Bénédicte Stengel

Université Paris-Saclay, Lutetia Parisorum, Île-de-France, France

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Publications (144)657.18 Total impact

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    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/1.73m² 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/1.73m² 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/1.73m² 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.
    Preview · Article · Jan 2016 · PLoS ONE
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    ABSTRACT: Importance Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed.Objective To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis.Data Sources Thirty-one cohorts, including 721 357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014.Study Selection Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease.Data Extraction and Synthesis Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed.Main Outcomes and Measures Kidney failure (treatment by dialysis or kidney transplant).Results During a median follow-up of 4 years of 721 357 participants with CKD, 23 829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02).Conclusions and Relevance Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.
    No preview · Article · Jan 2016 · JAMA The Journal of the American Medical Association
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    ABSTRACT: CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR<60 ml/min per 1.73 m(2), as calculated by the CKD-Epidemiology Collaboration equation, or albuminuria >30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2). CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% CI, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.
    Full-text · Article · Dec 2015 · Journal of the American Society of Nephrology
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    ABSTRACT: eGFR is a robust predictor of ESRD risk. However, the prognostic information gained from the past trajectory (slope) beyond that of the current eGFR is unclear. We examined 22 cohorts to determine the association of past slopes and current eGFR level with subsequent ESRD. We modeled hazard ratios as a spline function of slopes, adjusting for demographic variables, eGFR, and comorbidities. We used random effects meta-analyses to combine results across studies stratified by cohort type. We calculated the absolute risk of ESRD at 5 years after the last eGFR using the weighted average baseline risk. Overall, 1,080,223 participants experienced 5163 ESRD events during a mean follow-up of 2.0 years. In CKD cohorts, a slope of -6 versus 0 ml/min per 1.73 m(2) per year over the previous 3 years (a decline of 18 ml/min per 1.73 m(2) versus no decline) associated with an adjusted hazard ratio of ESRD of 2.28 (95% confidence interval, 1.88 to 2.76). In contrast, a current eGFR of 30 versus 50 ml/min per 1.73 m(2) (a difference of 20 ml/min per 1.73 m(2)) associated with an adjusted hazard ratio of 19.9 (95% confidence interval, 13.6 to 29.1). Past decline contributed more to the absolute risk of ESRD at lower than higher levels of current eGFR. In conclusion, during a follow-up of 2 years, current eGFR associates more strongly with future ESRD risk than the magnitude of past eGFR decline, but both contribute substantially to the risk of ESRD, especially at eGFR<30 ml/min per 1.73 m(2).
    No preview · Article · Dec 2015 · Journal of the American Society of Nephrology
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    ABSTRACT: While sleep disturbances are frequent in renal disease patients, no studies have examined prospectively the associations between sleep disturbances and kidney function decline in community-dwelling elderly subjects.Glomerular filtration rates (eGFRs) were estimated at baseline and at 11-year follow-up. A glomerular filtration decline over the follow-up period was defined as a percentage decline greater than or equal to the cut-off value of the highest tertile of kidney function decline (22%) in 1105 subjects. Excessive daytime sleepiness (EDS) and insomnia complaints were self-rated at baseline. Restless legs syndrome (RLS) and its age at onset were assessed at study end-point. An ambulatory polysomnography recording was performed during the follow-up in 277 subjects. Apnoea-hypopnoea index (AHI), periodic limb movements during sleep (PLMS) and total sleep time were analysed.An increased risk of eGFR decline was associated with EDS (OR 1.67, 95% CI 1.18-2.34) and RLS (OR 1.98, 95% CI 1.18-3.30) independently of potential confounders including cardiovascular risk factors. Among insomnia complaints, a borderline association with eGFR decline was found for early morning awakening only. High AHI (≥30 events·h(-1)) and short total sleep time (<6 h), but not PLMS were linked to eGFR decline in crude associations, but only AHI remained significantly associated after multi-adjustments.EDS, RLS and AHI constitute independent risk factors for kidney glomerular function decline.
