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1. Antihypertensive Treatment Patterns in CKD Stages 3 and 4: The CKD-REIN Cohort Study

Author: Margaux Costes-Albrespic, Sophie Liabeuf, Solène Laville, Christian Jacquelinet, Christian Combe, Denis Fouque, Maurice Laville, Luc Frimat, Roberto Pecoits-Filho, Oriane Lambert, Ziad A. Massy, Bénédicte Sautenet, Natalia Alencar de Pinho, Aghilès Hamroun, Abdou Omorou, Christophe Pascal, Bénédicte Stengel, Céline Lange, and Marie Metzger
Subjects: chronic kidney disease, hypertension, blood pressure, antihypertensive agents, renin-angiotensin system, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Rationale & Objective: Blood pressure (BP) control is essential for preventing cardiorenal complications in chronic kidney disease (CKD), but most patients fail to reach BP target. We assessed longitudinal patterns of antihypertensive drug prescription and systolic BP. Study Design: Prospective observational cohort study. Setting & Population: In total, 2,755 hypertensive patients with CKD stages 3-4, receiving care from a nephrologist, from the French CKD–Renal Epidemiology and Information Network (CKD-REIN cohort study). Exposure: Patient factors, including sociodemographic characteristics, medical history, and laboratory data, and provider factors, including number of primary care physician and specialist encounters. Outcomes: Changes in antihypertensive drug-class prescription during follow-up: add-on or withdrawal. Analytical Approach: Hierarchical shared-frailty models to estimate hazard ratios (HR) to deal with clustering at the nephrologist level and linear mixed models to describe systolic BP trajectory. Results: At baseline, median age was 69 years, and mean estimated glomerular filtration rate was 33 mL/min/1.73 m². In total, 66% of patients were men, 81% had BP ≥ 130/80 mm Hg, and 75% were prescribed ≥2 antihypertensive drugs. During a median 5-year follow-up, the rate of changes of antihypertensive prescription was 50 per 100 person-years, 23 per 100 for add-ons, and 25 per 100 for withdrawals. After adjusting for risk factors, systolic BP, and the number of antihypertensive drugs, poor medication adherence was associated with increased HR for add-on (1.35, 95% confidence interval [CI], 1.01-1.80), whereas a lower education level was associated with increased HR for withdrawal (1.23, 95% CI, 1.02-1.49) for 9-11 years versus ≥12 years. More frequent nephrologist visits (≥4 vs none) were associated with higher HRs of add-on and withdrawal (1.52, 95% CI, 1.06-2.18; 1.57, 95% CI, 1.12-2.19, respectively), whereas associations with visit frequency to other physicians varied with their specialty. Mean systolic BP decreased by 4 mm Hg following drug add-on but tended to increase thereafter. Limitations: Lack of information on prescriber and drug dosing. Conclusions: In patients with CKD and poor BP control, changes in antihypertensive drug prescriptions are common and relate to clinician preferences and patients’ tolerability. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved. Plain-Language Summary: Blood pressure (BP) control remains unattained in most patients with chronic kidney disease (CKD), raising questions about how antihypertensive treatment is managed. Our study highlights dynamic, yet heterogeneous patterns of antihypertensive drug prescriptions in patients with CKD stages 3-4 receiving care from a nephrologist over 5 years of follow-up. Modifiable factors such as high body mass index and poor medication adherence were associated with higher hazard of adding-on an antihypertensive drug class, independently of baseline BP and antihypertensive treatment. Similarly, lower education level was associated with antihypertensive drug withdrawn, as was more frequent visits to primary care physicians, underlining the importance of coordinated care. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved and may be related to drug withdrawal and poor treatment adherence.
Published: 2024
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2. De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease

Author: Maxime Pluquet, Marie Metzger, Christian Jacquelinet, Christian Combe, Denis Fouque, Maurice Laville, Luc Frimat, Ziad A. Massy, Sophie Liabeuf, and Solène M. Laville
Subjects: chronic kidney disease, diabetes mellitus, kidney function estimation, oral antidiabetic drug, prescribing, pharmacoepidemiology, Therapeutics. Pharmacology, RM1-950
Abstract: Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73 m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs).Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR 1.73 m2. Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively −4% and −10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs.Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI.
Published: 2024
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3. Combining robust urine biomarkers to assess chronic kidney disease progressionResearch in context

Author: Frank Bienaimé, Mordi Muorah, Marie Metzger, Melanie Broeuilh, Pascal Houiller, Martin Flamant, Jean-Philippe Haymann, Jacky Vonderscher, Jacques Mizrahi, Gérard Friedlander, Bénédicte Stengel, Fabiola Terzi, François Vrtovsnik, Eric Daugas, Emmanuelle Vidal-Petiot, Christian Jacquot, Alexandre Karras, Stéphane Roueff, Eric Thervet, Pascal Houillier, Marie Courbebaisse, Dominique Eladari et Gérard Maruani, Pablo Urena-Torres, Jean-Jacques Boffa, Pierre Ronco, H. Fessi, Eric Rondeau, Emmanuel Letavernier, and Nahid Tabibzadeh
Subjects: Chronic kidney disease progression, Urinary biomarkers, EGF, TGF-α, CCL2, NGAL, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. Methods: 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38 mL/min) from the NephroTest prospective cohort. Findings: Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652–0.795) vs. 0.682 (0.614–0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. Interpretation: This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. Funding: This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).
Published: 2023
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4. Consequences of oral antithrombotic use in patients with chronic kidney disease

Author: Solène M. Laville, Oriane Lambert, Aghiles Hamroun, Marie Metzger, Christian Jacquelinet, Maurice Laville, Luc Frimat, Denis Fouque, Christian Combe, Carole Ayav, Roberto Pecoits‐Filho, Bénédicte Stengel, Ziad A. Massy, Sophie Liabeuf, and the CKD‐REIN Study Collaborators
Subjects: Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract: Abstract We assessed the risks of bleeding, acute kidney injury (AKI), and kidney failure associated with the prescription of antithrombotic agents (oral anticoagulants and/or antiplatelet agents) in patients with moderate‐to‐advanced chronic kidney disease (CKD). CKD‐REIN is a prospective cohort of 3022 nephrology outpatients with CKD stages 2–5 at baseline. We used cause‐specific Cox proportional hazard models to estimate hazard ratios (HRs) for bleeding (identified through hospitalizations), AKI, and kidney failure. Prescriptions of oral antithrombotics were treated as time‐dependent variables. At baseline, 339 (11%) patients (65% men; 69 [60–76] years) were prescribed oral anticoagulants only, 1095 (36%) antiplatelets only, and 101 (3%) both type of oral antithrombotics. Over a median (interquartile range [IQR]) follow‐up period of 3.0 (IQR, 2.8–3.1) years, 152 patients experienced a bleeding event, 414 patients experienced an episode of AKI, and 270 experienced kidney failure. The adjusted HRs (95% confidence interval [95% CI]) for bleeding associated with prescriptions of antiplatelets only, oral anticoagulants only, and antiplatelet + oral anticoagulant were, respectively, 0.74 (95% CI, 0.46–1.19), 2.38 (95% CI, 1.45–3.89), and 3.96 (95% CI, 2.20–7.12). An increased risk of AKI risk was associated with the prescription of oral anticoagulants (adjusted HR, 1.90, 95% CI, 1.47–2.45) but not the prescription of antiplatelets (HR, 1.24, 95% CI, 0.98–1.56). Kidney failure was not associated with the prescription of oral antithrombotics of any type. This study confirms the high risk of AKI associated with oral anticoagulants prescription in patients with CKD and also highlights the potential aggravating effect of combining vitamin K antagonist (VKA) and antiplatelets on the risk of bleeding.
Published: 2021
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5. Longitudinal Bone Loss Occurs at the Radius in CKD

Author: Pierre-Emmanuel Cailleaux, Agnes Ostertag, Marie Metzger, Bénédicte Stengel, Julie Boucquemont, Pascal Houillier, Martin Flamant, Pablo Ureña-Torres, Martine Cohen-Solal, Emmanuel Letavernier, Pierre Ronco, Hafedh Fessi, Eric Daugas, Caroline du Halgouet, Renaud de La Faille, Christian d’Auzac, Gerard Maruani, Marion Vallet, Cédric Gauci, Jean Philippe Haymann, Eric Thervet, Jean-Jacques Boffa, François Vrtovsnik, Marc Froissart, Laurence Nicolet-Barousse, Mélanie Roland, and Christian Jacquot
Subjects: bone mineral density, chronic kidney disease–mineral bone disorders, fracture, osteoporosis, parathyroid hormone, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Introduction: Chronic kidney disease (CKD) exposes to an increased incidence of fragility fractures. International guidelines recommend performing bone mineral density (BMD) if the results will impact treatment decisions. It remains unknown where bone loss occurs and what would preclude the longitudinal loss in patients with CKD. Here, we aimed to investigate factors influencing BMD and to analyze the longitudinal BMD changes. Methods: In the NephroTest cohort, we measured BMD at the femoral neck, total hip, lumbar spine, and proximal radius, together with circulating biomarkers and standardized measured glomerular filtration rate (mGFR) by 51Cr-EDTA in a subset of patients with CKD stage 1 to 5 followed during 4.3 ± 2.0 years. A linear mixed model explored the longitudinal bone loss and the relationship of associated factors with BMD changes. A total of 858 patients (mean age 58.9 ± 15.2 years) had at least 1 and 477 had at least 2 BMD measures. Results: At baseline, cross-sectional analysis showed a significantly lower BMD at femoral neck and total hip and a significant higher serum parathyroid hormone (PTH) along with CKD stages. Baseline age, gender, tobacco, low body mass index (BMI), and high PTH levels were significantly associated with low BMD. Longitudinal analysis during the mean 4.3 years revealed a significant bone loss at the radius only. BMD changes at the femoral neck were associated with BMI, but not CKD stages or basal PTH levels. Conclusions: CKD is associated with low BMD and high PTH in the cross-sectional analysis. Longitudinal bone loss occurred at the proximal radius after 4.3 years.
Published: 2021
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6. Probiotic Intake and Inflammation in Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort

Author: Sandra Wagner, Thomas Merkling, Marie Metzger, Laetitia Koppe, Maurice Laville, Marie-Christine Boutron-Ruault, Luc Frimat, Christian Combe, Ziad A. Massy, Bénédicte Stengel, and Denis Fouque
Subjects: inflammation, C-reactive protein, yoghurt, probiotic, chronic kidney disease, epidemiology, Nutrition. Foods and food supply, TX341-641
Abstract: Background and AimsLittle is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD.MethodsWe performed a cross-sectional study of 888 patients with stage 3–5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily).ResultsThe 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers.ConclusionWe observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship.Clinical Trial Registration[https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].
Published: 2022
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7. Potential Surrogate Outcomes for Kidney Failure in Advanced CKD: Evaluation of Power and Predictive Ability in CKDoppsPlain-Language Summary

Author: Jarcy Zee, Daniel Muenz, Keith P. McCullough, Brian Bieber, Marie Metzger, Natalia Alencar de Pinho, Antonio A. Lopes, Danilo Fliser, Bruce M. Robinson, Eric Young, Ronald L. Pisoni, Bénédicte Stengel, Roberto Pecoits-Filho, Christian Combe, MD, Johannes Duttlinger, MD, Danilo Fliser, MD, Christian Jacquelinet, MD, Gerhard Lonnemann, MD, Antonio Lopes, MD, MPH, PhD, Ziad Massy, MD, PhD, Roberto Pecoits-Filho, MD, Helmut Reichel, MD, Bénédicte Stengel, MD, PhD, Takashi Wada, MD, and Kunihiro Yamagata, MD
Subjects: Chronic kidney disease progression, composite outcomes, estimated glomerular filtration rate, kidney failure, surrogate end points, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Rationale & Objective: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. Study Design: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). Setting & Participants: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. Outcomes: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. Analytical Approach: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. Results: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. Limitations: Variable visit frequency resulted in variable eGFR measurement frequency. Conclusions: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.
Published: 2022
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8. Achievement of Low-Density Lipoprotein Cholesterol Targets in CKD

