejuif cedex, France. Electronic address:

Kidney transplantation is the best treatment for the patient with end stage kidney disease in term of increasing the survival rate, reducing complications, improving quality of live and its lower cost compared to peritoneal dialysis or hemodialysis. However, the number of patients waiting for kidney transplantation is growing day by day and the gap between demand and supply is still huge. This situation is even more complicated in developing countries where the lack of legislation, infrastructure and government involvement is common. Some national transplantation programs have been implemented, with the support of the International Society for Transplantation and the International Society of Nephrology, in order to increase the transplantation activity of these countries in accordance with the Istanbul Declaration on organ trafficking and transplant tourism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2019.08.001DOI Listing
May 2020

[Sodium metabolism: An update in 2019].

Nephrol Ther 2020 Mar 29;16(2):77-82. Epub 2019 Nov 29.

Hôpital Ambroise-Paré, 9, avenue Charles-de-Gaulle, 92104 Boulogne-Billancourt, France; Inserm UMR 1248, 87000 Limoges, France.

The classical theory of sodium metabolism considers mostly its role on the extracellular volume according to a daily response to the variations of salt intake, correlated to the variations of water volume. Recent works consider sodium tissular storage. This non-osmotic pool could play a role in blood pressure regulation and in immunity mechanisms. The regulation modalities could be more complex, organised over the long term, with a modification of the sodium-water relationship. The aim of this article is to give a new insight on sodium metabolism, based on recent works, especially on the role and regulation of non osmotic tissular sodium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2019.06.004DOI Listing
March 2020

Adherence profiles in kidney transplant patients: Causes and consequences.

Patient Educ Couns 2020 01 7;103(1):189-198. Epub 2019 Aug 7.

CHU Limoges, Department of Pharmacology, Toxicology and Centre of Pharmacovigilance, F-87000 Limoges, France; INSERM, UMR-1248, F-87000 Limoges, France; FHU SUPORT, Limoges, F-87000, France.

Objective: Adherence is a dynamic phenomenon and a critical determinant of transplant patients outcome. The objective of this longitudinal study was to explore adherence in kidney transplant patients followed-up for up to three years after transplantation.

Methods: Adherence was repeatedly estimated using the Morisky-Green-Levine 4-Item Medication Adherence Scale, in two successive cohorts of 345 (EPIGREN) and 367 (EPHEGREN) kidney transplant recipients. Mixed effect modeling with latent processes and latent classes was used to describe adherence time-profiles.

Results: Two latent classes were identified. The adherent class represented 85% of the patients. Patients of the poorer-adherence class displayed a lower adherence at one month (p<10), which worsened over time. Good adherence was associated with age >50 years, fewer depression episodes (5% vs. 13%, p = 0.001) and a better mental health component of quality of life (MCS-SF36 47 ± 11 vs. 41 ± 13, p = 0.015). Survival without acute rejection episodes was longer in the adherent class (p = 0.004).

Conclusions: The risk of poor adherence in renal transplant patients can be detected as early as one month post-transplantation, using appropriate and easy tools adapted to routine monitoring.

Practice Implications: An early focus on vulnerable patients should allow putting into place actions in order to reduce the risk of poor outcome related to poor adherence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pec.2019.08.002DOI Listing
January 2020

Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: A multicentre, prospective study.

EBioMedicine 2019 Aug 1;46:463-472. Epub 2019 Aug 1.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium; University Hospitals Leuven, Department of Nephrology and Renal Transplantation, Leuven, Belgium. Electronic address:

Background: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available.

Methods: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661.

Findings: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p < 0·0001). The diagnostic accuracy of the 8-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. The 8-gene assay is correlated with microvascular inflammation and transplant glomerulopathy, but not with the histological lesions of T-cell mediated rejection.

Interpretation: We identified and validated a novel 8-gene expression assay that can be used for non-invasive diagnosis of antibody-mediated rejection.

Funding: The Seventh Framework Programme (FP7) of the European Commission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710906PMC
August 2019

Sum of peak intensities outperforms peak area integration in iTRAQ protein expression measurement by LC-MS/MS using a TripleTOF 5600+ platform.