    No preview · Article · Dec 2015 · European Respiratory Journal
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    ABSTRACT: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.
    Full-text · Article · Dec 2015 · Diabetes
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    ABSTRACT: Background: Recent randomized trials report that mortality is lower with high-convection-volume hemodiafiltration (HDF) than with hemodialysis (HD). Study design: We used data from the French national Renal Epidemiology and Information Network (REIN) registry to investigate trends in HDF use and its relationship with mortality in the total population of incident dialysis patients. Setting & participants: The study included those who initiated HD therapy from January 1, 2008, through December 31, 2011, and were dialyzed for more than 3 months; follow-up extended to the end of 2012. Factor: HDF use at the patient and facility level. Outcomes: All-cause and cardiovascular mortality, using Cox models to estimate HRs of HDF as time-dependent covariate at the patient level, with age as time scale and fully adjusted for comorbid conditions and laboratory data at baseline, catheter use, and facility type as time-dependent covariates. Analyses completed by Cox models for HRs of the facility-level exposure to HDF updated yearly. Results: Of 28,407 HD patients, 5,526 used HDF for a median of 1.2 (IQR, 0.9-1.9) years; 2,254 of them used HDF exclusively. HRs for all-cause and cardiovascular mortality associated with HDF use were 0.84 (95% CI, 0.77-0.91) and 0.73 (95% CI, 0.61-0.88), respectively. In patients treated exclusively with HDF, these HRs were 0.77 (95% CI, 0.67-0.87) and 0.66 (95% CI, 0.50-0.86). At the facility level, increasing the percentage of patients using HDF from 0% to 100% was associated with HRs for all-cause and cardiovascular mortality of 0.87 (95% CI, 0.77-0.99) and 0.72 (95% CI, 0.54-0.96), respectively. Limitations: Observational study. Conclusions: Whether analyzed as a patient- or facility-level predictor, HDF treatment was associated with better survival.
    No preview · Article · Dec 2015 · American Journal of Kidney Diseases
  • Jean-Marc Chillon · Ziad A. Massy · Bénédicte Stengel
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    ABSTRACT: Chronic kidney disease (CKD) is associated with a high prevalence of cerebrovascular disorders such as stroke, white matter diseases, intracerebral microbleeds and cognitive impairment. This situation has been observed not only in end-stage renal disease patients but also in patients with mild or moderate CKD. The occurrence of cerebrovascular disorders may be linked to the presence of traditional and non-traditional cardiovascular risk factors in CKD. Here, we review current knowledge on the epidemiological aspects of CKD-associated neurological and cognitive disorders and discuss putative causes and potential treatment. CKD is associated with traditional (hypertension, hypercholesterolaemia, diabetes etc.) and non-traditional cardiovascular risk factors such as elevated levels of oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anaemia and uraemic toxins. Clinical and animal studies indicate that these factors may modify the incidence and/or outcomes of stroke and are associated with white matter diseases and cognitive impairment. However, direct evidence in CKD patients is still lacking. A better understanding of the factors responsible for the elevated prevalence of cerebrovascular diseases in CKD patients may facilitate the development of novel treatments. Very few clinical trials have actually been performed in CKD patients, and the impact of certain treatments is subject to debate. Treatments that lower LDL cholesterol or blood pressure may reduce the incidence of cerebrovascular diseases in CKD patients, whereas treatment with erythropoiesis-stimulating agents may be associated with an increased risk of stroke but a decreased risk of cognitive disorders. The impact of therapeutic approaches that reduce levels of uraemic toxins has yet to be evaluated.
    No preview · Article · Sep 2015 · Nephrology Dialysis Transplantation