Author: Ziad A. Massy, Jean Ferrières, Eric Bruckert, Céline Lange, Sophie Liabeuf, Maja Velkovski-Rouyer, Bénédicte Stengel, Carole Ayav, Christian Combe, Denis Fouque, Luc Frimat, Yves-Edouard Herpe, Maurice Laville, Ziad Massy, Karine Legrand, Marie Metzger, Elodie Speyer, Bruno Moulin, Gaétan Lebrun, Éric Magnant, Gabriel Choukroun, Jean Philippe Bourdenx, Marie Essig, Raymond Azar, Mustafa Smati, Mohamed Jamali, Alexandre Klein, Michel Delahousse, Séverine Martin, Eric Thervet, Xavier Belenfant, Pablo Urena, Carlos Vela, Dominique Chauveau, Viktor Panescu, François Glowacki, Maxime Hoffmann, Maryvonne Hourmant, Dominique Besnier, Angelo Testa, Philippe Zaoui, Charles Chazot, Laurent Juillard, Stéphane Burtey, Adrien Keller, and Nassim Kamar
Subjects: Diseases of the genitourinary system. Urology, RC870-923
Abstract: Introduction: We describe the characteristics of patients with moderate/advanced chronic kidney disease (CKD) according to receipt of lipid-lowering therapy (LLT), and whether they achieved low-density lipoprotein cholesterol (LDL-C) targets for high- and very high-risk patients. Methods: CKD-REIN (NCT03381950), a prospective cohort study conducted in 40 nephrology clinics in France, enrolled 3033 patients with moderate (stage G3) or advanced (stage G4/G5) CKD (2013−2016) who had not been on chronic dialysis or undergone kidney transplantation. Data were collected from patients’ interviews and medical records. Patients were followed up at 1 year. Results: Among 2542 patients (mean [SD] age 67 [13] years, 34% women) with LDL-C measurements at baseline (mean [SD] LDL-C 2.7 [1.1] mmol/l; cholesterol 4.8 [1.3] mmol/l), 63% were on LLT; 24% were at high (CKD stage G3, no cardiovascular disease [CVD] or diabetes) and 74% at very high (CKD stage G3 with diabetes or CVD, or CKD stage G4/5) cardiovascular risk. Among high-risk patients, 45% of those on statin and/or ezetimibe achieved the LDL-C treatment target (
Published: 2019
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9. Increased PTH maintains bone mineral density in patients with CKD

Author: Pierre-Emmanuel Cailleaux, Agnes Ostertag, Pascal Houillier, Marie Metzger, Martin Flamant, Pablo Urena Torres, and Martine Cohen-Solal
Subjects: Diseases of the musculoskeletal system, RC925-935
Published: 2020
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10. Effects of the dialysate calcium concentrations and mineral bone disease treatments on mortality in The French Renal Epidemiology and Information Network (REIN) registry.

Author: Oriane Lambert, Cécile Couchoud, Marie Metzger, Gabriel Choukroun, Christian Jacquelinet, and Lucile Mercadal
Subjects: Medicine, Science
Abstract: BACKGROUND:In patients on hemodialysis (HD), the various chemical elements in the dialysate may influence survival rates. In particular, calcium modifies mineral and bone metabolism and the vascular calcification rate. We studied the influence of the dialysate calcium concentration and the treatments prescribed for mineral bone disease (MBD) on survival. METHODS:All patients in REIN having initiated HD from 2010 to 2013 were classified according to their exposure to the different dialysate calcium concentrations in their dialysis unit. Data on the individual patients' treatments for MBD were extracted from the French national health database. Cox proportional hazard models were used to estimate mortality hazard ratios (HR) associated with time-dependent exposure to dialysate calcium concentrations and MBD therapies, adjusted for comorbidities, laboratory and technical data. RESULTS:Dialysate calcium concentration of 1.5 mmol/L was used by 81% of the dialysis centers in 2010 and in 83% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. In full adjusted Cox survival analyses, the percentage of calcium >1.5 mmol/L and
Published: 2020
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11. Association of a Low-Protein Diet With Slower Progression of CKD

Author: Marie Metzger, Wen Lun Yuan, Jean-Philippe Haymann, Martin Flamant, Pascal Houillier, Eric Thervet, Jean-Jacques Boffa, François Vrtovsnik, Marc Froissart, Lise Bankir, Denis Fouque, and Bénédicte Stengel
Subjects: dietary protein intake, end-stage renal disease, glomerular filtration rate, mortality, urinary urea excretion, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Reducing protein intake is recommended for slowing chronic kidney disease (CKD) progression, but assessment of its true effectiveness is sparse. Methods: Using the Maroni formula, we assessed dietary protein intake (DPI) from 24-hour urinary urea excretion in 1594 patients (67% men and 33% women) with CKD, 784 of whom also had 7-day food records. Cause-specific hazard ratios (HRs) and 95% confidence intervals for the competing risks of DPI-associated end-stage renal disease (ESRD) or death were estimated in 1412 patients with baseline glomerular filtration rate ≥15 ml/min per 1.73 m2, measured by 51Cr-EDTA renal clearance (mGFR). Results: Overall, mean DPI estimated from urea excretion was 1.09 ± 0.30 g/kg of body weight per day (range = 0.34−2.76); 20% of patients had values > 1.3 g/kg per day, and 1.9% had values < 0.6 g/kg per day. Urea excretion and food records produced similar estimates of mean DPI. The lower the mGFR, the lower the mean DPI. Over a median follow-up of 5.6 years, there were 319 ESRD events and 189 pre-ESRD deaths. After adjusting for relevant covariates, each 0.1 g/kg daily higher baseline urea excretion−based DPI or food record−based DPI was associated with an HR for ESRD of 1.05 (95% confidence interval 1.01−1.10) or 1.09 (95% confidence interval 1.04−1.14), respectively. HRs were stronger in patients with baseline mGFR < 30 ml/min per 1.73 m2. There was no association with mortality. The mean age of the patients was 59 ± 15 years, and mean body mass index was 26.6 ± 5.2 kg/m2. Conclusion: In this prospective observational study, the lower the baseline DPI, the slower the progression toward ESRD. Most importantly, the absence of threshold for the relation between DPI and ESRD risk indicates that there is no optimal DPI in the range observed in this cohort.
Published: 2018
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12. Association of plasma potassium with mortality and end-stage kidney disease in patients with chronic kidney disease under nephrologist care - The NephroTest study

Author: Sandra Wagner, Marie Metzger, Martin Flamant, Pascal Houillier, Jean-Philippe Haymann, François Vrtovsnik, Eric Thervet, Jean-Jacques Boffa, Ziad A. Massy, Bénédicte Stengel, Patrick Rossignol, and for the NephroTest Study group
Subjects: Plasma potassium, Hypokalemia, Hyperkalemia, Chronic kidney disease, End-stage kidney disease, Mortality, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Abstract Background Low and high blood potassium levels are common and were both associated with poor outcomes in patients with chronic kidney disease (CKD). Whether such relationships may be altered in CKD patients receiving optimized nephrologist care is unknown. Methods NephroTest is a hospital-based prospective cohort study that enrolled 2078 nondialysis patients (mean age: 59 ± 15 years, 66% men) in CKD stages 1 to 5 who underwent repeated extensive renal tests including plasma potassium (PK) and glomerular filtration rate (GFR) measured (mGFR) by 51Cr-EDTA renal clearance. Test reports included a reminder of recommended targets for each abnormal value to guide treatment adjustment. Main outcomes were cardiovascular (CV) and all-cause mortality before end-stage kidney disease (ESKD), and ESKD. Results At baseline, median mGFR was 38.4 mL/min/1.73m2; prevalence of low PK (5 mmol/L) 6.4%; 74.4% of patients used angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). After excluding 137 patients with baseline GFR
Published: 2017
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13. Hypertension Control, Apparent Treatment Resistance, and Outcomes in the Elderly Population With Chronic Kidney Disease

Author: Jean Kaboré, Marie Metzger, Catherine Helmer, Claudine Berr, Christophe Tzourio, Tilman B. Drueke, Ziad A. Massy, and Bénédicte Stengel
Subjects: cardiovascular, chronic kidney disease, hypertension, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Chronic kidney disease (CKD) is often associated with poor hypertension control and treatment resistance, but whether CKD modifies the effect of hypertension control on outcomes is unknown. Methods: We studied 10-year mortality and cardiovascular events according to hypertension control status and CKD (glomerular filtration rate
Published: 2017
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14. Predicting kidney failure from longitudinal kidney function trajectory: A comparison of models.

Author: Jan A J G van den Brand, Tjeerd M H Dijkstra, Jack Wetzels, Bénédicte Stengel, Marie Metzger, Peter J Blankestijn, Hiddo J Lambers Heerspink, and Ron T Gansevoort
Subjects: Medicine, Science
Abstract: Rationale & objectiveEarly prediction of chronic kidney disease (CKD) progression to end-stage kidney disease (ESKD) currently use Cox models including baseline estimated glomerular filtration rate (eGFR) only. Alternative approaches include a Cox model that includes eGFR slope determined over a baseline period of time, a Cox model with time varying GFR, or a joint modeling approach. We studied if these more complex approaches may further improve ESKD prediction.Study designProspective cohort.Setting & participantsWe re-used data from two CKD cohorts including patients with baseline eGFR >30ml/min per 1.73m2. MASTERPLAN (N = 505; 55 ESKD events) was used as development dataset, and NephroTest (N = 1385; 72 events) for validation.PredictorsAll models included age, sex, eGFR, and albuminuria, known prognostic markers for ESKD.Analytical approachWe trained the models on the MASTERPLAN data and determined discrimination and calibration for each model at 2 years follow-up for a prediction horizon of 2 years in the NephroTest cohort. We benchmarked the predictive performance against the Kidney Failure Risk Equation (KFRE).ResultsThe C-statistics for the KFRE was 0.94 (95%CI 0.86 to 1.01). Performance was similar for the Cox model with time-varying eGFR (0.92 [0.84 to 0.97]), eGFR (0.95 [0.90 to 1.00]), and the joint model 0.91 [0.87 to 0.96]). The Cox model with eGFR slope showed the best calibration.ConclusionIn the present studies, where the outcome was rare and follow-up data was highly complete, the joint models did not offer improvement in predictive performance over more traditional approaches such as a survival model with time-varying eGFR, or a model with eGFR slope.
Published: 2019
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15. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox
Subjects: Science
Abstract: Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
Published: 2016
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16. Correction to: Association of plasma potassium with mortality and end-stage kidney disease in patients with chronic kidney disease under nephrologist care - The NephroTest study

Author: Sandra Wagner, Marie Metzger, Martin Flamant, Pascal Houillier, Jean-Philippe Haymann, François Vrtovsnik, Eric Thervet, Jean-Jacques Boffa, Ziad A. Massy, Bénédicte Stengel, Patrick Rossignol, and for the NephroTest Study group
Subjects: Diseases of the genitourinary system. Urology, RC870-923
Published: 2017
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17. Extracellular Fluid Volume Is an Independent Determinant of Uncontrolled and Resistant Hypertension in Chronic Kidney Disease: A NephroTest Cohort Study

Author: Emmanuelle Vidal‐Petiot, Marie Metzger, Anne‐Laure Faucon, Jean‐Jacques Boffa, Jean‐Philippe Haymann, Eric Thervet, Pascal Houillier, Guillaume Geri, Bénédicte Stengel, François Vrtovsnik, and Martin Flamant
Subjects: chronic kidney disease, extracellular water, hypertension, resistant hypertension, uncontrolled hypertension, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Hypertension is highly prevalent during chronic kidney disease (CKD) and, in turn, worsens CKD prognosis. We aimed to describe the determinants of uncontrolled and resistant hypertension during CKD. Methods and Results We analyzed baseline data from patients with CKD stage 1 to 5 (NephroTest cohort) who underwent thorough renal explorations, including measurements of glomerular filtration rate (clearance of 51Cr‐EDTA) and of extracellular water (volume of distribution of the tracer). Hypertension was defined as blood pressure (BP; average of 3 office measurements) ≥140/90 mm Hg or the use of antihypertensive drugs. In 2015 patients (mean age, 58.7±15.3 years; 67% men; mean glomerular filtration rate, 42±15 mL/min per 1.73 m2), prevalence of hypertension was 88%. Among hypertensive patients, 44% and 32% had uncontrolled (≥140/90 mm Hg) and resistant (uncontrolled BP despite 3 drugs, including a diuretic, or ≥4 drugs, including a diuretic, regardless of BP level) hypertension, respectively. In multivariable analysis, extracellular water, older age, higher albuminuria, diabetic nephropathy, and the absence of aldosterone blockers were independently associated with uncontrolled BP. Extracellular water, older age, lower glomerular filtration rate, higher albuminuria and body mass index, male sex, African origin, diabetes mellitus, and diabetic and glomerular nephropathies were associated with resistant hypertension. Conclusions In this large population of patients with CKD, a lower glomerular filtration rate, a higher body mass index, diabetic status, and African origin were associated with hypertension severity but not with BP control. Higher extracellular water, older age, and higher albuminuria were independent determinants of both resistant and uncontrolled hypertension during CKD. Our results advocate for the large use of diuretics in this population.
Published: 2018
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18. Predictors of nonfunctional arteriovenous access at hemodialysis initiation and timing of access creation: A registry-based study.