Biosci Rep 2019 06 7;39(6). Epub 2019 Jun 7.

INSERM, UMR 1248 IPPRITT, University of Limoges, Limoges, France

In the field of quantitative proteomics, the Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technology has demonstrated efficacy for proteome monitoring despite its lack of a consensus for data handling. In the present study, after peptide and protein identification, we compared the widespread quantitation method based on the calculation of MS/MS reporter ion peaks areas ratios (ProteinPilot) to the alternative method based on the calculation of ratios of the sum of peak intensities (jTRAQx [Quant]) and we processed output data with the in-house Customizable iTRAQ Ratios Calculator (CiR-C) algorithm. Quantitation based on peak area ratios displayed no significant linear correlation with Western blot quantitation. In contrast, quantitation based on the sum of peak intensities displayed a significant linear association with Western blot quantitation (non-zero slope; Pearson correlation coefficient test, r = 0.296, =0.010**) with an average bias of 0.087 ± 0.500 and 95% Limits of Agreement from -0.893 to 1.068. We proposed the Mascot-jTRAQx-CiR-C strategy as a simple yet powerful data processing adjunct to the iTRAQ technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BSR20190904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554230PMC
June 2019

A Prognostic Tool for Individualized Prediction of Graft Failure Risk within Ten Years after Kidney Transplantation.

J Transplant 2019 8;2019:7245142. Epub 2019 Apr 8.

INSERM, U1248, F-87000 Limoges, France.

Identification of patients at risk of kidney graft loss relies on early individual prediction of graft failure. Data from 616 kidney transplant recipients with a follow-up of at least one year were retrospectively studied. A joint latent class model investigating the impact of serum creatinine (Scr) time-trajectories and onset of donor-specific anti-HLA antibody (DSA) on graft survival was developed. The capacity of the model to calculate individual predicted probabilities of graft failure over time was evaluated in 80 independent patients. The model classified the patients in three latent classes with significantly different Scr time profiles and different graft survivals. Donor age contributed to explaining latent class membership. In addition to the SCr classes, the other variables retained in the survival model were proteinuria measured one-year after transplantation (HR=2.4, p=0.01), pretransplant non-donor-specific antibodies (HR=3.3, p<0.001), and DSA in patient who experienced acute rejection (HR=15.9, p=0.02). In the validation dataset, individual predictions of graft failure risk provided good predictive performances (sensitivity, specificity, and overall accuracy of graft failure prediction at ten years were 77.7%, 95.8%, and 85%, resp.) for the 60 patients who had not developed DSA. For patients with DSA individual risk of graft failure was not predicted with a so good performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/7245142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476124PMC
April 2019

[Middle-molecule uremic toxins: A renewed interest].

Nephrol Ther 2019 Apr;15(2):82-90

Service de néphrologie-hémodialyse, hôpital Ambroise Paré, AP-HP, 9, avenue du Général de Gaulle, 92104 Boulogne-Billancourt, France; Équipe 5 CESP, UVSQ, Inserm U1018, Paris Saclay, 16, avenue Paul Vaillant-Couturier, 94800 Villejuif, France.

Cardiovascular mortality in patients with chronic kidney disease remains a major problem. The uremic toxins among which the molecules of middle molecular weight are counted contribute significantly to this high mortality, alongside the traditional risk factors. They generate and maintain a chronic inflammatory state called low-level chronic inflammatory state. A growing interest in these molecules has been noted for some years and the uremic toxins associated with this cardiovascular mortality are currently identified: FGF23, cytokines, pentraxin-3 and recently light chains. The existence of an interaction between uremic toxins, inflammation and/or oxidative stress and cardiovascular mortality is well reported in the various epidemiological studies. While the use of anti-oxidative therapies and/or antibodies against uremic toxins or their site of action have not yet yielded a real benefit, hopes are turning to the use of new hemodialysis membranes medium cut-off (MCO), which have the advantage of purifying the uremic toxin middle molecules without a significant loss of albumin. However, additional works are needed to demonstrate the use of these membranes will lead to modulate the morbi-mortality in the dialysis patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2018.09.003DOI Listing
April 2019