Author: Natalia Alencar de Pinho, Raphael Coscas, Marie Metzger, Michel Labeeuw, Carole Ayav, Christian Jacquelinet, Ziad A Massy, and Bénédicte Stengel
Subjects: Medicine, Science
Abstract: Determinants of nonfunctional arteriovenous (AV) access, including timing of AV access creation, have not been sufficiently described. We studied 29 945 patients who had predialysis AV access placement and were included in the French REIN registry from 2005 through 2013. AV access was considered nonfunctional when dialysis began with a catheter. We estimated crude and adjusted odds ratio (OR) with 95% confidence intervals (CI) of nonfunctional versus functional AV access associated with case-mix, facility characteristics, and timing of AV access creation. Analyses were stratified by dialysis start condition (planned or as an emergency) and comorbidity profile. Overall, 18% patients had nonfunctional AV access at hemodialysis initiation. In the group with planned dialysis start, female gender (OR 1.43, 95% CI 1.32-1.56), diabetes (OR 1.28, 95% CI 1.15-1.44), and a higher number of cardiovascular comorbidities (OR 1.27, 95% CI 1.09-1.49, and 1.31, 1.05-1.64, for 3 and >3 cardiovascular comorbidities versus none, respectively) were independent predictors of nonfunctional AV access. A higher percentage of AV access creation at the region level was associated with a lower rate of nonfunctional AV access (OR 0.98, 95% CI 0.98-0.99 per 1% increase). The odds of nonfunctional AV access decreased as time from creation to hemodialysis initiation increased up to 3 months in nondiabetic patients with fewer than 2 cardiovascular comorbidities and 6 months in patients with diabetes or 2 or more such comorbidities. In conclusion, both patient characteristics and clinical practices may play a role in successful AV access use at hemodialysis initiation. Adjusting the timing of AV access creation to patients' comorbidity profiles may improve functional AV access rates.
Published: 2017
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19. Kidney Function Decline and Apparent Treatment-Resistant Hypertension in the Elderly.

Author: Jean Kaboré, Marie Metzger, Catherine Helmer, Claudine Berr, Christophe Tzourio, Ziad A Massy, and Bénédicte Stengel
Subjects: Medicine, Science
Abstract: BACKGROUND:Cross-sectional studies show a strong association between chronic kidney disease and apparent treatment-resistant hypertension, but the longitudinal association of the rate of kidney function decline with the risk of resistant hypertension is unknown. METHODS:The population-based Three-City included 8,695 participants older than 65 years, 4265 of them treated for hypertension. We estimated the odds ratios (OR) of new-onset apparent treatment-resistant hypertension, defined as blood pressure ≥ 140/90 mmHg despite use of 3 antihypertensive drug classes or ≥ 4 classes regardless of blood pressure, associated with the mean estimated glomerular filtration rate (eGFR) level and its rate of decline over 4 years, compared with both controlled hypertension and uncontrolled nonresistant hypertension with ≤ 2 drugs. GFR was estimated with three different equations. RESULTS:Baseline prevalence of apparent treatment-resistant hypertension and of controlled and uncontrolled nonresistant hypertension, were 6.5%, 62.3% and 31.2%, respectively. During follow-up, 162 participants developed apparent treatment-resistant hypertension. Mean eGFR decline with the MDRD equation was 1.5±2.9 mL/min/1.73 m² per year: 27.7% of the participants had an eGFR ≥3 and 10.1% ≥ 5 mL/min/1.73 m² per year. After adjusting for age, sex, obesity, diabetes, and cardiovascular history, the ORs for new-onset apparent treatment-resistant hypertension associated with a mean eGFR level, per 15 mL/min/1.73 m² drop, were 1.23 [95% confidence interval 0.91-1.64] compared to controlled hypertension and 1.10 [0.83-1.45] compared to uncontrolled nonresistant hypertension; ORs associated with a decline rate ≥ 3 mL/min/1.73 m² per year were 1.89 [1.09-3.29] and 1.99 [1.19-3.35], respectively. Similar results were obtained when we estimated GFR with the CKDEPI and the BIS1 equations. ORs tended to be higher for an eGFR decline rate ≥ 5 mL/min/1.73 m² per year. CONCLUSION:The speed of kidney function decline is associated more strongly than kidney function itself with the risk of apparent treatment-resistant hypertension in the elderly.
Published: 2016
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20. Low Serum Creatine Kinase Level Predicts Mortality in Patients with a Chronic Kidney Disease.

Author: Adrien Flahault, Marie Metzger, Jean-François Chassé, Jean-Philippe Haymann, Jean-Jacques Boffa, Martin Flamant, François Vrtovsnik, Pascal Houillier, Bénédicte Stengel, Eric Thervet, Nicolas Pallet, and NephroTest study group
Subjects: Medicine, Science
Abstract: Serum creatine kinase (sCK) reflects CK activity from striated skeletal muscle. Muscle wasting is a risk factor for mortality in patients with chronic kidney disease (CKD). The aim of this study is to evaluate whether sCK is a predictor of mortality and end-stage renal disease (ESRD) in a CKD population.We included 1801 non-dialysis-dependent CKD patients from the NephroTest cohort. We used time-fixed and time-dependent cause-specific Cox models to estimate hazard ratios (HRs) for the risk of death and for the risk of ESRD associated with gender-specific sCK tertiles.Higher sCK level at baseline was associated with a lower age, a higher body mass index, and a higher level of 24 h urinary creatinine excretion, serum albumin and prealbumin (p
Published: 2016
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21. Should we use standard survival models or the illness-death model for interval-censored data to investigate risk factors of chronic kidney disease progression?

Author: Julie Boucquemont, Marie Metzger, Christian Combe, Bénédicte Stengel, Karen Leffondre, and NephroTest Study Group
Subjects: Medicine, Science
Abstract: BackgroundIn studies investigating risk factors of chronic kidney disease (CKD) progression, one may be interested in estimating factors effects on both a fall of glomerular filtration rate (GFR) below a specific level (i.e., a CKD stage) and death. Such studies have to account for the fact that GFR is measured at intermittent visit only, which implies that progression to the stage of interest is unknown for patients who die before being observed at that stage. Our objective was to compare the results of an illness-death model that handles this uncertainty, with frequently used survival models.MethodsThis study included 1,519 patients from the NephroTest cohort with CKD stages 1-4 at baseline (69% males, 59±15 years, median protein/creatinine ratio [PCR] 27.4 mg/mmol) and subsequent annual measures of GFR (follow-up time 4.3±2.7 years). Each model was used to estimate the effects of sex, age, PCR, and GFR at baseline on the hazards of progression to CKD stage 5 (GFRResultsFor progression to stage 5, there were only minor differences between results from the different models. The differences between results were higher for the hazard of death before or after progression. Our results also suggest that previous findings on the effect of age on end-stage renal disease are more likely due to a strong impact of age on death than to an effect on progression. The probabilities of progression were systematically under-estimated with the survival model as compared with the illness-death model.ConclusionsThis study illustrates the advantages of the illness-death model for accurately estimating the effects of risk factors on the hazard of progression and death, and probabilities of progression. It avoids the need to choose arbitrary time-to-event and time-to-censoring, while accounting for both interval censoring and competition by death, using a single analytical model.
Published: 2014
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22. The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease.

Author: Lucile Mercadal, Marie Metzger, Jean Philippe Haymann, Eric Thervet, Jean-Jacques Boffa, Martin Flamant, François Vrtovsnik, Pascal Houillier, Marc Froissart, Bénédicte Stengel, and NephroTest Study Group
Subjects: Medicine, Science
Abstract: The metabolism of hepcidin is profoundly modified in chronic kidney disease (CKD). We investigated its relation to iron disorders, inflammation and hemoglobin (Hb) level in 199 non-dialyzed, non-transplanted patients with CKD stages 1-5. All had their glomerular filtration rate measured by 51Cr-EDTA renal clearance (mGFR), as well as measurements of iron markers including hepcidin and of erythropoietin (EPO). Hepcidin varied from 0.2 to 193 ng/mL. The median increased from 23.3 ng/mL [8.8-28.7] to 36.1 ng/mL [14.1-92.3] when mGFR decreased from ≥60 to
Published: 2014
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23. Decrease in urinary creatinine excretion in early stage chronic kidney disease.

Author: Elena Tynkevich, Martin Flamant, Jean-Philippe Haymann, Marie Metzger, Eric Thervet, Jean-Jacques Boffa, François Vrtovsnik, Pascal Houillier, Marc Froissart, Bénédicte Stengel, and NephroTest Study Group
Subjects: Medicine, Science
Abstract: BACKGROUND:Little is known about muscle mass loss in early stage chronic kidney disease (CKD). We used 24-hour urinary creatinine excretion rate to assess determinants of muscle mass and its evolution with kidney function decline. We also described the range of urinary creatinine concentration in this population. METHODS:We included 1072 men and 537 women with non-dialysis CKD stages 1 to 5, all of them with repeated measurements of glomerular filtration rate (mGFR) by (51)Cr-EDTA renal clearance and several nutritional markers. In those with stage 1 to 4 at baseline, we used a mixed model to study factors associated with urinary creatinine excretion rate and its change over time. RESULTS:Baseline mean urinary creatinine excretion decreased from 15.3 ± 3.1 to 12.1 ± 3.3 mmol/24 h (0.20 ± 0.03 to 0.15 ± 0.04 mmol/kg/24 h) in men, with mGFR falling from ≥ 60 to
Published: 2014
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24. A 3-marker index improves the identification of iron disorders in CKD anaemia.

Author: Lucile Mercadal, Marie Metzger, Jean Philippe Haymann, Eric Thervet, Jean-Jacques Boffa, Martin Flamant, François Vrtovsnik, Cédric Gauci, Marc Froissart, Bénédicte Stengel, and NephroTest Study Group
Subjects: Medicine, Science
Abstract: BACKGROUND: Iron disorders are common and complex in chronic kidney disease (CKD). We sought to determine whether a 3-marker index would improve the classification of iron disorders in CKD anaemia. METHODS: We studied the association between Hb level and iron indexes combining 2 or 3 of the following markers: serum ferritin (
Published: 2014
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25. Renal function can improve at any stage of chronic kidney disease.

Author: Lise Weis, Marie Metzger, Jean-Philippe Haymann, Eric Thervet, Martin Flamant, François Vrtovsnik, Cédric Gauci, Pascal Houillier, Marc Froissart, Emmanuel Letavernier, Bénédicte Stengel, Jean-Jacques Boffa, and NephroTest Study Group
Subjects: Medicine, Science
Abstract: INTRODUCTION: Even though renal function decline is considered relentless in chronic kidney disease (CKD), improvement has been shown in patients with hypertensive nephropathy. Whether this can occur in any type of nephropathy and at any stage is unknown as are the features of patients who improve. METHODS: We identified 406 patients in the NephroTest cohort with glomerular filtration rates (mGFR) measured by (51)Cr-EDTA clearance at least 3 times during at least 2 years of follow-up. Individual examination of mGFR trajectories by 4 independent nephrologists classified patients as improvers, defined as those showing a sustained mGFR increase, or nonimprovers. Twelve patients with erratic trajectories were excluded. Baseline data were compared between improvers and nonimprovers, as was the number of recommended therapeutic targets achieved over time (specifically, for systolic and diastolic blood pressure, proteinuria, and use of renin angiotensin system blockers). RESULTS: Measured GFR improved over time in 62 patients (15.3%). Their median mGFR slope was +1.88[IQR 1.38, 3.55] ml/min/year; it was -2.23[-3.9, -0.91] for the 332 nonimprovers. Improvers had various nephropathies, but not diabetic glomerulopathy or polycystic kidney disease. They did not differ from nonimprovers for age, sex, cardiovascular history, or CKD stage, but their urinary albumin excretion rate was lower. Improvers achieved significantly more recommended therapeutic targets (2.74±0.87) than nonimprovers (2.44±0.80, p
Published: 2013
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26. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author: Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Conall M O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching-Ti Liu, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D Johnson, Hinco J Gierman, Mary Feitosa, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Chouraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank B Hu, Ayse Demirkan, Ben A Oostra, Mariza de Andrade, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Ivana Kolcic, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Karlhans Endlich, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Franco Giulianini, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Marie Metzger, Paul Mitchell, Marina Ciullo, Stuart K Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S Siscovick, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, and Caroline S Fox
Subjects: Genetics, QH426-470
Abstract: Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Published: 2012
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27. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

Author: Krzysztof Kiryluk, Yifu Li, Simone Sanna-Cherchi, Mersedeh Rohanizadegan, Hitoshi Suzuki, Frank Eitner, Holly J Snyder, Murim Choi, Ping Hou, Francesco Scolari, Claudia Izzi, Maddalena Gigante, Loreto Gesualdo, Silvana Savoldi, Antonio Amoroso, Daniele Cusi, Pasquale Zamboli, Bruce A Julian, Jan Novak, Robert J Wyatt, Krzysztof Mucha, Markus Perola, Kati Kristiansson, Alexander Viktorin, Patrik K Magnusson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari Stefansson, Anne Boland, Marie Metzger, Lise Thibaudin, Christoph Wanner, Kitty J Jager, Shin Goto, Dita Maixnerova, Hussein H Karnib, Judit Nagy, Ulf Panzer, Jingyuan Xie, Nan Chen, Vladimir Tesar, Ichiei Narita, Francois Berthoux, Jürgen Floege, Benedicte Stengel, Hong Zhang, Richard P Lifton, and Ali G Gharavi
Subjects: Genetics, QH426-470
Abstract: 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.
Published: 2012
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28. Does kin recognition and sib-mating avoidance limit the risk of genetic incompatibility in a parasitic wasp?

Author: Marie Metzger, Carlos Bernstein, Thomas S Hoffmeister, and Emmanuel Desouhant
Subjects: Medicine, Science
Abstract: When some combinations of maternal and paternal alleles have a detrimental effect on offspring fitness, females should be able to choose mates on the basis of their genetic compatibility. In numerous Hymenoptera, the sex of an individual depends of the allelic combination at a specific locus (single-locus Complementary Sex Determination), and in most of these species individuals that are homozygous at this sexual locus develop into diploid males with zero fitness.In this paper, we tested the hypothesis of genetic incompatibility avoidance by investigating sib-mating avoidance in the solitary wasp parasitoid, Venturia canescens. In the context of mate choice we show, for the first time in a non-social hymenopteran species, that females can avoid mating with their brothers through kin recognition. In "no-choice" tests, the probability a female will mate with an unrelated male is twice as high as the chance of her mating with her brothers. In contrast, in choice tests in small test arenas, no kin discrimination effect was observed. Further experiments with male extracts demonstrate that chemical cues emanating from related males influence the acceptance rate of unrelated males.Our results are compatible with the genetic incompatibility hypothesis. They suggest that the female wasps recognize sibs on the basis of a chemical signature carried or emitted by males possibly using a "self-referent phenotype matching" mechanism.
Published: 2010
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29. Machine Learning-Based Urine Peptidome Analysis to Predict and Understand Mechanisms of Progression to Kidney Failure

Author: Ziad A. Massy, Oriane Lambert, Marie Metzger, Mohammed Sedki, Adeline Chaubet, Benjamin Breuil, Acil Jaafar, Ivan Tack, Thao Nguyen-Khoa, Melinda Alves, Justyna Siwy, Harald Mischak, Francis Verbeke, Griet Glorieux, Yves-Edouard Herpe, Joost P. Schanstra, Bénédicte Stengel, Julie Klein, Natalia ALENCAR DE PINHO, Carole AYAV, Dorothée CANNET, Christian COMBE, Jean-François DELEUZE, Denis FOUQUE, Luc FRIMAT, Yves-Edouard HERPE, Christian JACQUELINET, Maurice LAVILLE, Sophie LIABEUF, Ziad A. MASSY, Christophe PASCAL, Bruce ROBINSON, Roberto PECOITS-FILHO, Joost SCHANSTRA, Bénédicte STENGEL, Céline LANGE, Marie METZGER, and Elodie SPEYER
Subjects: Nephrology
Published: 2023
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30. Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes

Author: Morgan E, Grams, Nigel J, Brunskill, Shoshana H, Ballew, Yingying, Sang, Josef, Coresh, Kunihiro, Matsushita, Aditya, Surapaneni, Samira, Bell, Juan J, Carrero, Gabriel, Chodick, Marie, Evans, Hiddo J L, Heerspink, Lesley A, Inker, Kunitoshi, Iseki, Philip A, Kalra, H Lester, Kirchner, Brian J, Lee, Adeera, Levin, Rupert W, Major, James, Medcalf, Girish N, Nadkarni, David M J, Naimark, Ana C, Ricardo, Simon, Sawhney, Manish M, Sood, Natalie, Staplin, Nikita, Stempniewicz, Benedicte, Stengel, Keiichi, Sumida, Jamie P, Traynor, Jan, van den Brand, Chi-Pang, Wen, Mark, Woodward, Jae Won, Yang, Angela Yee-Moon, Wang, Navdeep, Tangri, John, Chalmers, Chi-Yuan, Hsu, Amanda, Anderson, Panduranga, Rao, Harold, Feldman, Alex R, Chang, Kevin, Ho, Jamie, Green, Moneeza, Siddiqui, Colin, Palmer, Varda, Shalev, Marie, Metzger, Martin, Flamant, Pascal, Houillier, Jean-Philippe, Haymann, John, Cuddeback, Elizabeth, Ciemins, Csaba P, Kovesdy, Marco, Trevisan, Carl Gustaf, Elinder, Björn, Wettermark, Philip, Kalra, Rajkumar, Chinnadurai, James, Tollitt, Darren, Green, Ron T, Gansevoort, Orlando, Gutierrez, Tsuneo, Konta, Anna, Köttgen, Andrew S, Levey, Kevan, Polkinghorne, Elke, Schäffner, Luxia, Zhang, Jingsha, Chen, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)
Subjects: Advanced and Specialized Nursing, Endocrinology, Diabetes and Metabolism, Internal Medicine, Diabetes Mellitus, Albuminuria, Humans, Renal Insufficiency, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], Renal Insufficiency, Chronic, Kidney, Glomerular Filtration Rate
Abstract: OBJECTIVE To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; ≥60 or RESULTS There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting ≥40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS Novel prediction equations for a decline of ≥40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR.
Published: 2022

31. New insights into acute-on-chronic kidney disease in nephrology patients: the CKD-REIN study

Author: Christian Combe, Jarcy Zee, Denis Fouque, Ziad A. Massy, Maurice Laville, Sophie Liabeuf, Céline Lange, Bruce G. Robinson, Carole Ayav, Luc Frimat, Marie Metzger, Bénédicte Stengel, Aghilès Hamroun, Chronic Kidney Disease-Renal Epidemiology, Yves-Edouard Herpe, François Glowacki, and Christian Jacquelinet
Subjects: Male, Nephrology, medicine.medical_specialty, medicine.medical_treatment, Renal function, urologic and male genital diseases, Cohort Studies, Renal Dialysis, Risk Factors, Internal medicine, Diabetes mellitus, medicine, Humans, Renal Insufficiency, Chronic, Dialysis, Aged, Transplantation, business.industry, Hazard ratio, Acute kidney injury, Acute Kidney Injury, medicine.disease, Kidney Failure, Chronic, Female, business, Glomerular Filtration Rate, Kidney disease, Cohort study
Abstract: Background Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants and outcomes in patients with CKD. Methods We used the Kidney Disease: Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD Stages 3–5 participating in the CKD-Renal Epidemiology and Information Network cohort study (2013–20), and cause-specific Cox models to estimate hazard ratios [HRs; 95% confidence intervals (CIs)] of AKI-associated risk factors. Results At baseline, 22% of the patients [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were Stage 2 or 3 and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; and a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8/100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight ( Conclusions The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anaemia as possible new risk factors in CKD patients.
Published: 2021
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32. MO496: Serum Urea Levels and Cardiovascular Disease in Patients With Chronic Kidney Disease

Author: Solene Laville, Aymeric Couturier, Oriane Lambert, Marie Metzger, Mansencal Nicolas, Christian Jacquelinet, Maurice Laville, Luc Frimat, Denis Fouque, Christian Combe, Bruce Robinson, Benedicte Stengel, Sophie Liabeuf, and Ziad Massy
Subjects: Transplantation, Nephrology
Abstract: BACKGROUND AND AIMS Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before kidney replacement therapy (KRT) in patients with CKD. METHOD CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 RESULTS Of the 2507 included patients {median [first quartile–third quartile (Q1–Q3)] age: 69 (61–77); mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²}, 54% had a history of cardiovascular disease. Over a median follow-up of 3.0 years [Q1–Q3, 2.2–3.1], 451 experienced their first atheromatous or nonatheromatous cardiovascular event (fatal or nonfatal), leading to an incidence rate (IR) [95% confidence interval (95% CI)] of 7.1 (6.4–7.7)/100 person-years (PYs) (Fig. 1). Over a median follow-up period of 4.8 (3.3–5.1) years, 407 patients died before KRT, leading to an IR of 4.0 (3.6–4.3)/100 PYs. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patients in T1 [HR (95% CI), 2.08 (1.50–2.88), Fig. 1]. A nonsignificant trend towards a higher risk was also noted for patients in T2 [1.28 (0.96–1.71)]. The adjusted HRs for death before KRT were 1.30 (0.96–1.75] and 1.73 (1.22–2.45) for patients in T2 and those in T3, respectively. CONCLUSION Beyond CV risk factors including eGFR, this hypothesis-generating study suggests that serum urea level is a predictor of cardiovascular outcomes in patients with moderate to advanced CKD. Further research is needed to confirm current findings and explore mechanisms.
Published: 2022
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33. Urinary Sodium-to-Potassium Ratio and Blood Pressure in CKD

Author: Natalia Alencar de Pinho, Jean Kaboré, Maurice Laville, Marie Metzger, Céline Lange, Christian Jacquelinet, Christian Combe, Denis Fouque, Luc Frimat, Carol Ayav, Bruce M. Robinson, Tilman Drueke, Ziad A. Massy, Bénédicte Stengel, Thierry Hannedouche, Bruno Moulin, Sébastien Mailliez, Gaétan Lebrun, Eric Magnant, Gabriel Choukroun, Benjamin Deroure, Adeline Lacraz, Guy Lambrey, Jean Philippe Bourdenx, Marie Essig, Thierry Lobbedez, Raymond Azar, Hacène Sekhri, Mustafa Smati, Mohamed Jamali, Alexandre Klein, Michel Delahousse, Séverine Martin, Isabelle Landru, Eric Thervet, Philippe Lang, Xavier Belenfant, Pablo Urena, Carlos Vela, Dominique Chauveau, Viktor Panescu, Christian Noel, François Glowacki, Maxime Hoffmann, Maryvonne Hourmant, Dominique Besnier, Angelo Testa, François Kuentz, Philippe Zaoui, Charles Chazot, Laurent Juillard, Stéphane Burtey, Adrien Keller, Nassim Kamar, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de Recherche en Sciences de la Santé (IRSS), CNRST, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Agence de la biomédecine [Saint-Denis la Plaine], Service de Néphrologie Transplantation, Dialyse et Aphérèse [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Arbor Research Collaborative for Health, Hôpital Ambroise Paré [AP-HP], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Agence Nationale de la Recherche, ANR Agence Nationale de la Recherche, ANR, The CKD-REIN study is funded by the Agence Nationale de la Recherche through the 2010 «Cohortes-Investissements d’Avenir » program (ANR) and by the 2010 national Programme Hospitalier de Recherche Clinique . CKD-REIN is also supported through a public–private partnership with Amgen , Fresenius Medical Care , and GlaxoSmithKline (GSK) since 2012, Lilly France since 2013, Otsuka Pharmaceutical since 2015, Baxter and Merck Sharp & Dohme-Chibret (MSD France) from 2012 to 2017, Sanofi-Genzyme from 2012 to 2015, and Vifor Fresenius and AstraZeneca , since 2018. Inserm Transfert set up and has managed this partnership since 2011., Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Chronic Kidney Disease - Réseau Epidémiologie et Information en Néphrologie (CKD REIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Urinary system, Population, 030232 urology & nephrology, 030204 cardiovascular system & hematology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gastroenterology, Excretion, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Interquartile range, Internal medicine, medicine, salt, 10. No inequality, education, sodium, education.field_of_study, business.industry, potassium, blood pressure, medicine.disease, 3. Good health, Blood pressure, Quartile, Nephrology, Albuminuria, medicine.symptom, business, chronic kidney disease, Kidney disease
Abstract: Introduction In the general population, urinary sodium-to-potassium (uNa/K) ratio associates more strongly with high blood pressure (BP) than either urinary sodium or potassium alone. Whether this is also the case among patients with chronic kidney disease (CKD) is unknown. Methods We studied the associations of spot urine sodium-to-creatinine (uNa/Cr), potassium-to-creatinine (uK/Cr), and uNa/K ratios with a single office BP reading in 1660 patients with moderate to severe CKD at inclusion in the CKD-REIN cohort. Results Patients' median age was 68 (interquartile range [IQR], 59–76) years; most were men (65%), had moderate CKD (57%), and albuminuria (72%). Mean systolic and diastolic BP was 142/78 mm Hg. Spot uNa/Cr and uNa/K ratios were positively associated with systolic, mean arterial, and pulse pressures. The mean adjusted difference in systolic BP between the highest and the lowest quartile (Q4 vs. Q1) was 4.24 (95% confidence interval [CI], 1.53–6.96) mm Hg for uNa/Cr and 4.79 (95% CI, 2.18–7.39) mm Hg for uNa/K. Quartiles of spot uK/Cr were not associated with any BP index. The higher the quartile of uNa/K, the higher the prevalence ratio of uncontrolled (Q4 vs. Q1, 1.43; 95% CI, 1.19–1.72) or apparently treatment-resistant hypertension (Q4 vs. Q1, 1.35; 95% CI, 1.14–1.60). Findings were consistent in a subset of 803 individuals with 2 BP readings. Conclusion In patients with CKD, higher urinary sodium excretion is associated with higher BP, but unlike in general population, lower potassium excretion is not. Urinary Na/K does not add significant value in assessing high BP risk, except perhaps for hypertension control assessment., Graphical abstract
Published: 2020
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34. Urea levels and cardiovascular disease in patients with chronic kidney disease

Author: Solène M, Laville, Aymeric, Couturier, Oriane, Lambert, Marie, Metzger, Nicolas, Mansencal, Christian, Jacquelinet, Maurice, Laville, Luc, Frimat, Denis, Fouque, Christian, Combe, Bruce M, Robinson, Bénédicte, Stengel, Sophie, Liabeuf, Ziad A, Massy, CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de cardiologie et maladies vasculaires [CHU Ambroise Paré], Agence de la biomédecine [Saint-Denis la Plaine], Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Bordeaux [Bordeaux], INSERM U1026 (INSERM, U1026), Institut National de la Santé et de la Recherche Médicale (INSERM), Arbor Research Collaborative for Health, and LAVILLE, Solène
Subjects: Transplantation, Nephrology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Background Elevated serum urea levels are common in moderate-to-advanced chronic kidney disease (CKD). Several studies have shown that urea is a direct and indirect uraemic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. Methods CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 Findings Of the 2507 included patients {median [interquartile range (IQR)] age: 69 [61–77]; mean (standard deviation) estimated glomerular filtration rate (eGFR) 33.5 (11.6) mL/min/1.73 m²}, 54% had a history of cardiovascular disease. After multiple adjustments for CV risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and non-atheromatous CV events than patient in T1 (n events = 451, HR [95% CI]: 1.93 [1.39; 2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31 [0.97; 1.76] and 1.73 [1.22; 2.45] for patients T2 and those in T3, respectively. Interpretation Our data suggested that urea is a predictor of CV outcomes beyond CV risk factors including eGFR.
Published: 2022
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35. GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy

Author: Dmitry Samsonov, Edyta Machura, Dita Maixnerova, Bénédicte Stengel, Domenico Santoro, Loreto Gesualdo, Silvana Savoldi, Raoul D. Nelson, Florian Kronenberg, Hajeong Lee, Licia Peruzzi, Gianluca Caridi, Magdalena Krajewska, Vladimir Tesar, Richard P. Lifton, William E. Smoyer, Erica Salvi, Marcin Zaniew, Magdalena Durlik, Guillaume Canaud, Heather N. Reich, Luisa Bono, Anna Köttgen, Pietro A. Canetta, Maurizio Garozzo, Marco Galliani, Bertrand Fontaine, Thomas Rauen, Renzo Mignani, Maria Szczepańska, Carmelita Marcantoni, Lili Liu, Pietro Ravani, Andrea Magnano, Aftab S. Chishti, Ulf Panzer, Dong Ki Kim, T Baczkowska, Ben Sprangers, Lucia Del Vecchio, Dorota Drozdz, Larisa Prikhodina, John B. Harley, Tomasz Liberek, Monika Pawlak-Bratkowska, Maria Stangou, Ichiei Narita, José Ballarín, Hernán Trimarchi, Barbara Moszczuk, Agnieszka Perkowska-Ptasińska, Maurizio Salvadori, Laureline Berthelot, Francesca Lugani, Katarzyna Siniewicz-Luzeńczyk, Claudia Izzi, Peter K. Gregersen, Isabella Pisani, Michelle N. Rheault, Adele Mitrotti, Ruth J. F. Loos, Xu-jie Zhou, Krzysztof Pawlaczyk, Kai-Uwe Eckardt, Giovanni Frasca, Piergiorgio Messa, Elisabet Ars, Antonio Amoroso, Evangeline Pillebout, Vito Annese, Kresimir Galesic, Tibor Kovács, Hitoshi Suzuki, Krzysztof Kiryluk, Nan Chen, Guido Gembillo, Olivia Balderes, Ciro Esposito, Małgorzata Mizerska-Wasiak, Daniel P. Gale, Sreeja Parameswaran, Michał Florczak, Jai Radhakrishnan, Alicja Dbska-Slizien, Ireneusz Habura, Matthew T. Weirauch, Belong Cho, Guillermo Hidalgo, John D. Mahan, Bruce A. Julian, Andre Franke, Alejandro Quiroga, Rosanna Coppo, Atlas Khan, Murim Choi, Giuliano Boscutti, Izabella Kuzmiuk-Glembin, Nicolas Maillard, Rosaria Polci, Jonathan Barratt, Dario Roccatello, Donna J. Claes, Marie Metzger, Chris Cotsapas, Yasar Caliskan, Raji Sreedharan, Judit Nagy, Francesca Zanoni, Monica Bodria, Dariusz Runowski, Hong Zhang, Magorzata Panczyk-Tomaszewska, Robert J. Wyatt, Claudio Ponticelli, Nikol Mladkova, Przemysław Sikora, Marcin Tkaczyk, Riccardo Magistroni, Gerald B. Appel, Ans van Wijk, Krzysztof Mucha, Barbara Bułło-Piontecka, Jan Novak, Giovanni-Giorgio Battaglia, Anna Materna-Kiryluk, Emanuela Boer, Francesco Scolari, David A. van Heel, Tomasz Hryszko, Keefe Davis, Thilini Abeygunaratne, Simone Sanna-Cherchi, Zbigniew Heleniak, Eimear E. Kenny, Sigrid Lundberg, Al-Akash Samhar, Francesco Londrino, Tetyana L. Vasylyeva, Scott E. Wenderfer, Federico Alberici, Yon Su Kim, Enrico Fiaccadori, Bruno Vogt, Gianluigi Zaza, Stanisaw Niemczyk, Patricia L. Weng, Donatella Spotti, Gian Marco Ghiggeri, Dimitrios Goumenos, Daniel Ranch, David T. Selewski, Monika Miklaszewska, Laila-Yasmin Mani, Jin-Ho Park, Jürgen Floege, Antonello Pani, Renato C. Monteiro, Leszek Paczek, Akchurin Oleh, Maddalena Marasa, Ana Huerta, Sandro Feriozzi, Simona Granata, Andrew S. Bomback, Pascal Schlosser, York Pei, Vittoria Esposito, Mahmoud Kallash, Pasquale Zamboli, Cisca Wijmenga, Daniele Cusi, Elena Sanchez-Rodriguez, Ali G. Gharavi, Francois Berthoux, Shin Goto, Natalia Krata, Leah C. Kottyan, Norbert Kwella, Iuliana Ionita-Laza, Daniel C. Cattran, Cristina Barlassina, Arif B. Ekici, Katarzyna Dyga, Philip A. Kalra, Dorota Kamińska, Jingyuan Xie, Elisa Delbarba, and Jun-Ying Zhang
Subjects: Immune system, Intestinal mucosa, Immunology, medicine, SNP, Genome-wide association study, IRF8, Biology, urologic and male genital diseases, medicine.disease, Inflammatory bowel disease, Kidney disease, Nephropathy
Abstract: IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
Published: 2021
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36. Probiotic Intake and Inflammation in Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort

Author: Sandra Wagner, Thomas Merkling, Marie Metzger, Laetitia Koppe, Maurice Laville, Marie-Christine Boutron-Ruault, Luc Frimat, Christian Combe, Ziad A. Massy, Bénédicte Stengel, and Denis Fouque
Subjects: Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Food Science
Abstract: Background and AimsLittle is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD.MethodsWe performed a cross-sectional study of 888 patients with stage 3–5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily).ResultsThe 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers.ConclusionWe observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship.Clinical Trial Registration[https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].
Published: 2021

37. Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression

Author: Bénédicte Janbon, Sophie Caillard, Isabelle Jollet, Elisabeth Cassuto, Elodie Bailly, Bruno Hurault de Ligny, Michel Delahousse, Marc Hazzan, Anne Devys, Antoine Thierry, Pierre Merville, Sophie Girerd, Renaud Snanoudj, Dany Anglicheau, Vincent Vuiblet, Nassim Kamar, Kahina Amokrane, Philippe Grimbert, Eric Rondeau, Gabriel Choukroun, Alexandre Hertig, Marie Metzger, Jean-Luc Taupin, Yann Le Meur, Christophe Legendre, Emmanuel Morelon, Service de Néphrologie - Immunologie Clinique [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse]-PRES Université de Toulouse, Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Néphrologie et Transplantation [Strasbourg], Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de Néphrologie-Hémodialyse-Transplantation rénale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Etablissement français du sang [Poitiers] (EFS), Service de néphrologie [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Département de Néphrologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie et Transplantation rénale [CHRU-lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Néphrologie [Amiens], CHU Amiens-Picardie-hôpital Sud, Service de Néphrologie-Dialyse-Transplantation rénale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Transplantation rénale [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Etablissement français du sang [Angers], Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Foch [Suresnes], Service de néphrologie, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, France (Service de néphrologie, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, France), Service de néphrologie et immunologie clinique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de néphrologie et de transplantation rénale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Service de néphrologie et immunologie clinique [CHRU Tours] (EA4245 UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: Adult, Graft Rejection, Male, 0301 basic medicine, Isoantigens, Allosensitization, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, 030232 urology & nephrology, kidney transplantation, Human leukocyte antigen, acute rejection, Epitope, 03 medical and health sciences, 0302 clinical medicine, Antigen, HLA-DQ Antigens, immunosuppression minimization, Humans, Transplantation, Homologous, Medicine, Everolimus, education, Kidney transplantation, education.field_of_study, biology, Drug Substitution, business.industry, Histocompatibility Testing, Patient Selection, Graft Survival, Immunosuppression, Middle Aged, epitopes, medicine.disease, HLA mismatching, 3. Good health, 030104 developmental biology, Nephrology, Immunology, Cyclosporine, antibody-mediated rejection, biology.protein, Female, Antibody, business, Immunosuppressive Agents, Follow-Up Studies
Abstract: International audience; Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.
Published: 2019
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38. MO484ADVERSE OUTCOMES ASSOCIATED WITH ORAL ANTITHROMBOTIC USE IN PATIENTS WITH MODERATE-TO-ADVANCED CHRONIC KIDNEY DISEASE*

Author: Sophie Liabeuf, Luc Frimat, Oriane Lambert, Marie Metzger, Solène M. Laville, Ziad A. Massy, Maurice Laville, Bénédicte Stengel, Denis Fouque, Carole Ayav, Christian Combe, Christian Jacquelinet, Roberto Pecoits-Filho, and Aghilès Hamroun
Subjects: Transplantation, medicine.medical_specialty, Nephrology, business.industry, Internal medicine, Antithrombotic, Medicine, In patient, business, medicine.disease, Kidney disease
Abstract: Background and Aims The use of oral antithrombotics in patients with chronic kidney disease (CKD) is challenging because of altered pharmacodynamics/pharmacokinetics. Patients prescribed oral anticoagulant are at high risk of bleeding, and possibly also acute kidney injury (AKI) and progression to kidney failure. We assessed bleeding, AKI, and kidney failure risks associated with oral anticoagulant and/or antiplatelet agent prescription in patients with moderate-to-advanced CKD. Method CKD-REIN is a prospective cohort of 3022 nephrology outpatients with CKD stages 2-5 at inclusion. Drug prescriptions and their duration were collected prospectively. We used cause-specific Cox proportional hazard models to estimate hazard ratios (HR) for bleeding (identified through hospitalizations), AKI (as defined according to KDIGO 2012), and kidney failure. Prescriptions of oral antithrombotics were treated as a time dependent variable and models were adjusted for baseline comorbidities, laboratory data, and other medications. Results At baseline, 339 (11%) patients (65% men; median age 69 [interquartile range (IQR), 60-76] years; median eGFR 32 [IQR, 23-41] were prescribed oral anticoagulants only, 1095 (36%) antiplatelet only, and 101 (3%) both anticoagulant and antiplatelet. Over a median follow-up of 3 years (IQR, 2.8-3.1), 152 patients experienced a bleeding event requiring hospital visit/stay (crude incidence rate (IR): 1.9% person-years [95%CI,1.6-2.2]), 414 patients experienced AKI (crude IR: 5.4 % person-years [4.9-5.9]), and 270 experienced kidney failure (crude IR: 3.4 % person-years [3.0-3.8]). A significant interaction was found between oral antithrombotics and eGFR (interaction p=0.03). The adjusted HRs [95%CI] for bleeding associated with prescriptions of antiplatelets only, oral anticoagulants only, and antiplatelet + oral anticoagulant were respectively 0.58 [0.30; 1.11], 2.62 [1.39; 4.93], and 5.76 [2.85; 11.66] in patients with a baseline eGFR < 30 mL/min/1.73m2. In patients with baseline eGFR ≥ 30 mL/min/1.73m2, the adjusted HRs [95%CI] for bleeding associated with prescriptions of antiplatelets only, oral anticoagulants .......only, and antiplatelet + oral anticoagulant were respectively 0.98 [0.48; 1.98], 1.91 [0.87; 4.20], and 1.54 [0.46; 5.12] (Figure 1A). An increased risk of AKI risk was associated with the prescription of oral anticoagulants (adjusted HR [95%CI]: 1.91[1.48; 2.46]) but not the prescription of antiplatelets (1.24[0.98; 1.56], Figure 1B). No significant interactions were found between oral anticoagulants and eGFR or antiplatelet agents. Kidney failure was not associated with the prescription of oral antithrombotics of any type (Figure 1C). No significant interactions were found with eGFR and antiplatelet agents. Conclusion This study confirms the risk of AKI in CKD patients prescribed oral anticoagulants. It also highlights the potential aggravating effect of combining anticoagulants and antiplatelet on the risk of bleeding in this population.
Published: 2021
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39. Water intake and progression of chronic kidney disease: the CKD-REIN cohort study

Author: Christian Jacquelinet, Denis Fouque, Marie Metzger, Bénédicte Stengel, Lise Bankir, Christian Combe, Thomas Merkling, Maurice Laville, L. Frimat, Ziad A. Massy, Sandra Wagner, Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Agence de la biomédecine [Saint-Denis la Plaine], Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], The CKD-REIN study is funded by the Agence Nationale de la Recherche through the 2010 Cohortes-Investissements d’Avenir programme and by the 2010 national Programme Hospitalier de Recherche Clinique, CarMeN, laboratoire, Université Paris-Saclay, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Urology, Drinking, Renal function, Urine, water intake, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Risk Factors, urine osmolarity, Medicine, Humans, 030212 general & internal medicine, Renal Insufficiency, Chronic, kidney function, Aged, Osmole, Transplantation, Kidney, business.industry, Hazard ratio, Water, urine volume, medicine.disease, 3. Good health, kidney failure, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Nephrology, Urine osmolality, Disease Progression, Female, business, Kidney disease, Glomerular Filtration Rate
Abstract: Background Optimal daily water intake to prevent chronic kidney disease (CKD) progression is unknown. Taking the kidney’s urine-concentrating ability into account, we studied the relation of kidney outcomes in patients with CKD to total and plain water intake and urine volume. Methods Including 1265 CKD patients [median age 69 years; mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] from the Chronic Kidney Disease–Renal Epidemiology and Information Network cohort (2013–19), we assessed fluid intake at baseline interviews, collected 24-h urine volumes and estimated urine osmolarity (eUosm). Using Cox and then linear mixed models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney failure and eGFR decline associated with hydration markers, adjusting for CKD progression risk factors and eUosm. Results Patients’ median daily intake was 2.0 L [interquartile range (IQR) 1.6–2.6] for total water and 1.5 L (1–1.7) for plain water, median urine volume was 1.9 L/24 h (IQR 1.6–2.4) and mean eUosm was 374 ± 104 mosm/L. Neither total water intake nor urine volume was associated with either kidney outcome. Kidney failure risk increased significantly with decreasing eUosm ˂292 mosm/L. Adjusted HRs (95% CIs) for kidney failure associated with plain water intake were 1.88 (1.02–3.47), 1.59 (1.06–2.38), 1.76 (0.95–3.24) and 1.55 (1.03–2.32) in patients drinking 2.0 L/day compared with those drinking 1.0–1.5 L/day. High plain water intake was also significantly associated with faster eGFR decline. Conclusions In patients with CKD, the relation between plain water intake and progression to kidney failure appears to be U-shaped. Both low and high intake may not be beneficial in CKD.
Published: 2021
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40. Higher mortality risk among kidney transplant recipients than among estimated glomerular filtration rate-matched patients with CKD-preliminary results

Author: Lynda Cheddani, Marie Metzger, Ziad A. Massy, Maryvonne Hourmant, Marie Essig, Tilman B. Drüeke, C. Kerleau, Christian Jacquelinet, Renaud Snanoudj, Sophie Liabeuf, Beverley Balkau, Nantes Kidney, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Foch [Suresnes], Agence de la biomédecine [Saint-Denis la Plaine], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Ambroise Paré [AP-HP], Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC) (U1018 (Équipe 5)), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Risk Factors, Internal medicine, Risk of mortality, Humans, Medicine, Prospective Studies, Renal Insufficiency, Chronic, education, Dialysis, Kidney transplantation, Aged, Transplantation, education.field_of_study, business.industry, Mortality rate, Hazard ratio, Middle Aged, Prognosis, medicine.disease, Kidney Transplantation, Transplant Recipients, Survival Rate, Cardiovascular Diseases, Nephrology, Case-Control Studies, Female, business, Glomerular Filtration Rate, Kidney disease
Abstract: BackgroundAlthough 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.MethodsAfter 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.ResultsAfter 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%).ConclusionBeyond 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.
Published: 2021
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41. Valeurs de références du débit de filtration glomérulaire par sexe chez le sujet sain de 18 à 90 ans

Author: Bénédicte Stengel, Marc Froissart, Marie Metzger, Martin Flamant, Jean-Philippe Haymann, Pascal Houillier, Cédric Gauci, A.-L. Faucon, and A. Banchard
Subjects: Nephrology
Abstract: Introduction Les valeurs normales du debit de filtration glomerulaire (DFG) ne sont pas clairement etablies, notamment chez le sujet âge. Description L’objectif etait de decrire le declin physiologique du DFG selon l’âge et le sexe, chez le sujet sain, et d’evaluer les performances des equations d’estimation du DFG. Methodes Le DFG etait mesure par la clairance renale du 51Cr-EDTA chez 630 femmes et hommes en bonne sante, âges de 18–90 ans. Un modele GAMLSS a permis d’etablir les valeurs de reference du DFG. La relation entre DFG, âge et sexe a ete analysee a l’aide d’un modele lineaire par morceaux. Enfin, biais, precision et exactitude des equations CKD-EPI et FAS ont ete evaluees. Resultats Les participants (43 % d’hommes) avaient un DFG mesure (mDFG) moyen de 90,5 ± 15,9 mL/min/1,73 m2. Le 5e percentile restait superieur a 60 mL/min/1,73 m2 jusqu’a 80 ans chez les hommes, alors que ce seuil etait atteint par 5 % des femmes a 63 ans et par 25 % a 76 ans. Le mDFG diminuait physiologiquement avec l’âge a partir de 40 ans ( Fig. 1 ), plus rapidement chez la femme que chez l’homme, 0,83 ± 0,09 vs 0,67 ± 0,07 mL/min/1,73 m2 par an, p Globalement, le biais dans l’estimation du DFG etait significativement plus faible avec l’equation FAS qu’avec CKD-EPI, alors que la precision et l’exactitude ne differaient pas. Les performances des equations etaient similaires entre les deux sexes, mais CKD-EPI tendait a surestimer et FAS a sous-estimer le mDFG au-dessus de 65 ans. Conclusion Un declin physiologique plus rapide du DFG chez les femmes que chez les hommes pourrait expliquer le paradoxe associant une plus forte prevalence de la maladie renale chronique (MRC) a une plus faible incidence de la defaillance renale chez la femme. Les valeurs de reference sont a considerer pour le diagnostic de MRC et la prescription medicamenteuse, en particulier chez le sujet âge.
Published: 2021
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42. Conversion of Urine Protein-Creatinine Ratio or Urine Dipstick Protein to Urine Albumin-Creatinine Ratio for Use in Chronic Kidney Disease Screening and Prognosis: An Individual Participant-Based Meta-analysis

Author: Keiichi, Sumida, Girish N, Nadkarni, Morgan E, Grams, Yingying, Sang, Shoshana H, Ballew, Josef, Coresh, Kunihiro, Matsushita, Aditya, Surapaneni, Nigel, Brunskill, Steve J, Chadban, Alex R, Chang, Massimo, Cirillo, Kenn B, Daratha, Ron T, Gansevoort, Amit X, Garg, Licia, Iacoviello, Takamasa, Kayama, Tsuneo, Konta, Csaba P, Kovesdy, James, Lash, Brian J, Lee, Rupert W, Major, Marie, Metzger, Katsuyuki, Miura, David M J, Naimark, Robert G, Nelson, Simon, Sawhney, Nikita, Stempniewicz, Mila, Tang, Raymond R, Townsend, Jamie P, Traynor, José M, Valdivielso, Jack, Wetzels, Kevan R, Polkinghorne, Hiddo J L, Heerspink, Aditya, Surapeneni, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Male, musculoskeletal diseases, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Urology, Renal function, Urine, Urinalysis, 01 natural sciences, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Diabetes mellitus, Internal Medicine, Medicine, Albuminuria, Humans, Mass Screening, 030212 general & internal medicine, 0101 mathematics, Stage (cooking), Renal Insufficiency, Chronic, skin and connective tissue diseases, Reagent Strips, Kidney, business.industry, 010102 general mathematics, General Medicine, Dipstick, Middle Aged, medicine.disease, Prognosis, 3. Good health, Proteinuria, medicine.anatomical_structure, Creatinine, Female, medicine.symptom, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business, Kidney disease
Abstract: BACKGROUND: Although measuring albuminuria is the preferred method for defining and staging chronic kidney disease (CKD), total urine protein or dipstick protein is often measured instead.OBJECTIVE: To develop equations for converting urine protein-creatinine ratio (PCR) and dipstick protein to urine albumin-creatinine ratio (ACR) and to test their diagnostic accuracy in CKD screening and staging.DESIGN: Individual participant-based meta-analysis.SETTING: 12 research and 21 clinical cohorts.PARTICIPANTS: 919 383 adults with same-day measures of ACR and PCR or dipstick protein.MEASUREMENTS: Equations to convert urine PCR and dipstick protein to ACR were developed and tested for purposes of CKD screening (ACR ≥30 mg/g) and staging (stage A2: ACR of 30 to 299 mg/g; stage A3: ACR ≥300 mg/g).RESULTS: Median ACR was 14 mg/g (25th to 75th percentile of cohorts, 5 to 25 mg/g). The association between PCR and ACR was inconsistent for PCR values less than 50 mg/g. For higher PCR values, the PCR conversion equations demonstrated moderate sensitivity (91%, 75%, and 87%) and specificity (87%, 89%, and 98%) for screening (ACR >30 mg/g) and classification into stages A2 and A3, respectively. Urine dipstick categories of trace or greater, trace to +, and ++ for screening for ACR values greater than 30 mg/g and classification into stages A2 and A3, respectively, had moderate sensitivity (62%, 36%, and 78%) and high specificity (88%, 88%, and 98%). For individual risk prediction, the estimated 2-year 4-variable kidney failure risk equation using predicted ACR from PCR had discrimination similar to that of using observed ACR.LIMITATION: Diverse methods of ACR and PCR quantification were used; measurements were not always performed in the same urine sample.CONCLUSION: Urine ACR is the preferred measure of albuminuria; however, if ACR is not available, predicted ACR from PCR or urine dipstick protein may help in CKD screening, staging, and prognosis.PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases and National Kidney Foundation.
Published: 2020
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43. P0789SERUM URIC ACID IS ASSOCIATED WITH CHRONIC KIDNEY DISEASE PROGRESSION AND MORTALITY: INSIGHTS FROM THE CKD-REIN COHORT

Author: Christian Combe, Karen Leffondré, Jérôme Harambat, Bénédicte Stengel, Céline Lange, Marie Metzger, Oriane Lambert, Ziad A. Massy, and Mathilde Prezelin-Reydit
Subjects: Nephrology, medicine.medical_specialty, medicine.medical_treatment, 030232 urology & nephrology, Urology, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Medicine, Renal replacement therapy, Hyperuricemia, Prospective cohort study, Transplantation, Creatinine, business.industry, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, chemistry, Uric acid, business, Kidney disease
Abstract: Background and Aims The association between hyperuricemia and CKD progression is not well established in Europe and, to our knowledge, has not yet been investigated using longitudinal measurements. Method We used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics, which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum uric acid or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All uric acid measures were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of uric acid and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline. In a sensitivity analysis, we further adjusted for individual eGFR trajectory. Results A total of 2781 patients (65.5% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median uric acid value was 425 µmol/L. During a median follow-up of 3.2 years, 434 patients received RRT and 264 died before RRT. At any time of follow-up, an increase of 100 µmol/l of the current value of uric acid was associated with a 16% increased hazard of RRT or death before RRT (aHR 1.16, 95% CI 1.07-1.26). The estimated effect of uric acid was similar with RRT (aHR 1.18, 95% CI 1.04-1.34) and death before RRT (aHR 1.16, 95% CI 1.05-1.28). When further adjusted for eGFR trajectory, the estimated effect of uric acid on the composite outcome was much weaker (aHR 1.06, 95% CI 0.98-1.16). Conclusion A higher current level of uric acid is associated with a strong increase in the hazard of RRT or death before RRT in European patients with CKD stage 3 to 5. However, the association is much weaker after adjustment for eGFR trajectory. Further analyses are necessary to better understand the dynamic of the association between uric acid and GFR.
Published: 2020
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44. MO072LONGITUDINAL SERUM BICARBONATE MEASUREMENTS AND RISK OF CHRONIC KIDNEY DISEASE PROGRESSION AND MORTALITY: INSIGHTS FROM THE CKD-REIN COHORT

Author: Céline Lange, Mathilde Prezelin-Reydit, Karen Leffondré, Oriane Lambert, Marie Metzger, Christian Combe, Bénédicte Stengel, Jérôme Harambat, and Ziad A. Massy
Subjects: Nephrology, medicine.medical_specialty, medicine.medical_treatment, 030232 urology & nephrology, 030204 cardiovascular system & hematology, urologic and male genital diseases, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Renal replacement therapy, 10. No inequality, Prospective cohort study, Transplantation, Creatinine, Proteinuria, business.industry, Metabolic acidosis, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, chemistry, Cohort, medicine.symptom, business, Kidney disease
Abstract: Background and Aims Metabolic acidosis is a common complication of CKD and may contribute to CKD progression. However, the association between serum bicarbonate and CKD progression has not yet been investigated using longitudinal measurements. Method We used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum bicarbonate or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All serum bicarbonate measurements were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of serum bicarbonate and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline. Results A total of 2977 patients (65.4% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median bicarbonate concentration was 25 mmol/L. During a median follow-up of 4.5 years, 615 patients received RRT and 378 died before RRT. At any time of follow-up, a decrease of 1 mmol/l of the current level of serum bicarbonate was associated with a significantly increased hazard of RRT or death before RRT (aHR 1.05, 95%CI 1.02-1.08). The estimated effect was stronger on death before RRT (aHR 1.05, 95% CI 1.00-1.09) than on RRT (aHR 1.02, 95% CI 0.99-1.06). Conclusion A lower current level of serum bicarbonate is associated with an increased mortality in patients with CKD stage 3 to 5.
Published: 2020
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45. Letter: how can we reduce mortality in elderly patients with acute severe ulcerative colitis? Authors' reply

Author: Catherine Dong, Marie Metzger, Einar E. Holsbø, Franck Carbonnel, Vittorio Perduca, Evolution, adaptation et comportement, Département écologie évolutive [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, MEDLINE, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Ulcerative colitis, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Humans, Colitis, Ulcerative, 030211 gastroenterology & hepatology, Pharmacology (medical), Colitis, business, Immunosuppressive Agents, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged
Abstract: International audience
Published: 2020
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46. Trajectory of extracellular fluid volume over time and subsequent risks of end-stage kidney disease and mortality in chronic kidney disease: a prospective cohort study

Author: Bénédicte Stengel, Pascal Houillier, A L Faucon, Karen Leffondré, Martin Flamant, C. Proust‐Lima, Jean-Jacques Boffa, Marie Metzger, Eric Thervet, François Vrtovsnik, Emmanuelle Vidal-Petiot, Jean-Philippe Haymann, Guillaume Geri, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Research Center, Inserm, Bordeaux, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Ministère des Affaires Sociales et de la Santé: AOM 09114 R0 8156LL Institut National de la Santé et de la Recherche Médicale, Inserm Roche, and The NephroTest CKD cohort study is supported by the following grants: INSERM GIS-IReSP AO 8113LS TGIR, French Ministry of Health AOM 09114, INSERM AO 8022LS, Agence de la Biom?decine R0 8156LL, AURA and Roche 2009-152-447G.
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Volume overload, Urology, Renal function, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, extracellular fluid volume, Extracellular fluid, Internal Medicine, medicine, Humans, Prospective Studies, Prospective cohort study, sodium, business.industry, Hazard ratio, Confounding, volume overload, joint modelling, Extracellular Fluid, Middle Aged, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, trajectory, Cohort, Disease Progression, Kidney Failure, Chronic, Female, business, chronic kidney disease, Kidney disease, Glomerular Filtration Rate
Abstract: International audience; Background: Extracellular fluid volume (ECF) is independently associated with chronic kidney disease (CKD) progression and mortality in patients with CKD, but the prognostic value of the trajectory of ECF over time beyond that of baseline value is unknown. Objectives: To characterize ECF trajectory and evaluate its association with the risks of end-stage kidney disease (ESKD) and mortality. Methods: From the prospective tricentric NephroTest cohort, we included 1588 patients with baseline measured glomerular filtration rate (mGFR) ≥15 mL min−1/1.73 m2 and ECF measurement. ECF and GFR were measured repeatedly using the distribution volume and clearance of 51Cr-EDTA, respectively. ESKD and mortality were traced through record linkage with the national registries. Adjusted shared random-effect joint models were used to analyse the association between the trajectory of ECF over time and the two competing outcomes. Results: Patients were mean age 58.7 years, 66.7% men, mean mGFR of 43.6 ± 18.6 mL min−1/1.73 m2 and mean ECF of 16.1 ± 3.6 L. Over a median follow-up of 5.3 [IQR: 3.0;7.4] years, ECF increased by 136 [95%CI 106;167] mL per year on average, whilst diuretic prescription and 24-hour urinary sodium excretion remained stable. ESKD occurred in 324 (20.4%) patients, and 185 (11.6%) patients died before ESKD. A higher current value of ECF was associated with increased hazards of ESKD (adjusted hazard ratio [aHR]: 1.12 [95%CI 1.06;1.18]; P
Published: 2020
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47. Impact of age on cardiovascular drug use in patients with chronic kidney disease

Author: Sophie Liabeuf, Marie Metzger, Christian Jacquelinet, Denis Fouque, Ronald L. Pisoni, Luc Frimat, Ziad A. Massy, Cédric Villain, Nicolas Mansencal, Maurice Laville, Serge Briançon, Christian Combe, Bénédicte Stengel, Épidémiologie et recherches translationnelles sur les maladies rénales et cardiovasculaires (EPREC) (U1018 (Équipe 5)), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], CHU Amiens-Picardie, Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie, Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Agence de la biomédecine [Saint-Denis la Plaine], Service de Néphrologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Arbor Research Collaborative for Health, Service de cardiologie et maladies vasculaires [CHU Ambroise Paré], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Vialaron, Sylvie
Subjects: medicine.medical_specialty, underuse, 030204 cardiovascular system & hematology, elderly, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antithrombotic, Medicine, atrial fibrillation, Stroke, Transplantation, business.industry, Atrial fibrillation, Odds ratio, Original Articles, medicine.disease, stroke, 3. Good health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Nephrology, Cardiovascular agent, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery, Fibrinolytic agent, chronic kidney disease, coronary artery disease, Kidney disease
Abstract: Background Elderly patients with chronic kidney disease (CKD) are often excluded from clinical trials; this may affect their use of essential drugs for cardiovascular complications. We sought to assess the impact of age on cardiovascular drug use in elderly patients with CKD. Methods We used baseline data from the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort including 3033 adult patients with CKD Stages 3 and 4. We studied the use of recommended drugs for coronary artery disease (CAD), stroke and atrial fibrillation by age, after adjusting for socio-demographic and clinical conditions. Results The patients’ mean age was 66.8 years (mean estimated glomerular filtration rate 32.9 mL/min/1.73 m2). The prevalence of CAD was 24.5% [81.3% receiving antiplatelet agents, 75.6% renin–angiotensin system (RAS) blockers, 65.4% β-blockers and 81.3% lipid-lowering therapy], that of stroke 10.0% (88.8% receiving antithrombotic drugs) and that of atrial fibrillation 11.1% (69.5% receiving oral anticoagulants). Compared with patients aged Conclusions In patients with CKD, older age per se was not associated with the underuse of antithrombotic drugs but was for other major drugs, with a potential impact on cardiovascular outcomes.
Published: 2020
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48. Adverse Drug Reactions in Patients with CKD

Author: Valérie Gras-Champel, Luc Frimat, Solène M. Laville, Marie Metzger, Ziad A. Massy, Maurice Laville, Christian Combe, Christian Jacquelinet, Julien Moragny, Sophie Liabeuf, Bruce M. Robinson, Bénédicte Stengel, Denis Fouque, Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Hôpital Paul Brousse, CHU Amiens-Picardie, Service de dermatologie [CHU d'Amiens-Picardie], Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Nutrition Humaine Rhône - Alpes, Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de néphrologie-hémodialyse-transplantation [CHRU Nancy], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Mécanismes physiologiques et conséquences des calcifications cardiovasculaires: rôle des remodelages cardiovasculaires et osseux, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Agence de la biomédecine [Saint-Denis la Plaine], Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Arbor Research Collaborative for Health, Service Néphrologie/Dialyse [AP-HP Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, LAVILLE, Solène, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Hôpital Paul Brousse, INSERM U1026 (INSERM, U1026), Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour l'Utilisation du Rein Artificiel Région Lyonnaise (AURAL), Centre Hospitalier Universitaire Ambroise Paré (CHU Ambroise Paré), and Université de Picardie Jules Verne (UPJV)
Subjects: medicine.medical_specialty, pharmacoepidemiology, Drug-Related Side Effects and Adverse Reactions, Epidemiology, [SDV]Life Sciences [q-bio], adverse drug reaction, 030232 urology & nephrology, Critical Care and Intensive Care Medicine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Medical Records, Cohort Studies, Renin-Angiotensin System, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, Humans, Medicine, risk factors, 030212 general & internal medicine, Renal Insufficiency, Renal Insufficiency, Chronic, Chronic, Transplantation, glomerular filtration rate, adverse drug reactions, business.industry, Incidence (epidemiology), renin-angiotensin system inhibitors, Original Articles, Pharmacoepidemiology, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, antithrombotic agents, diuretics, 3. Good health, Clinical trial, Pharmaceutical Preparations, Nephrology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cohort, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Adverse drug reaction, chronic kidney disease, Cohort study, hospitalization
Abstract: International audience; BACKGROUND AND OBJECTIVES: Little is known about the burden of adverse drug reactions in CKD. We estimated the incidence of overall and serious adverse drug reactions and assessed the probability of causation, preventability, and factors associated with adverse drug reactions in patients seen by nephrologists. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Chronic Kidney Disease-Renal Epidemiology and Information Network cohort included 3033 outpatients (65% men) with CKD and eGFR\textless60 ml/min per 1.73 m(2), with follow-up for 2 years. Adverse drug reactions were identified from hospitalization reports, medical records, and participant interviews and finally assessed for causality, preventability, and immediate therapeutic management by experts in pharmacology. RESULTS: Median (interquartile range) age was 69 (60-76) years old; 55% had eGFR≥30 ml/min per 1.73 m(2), and 45% had eGFR\textless30 ml/min per 1.73 m(2). Participants were prescribed a median (range) of eight (five to ten) drugs. Over 2 years, 536 patients had 751 adverse drug reactions, 150 (in 125 participants) classified as serious, for rates of 14.4 (95% confidence interval, 12.6 to 16.5) and 2.7 (95% confidence interval, 1.7 to 4.3) per 100 person-years, respectively. Among the serious adverse drug reactions, 32% were considered preventable or potentially preventable; 16 caused death, directly or indirectly. Renin-angiotensin system inhibitors (15%), antithrombotic agents (14%), and diuretics (10%) were the drugs to which the most adverse drug reactions were imputed, but antithrombotic agents caused 34% of serious adverse drug reactions. The drug was discontinued in 71% of cases, at least temporarily. Adjusted hazard ratios for serious adverse drug reaction were significantly higher in patients with eGFR\textless30 versus ≥30 ml/min per 1.73 m(2) (1.8; 95% confidence interval, 1.3 to 2.6), in those prescribed more than ten versus less than five medications (2.4; 95% confidence interval, 1.1 to 5.2), or in those with poor versus good adherence (1.6; 95% confidence interval, 1.4 to 2.4). CONCLUSIONS: Adverse drug reactions are common and sometimes serious in patients with CKD. Many serious adverse drug reactions may be preventable. Some specific pharmacologic classes, particularly antithrombotic agents, are at risk of serious adverse drug reactions. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN), NCT03381950.
Published: 2020
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49. Adverse outcomes of proton pump inhibitors in patients with chronic kidney disease: The CKD-REIN cohort study

Author: Sophie Liabeuf, Solène M Laville, Roberto Pecoits-Filho, Marie Metzger, Chronic Kidney Disease-Renal Epidemiology, Ziad A. Massy, Luc Frimat, Denis Fouque, Bénédicte Stengel, Maurice Laville, Oriane Lambert, Christian Jacquelinet, Aghilès Hamroun, CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Adaptation, mesure et évaluation en santé. Approches interdisciplinaires (APEMAC), Université de Lorraine (UL), Arbor Research Collaborative for Health, Université de Lyon, Agence de la biomédecine [Saint-Denis la Plaine], Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Chronic Kidney Disease - Réseau Epidémiologie et Information en Néphrologie (CKD REIN), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and CarMeN, laboratoire
Subjects: Male, Nephrology, medicine.medical_specialty, pharmacoepidemiology, renal risk, [SDV]Life Sciences [q-bio], Population, 030226 pharmacology & pharmacy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Interquartile range, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Renal Insufficiency, Chronic, education, Pharmacology, education.field_of_study, business.industry, Hazard ratio, Acute kidney injury, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], acute kidney injury, Cohort, Kidney Failure, Chronic, Female, proton pump inhibitors, business, chronic kidney disease, Glomerular Filtration Rate, Cohort study, Kidney disease
Abstract: International audience; AIMS: Long-term use of proton pump inhibitors (PPIs) has been associated with adverse kidney events in the general population, but their impact among chronic kidney disease (CKD) patients is unclear. We studied the prevalence and incidence (new users) of PPI prescriptions and their relation to kidney outcomes and mortality in CKD patients. METHODS: We collected drug prescriptions prospectively in a cohort of 3023 nephrology outpatients with CKD stages 2-5 at inclusion. Hazard ratios (HR, 95% confidence intervals [95% CI]) for acute kidney injury (AKI), end-stage kidney disease (ESKD), and mortality associated with new PPI prescriptions as a time-dependent variable were estimated with cause-specific Cox models in 1940 non-users with eGFR ≥ 15 mL/min/1.73 m(2) at baseline, adjusted for comorbidities, laboratory data and drugs. RESULTS: There were 981/3023 (32%) prevalent users (67 ± 13 years, 65% men) at baseline, and 366/3023 (12%) were prescribed PPI (new users) over a median follow-up of 3.9 years (interquartile range, 3-4.2). Among these new users, their median cumulative duration of prescription was 1 year (interquartile range: 0.4-2.3). During follow-up, 354 patients developed ESKD and 216 died before ESKD. The adjusted HRs associated with PPI prescription were 1.74 (95% CI, 1.26-2.40) for ESKD and 2.42 (95% CI, 1.73-3.39) for all-cause mortality. Over the first 3 years of follow-up, 211 AKI events had occurred. The adjusted HR for AKI associated with PPI prescription was 2.89 (95% CI, 1.91-4.38). CONCLUSIONS: Long-term PPI prescription was common in CKD patients. Our results call attention to its potential risks of both acute and chronic kidney failure.
Published: 2020
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50. A Predictive Model for Progression of CKD to Kidney Failure Based on Routine Laboratory Tests

Author: Philip A. Kalra, Peter J. Oefner, Anna Köttgen, Sahar Ghasemi, Peggy Sekula, Helena U. Zacharias, Ulla T. Schultheiss, Ibrahim Ali, Bénédicte Stengel, Kai-Uwe Eckardt, Johannes Raffler, Michael Altenbuchinger, Marie Metzger, Wolfram Gronwald, Florian Kronenberg, Matthias Schmid, Ziad A. Massy, Christian Combe, Fruzsina Kotsis, Inga Steinbrenner, Barbara Kollerits, Bioingénierie tissulaire (BIOTIS), and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: German Chronic Kidney Disease Study, Chronic Kidney Disease, Kidney Failure Requiring Kidney Replacement Therapy, Machine Learning, Risk Equation, medicine.medical_specialty, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, end-stage kidney disease (ESKD), kidney failure risk equation, CKD progression, Concordance, 030232 urology & nephrology, Chronic kidney disease (CKD), kidney disease trajectory, kidney failure requiring kidney replacement therapy (KFRT), German Chronic Kidney Disease study, risk equation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Renal Insufficiency, 030212 general & internal medicine, Renal Insufficiency, Chronic, Creatinine, Framingham Risk Score, Proportional hazards model, business.industry, medicine.disease, machine learning, chemistry, Nephrology, Cohort, Disease Progression, Kidney Failure, Chronic, Observational study, business, Glomerular Filtration Rate, Cohort study, Kidney disease
Abstract: RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort was comprised of 4,915 CKD patients and three independent validation cohorts were comprised of a total of 3,063. Patients were followed-up for approximately five years. NEW PREDICTORS & ESTABLISHED PREDICTORS: 22 demographic, anthropometric and laboratory variables commonly assessed in CKD patients. OUTCOMES: Progression to ESKD requiring KRT. ANALYTICAL APPROACH: A Least Absolute Shrinkage and Selection Operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for ESKD. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation. Both used a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable (Z6) risk score included serum creatinine, albumin, cystatin C and urea, as well as hemoglobin and the urine albumin-to-creatinine ratio. Based on the resampling approach, Z6 achieved a median C value of 0.909 (95% CI, 0.868-0.937) at two years after the baseline visit, whereas the T4 achieved a median C value of 0.855 (95% CI, 0.799-0.915). In the three independent validation cohorts, Z6 C values were 0.894, 0.921, and 0.891, whereas the T4 C values were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation, based on six routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to ESKD.
Published: 2022
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