  • No preview · Article · Sep 2015
  • J. Kaboré · M. Metzger · C. Helmer · Z.A. Massy · B. Stengel

    No preview · Article · Sep 2015

  • No preview · Article · Sep 2015
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    ABSTRACT: Background Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods. Methods For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers. Results We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m2 in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval. Conclusions The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.
    Full-text · Article · Aug 2015 · Nephrology Dialysis Transplantation
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    ABSTRACT: Acetate-free dialysis (AFD) improves haemodynamic stability during dialysis, compared with standard haemodialysis (HD) with a small amount of acetic acid. Using the national REIN registry, we classified 15 160 incident patients who started HD from 2008 to 2010 into three exposure categories according to the type of dialysate used in their dialysis unit: standard dialysate only (reference), both standard and AFD (mixed unit) or HCl dialysate only (100% HCl unit). Cox survival analysis was adjusted for 15 baseline comorbidities, laboratory data and haemodiafiltration (HDF). We took patient clustering within units into account, used age as the time scale and treated patient exposure to AFD and to HDF as time-dependent variables. Median age (interquartile range) was 70.5 years (58.1-78.8). Over a median follow-up of 1.8 years (1.2-2.6), 658 patients were dialysed in a 100% HCl unit, 3021 in a mixed unit and 11 481 were never exposed to AFD. The relation between AFD and mortality was not constant with age (Schoenfeld residuals test P = 0.01 for mixed group and P = 0.03 for 100%HCl group). Patients older than 70 years had a significantly lower mortality risk associated with AFD [hazard ratio (HR) = 0.79, 95% confidence interval (CI) = 0.67 to 0.94 for patients exposed in a 100% HCl unit; HR = 0.83, 95% CI = 0.74 to 0.94 for patients exposed in a mixed unit], but no association was found in younger patients. AFD was associated with improved survival independent of comorbidities and HDF in patients aged 70 years and older but not in patient younger than 70 years. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    No preview · Article · Jun 2015 · Nephrology Dialysis Transplantation
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    ABSTRACT: Glycated hemoglobin (HbA1c) is used to diagnose diabetes mellitus (DM) and guide its management. The association between higher HbA1c and progression to ESRD and mortality has been demonstrated in populations with DM. This study examined the association between HbA1c and these end points in a population with CKD and without DM. In the hospital-based NephroTest cohort study, measured GFR (mGFR) was taken by (51)Cr-EDTA renal clearance and HbA1c in 1165 adults with nondialysis CKD stages 1-5 and without DM between January 2000 and December 2010. The median follow-up was 3.48 years (interquartile range, 1.94-5.82) for the competing events of ESRD and pre-ESRD mortality. Time-fixed and time-dependent Cox models were used to estimate hazard ratios (HRs) for ESRD and mortality according to HbA1c, treated continuously or in tertiles. At inclusion, the mean mGFR was 42.2±19.9 ml/min per 1.73 m(2), and the mean HbA1c value was 5.5%±0.5%. During follow-up, 109 patients died, and 162 patients reached ESRD. Pre-ESRD mortality was significantly associated with HbA1c treated continuously: for every 1% higher HbA1c, the crude HR was 2.16 (95% confidence interval [95% CI], 1.27 to 3.68), and it was 1.85 (95% CI, 1.05 to 3.24) after adjustment for mGFR and other risk factors of death. After excluding incident diabetes over time, the updated mean of HbA1c remained significantly associated with higher mortality risk: adjusted HR for the highest (5.7%-6.4%) versus the lowest tertile (<5.3%) was 2.62 (95% CI, 1.16 to 5.91). There was no association with ESRD risk after adjustment for risk factors of CKD progression. In a CKD cohort, HbA1c values in the prediabetes range are associated with mortality. Such values should be therefore included among the risk factors for negative outcomes in CKD populations. Copyright © 2015 by the American Society of Nephrology.
    No preview · Article · May 2015 · Clinical Journal of the American Society of Nephrology
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    ABSTRACT: Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white). Collaborative meta-analysis. 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Available eGFR, ACR, and 50 or more AKI events. Age, sex, race, eGFR, urine ACR, and interactions. Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code. Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    No preview · Article · May 2015 · American Journal of Kidney Diseases
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    ABSTRACT: Muscle wasting predicts mortality in patients with end-stage renal disease (ESRD), but its role in the progression of chronic kidney disease (CKD) is uncertain. We studied CKD outcomes associated with low muscle mass, assessed by urinary creatinine excretion (UCr). The NephroTest cohort included 1429 patients with CKD stages 1-4 and both measured glomerular filtration rate (mGFR) (by (51)Cr-EDTA) and estimated glomerular filtration rate (eGFR) (by CKD-Epidemiology Collaboration equation). We used cause-specific Cox models to estimate hazard ratios (HRs) for the competing risks of ESRD and death associated with gender-specific UCr quartiles. UCr was 13.6 ± 3.2 mmol/24 h (0.17 ± 0.05 mmol/kg/24 h) in men and 9.2 ± 2.1 (0.14 ± 0.05) in women. It was positively associated with mGFR, but not with eGFR. Over a median follow-up of 3.6 (2.1-5.8) years, 229 patients developed ESRD and 113 patients died before ESRD. Compared with patients in the highest UCr quartile, those in the lowest quartile had a higher crude HR (95% confidence interval) for pre-ESRD death: 4.3 (2.4-7.7), which was weakened, but remained statistically significant, independent of demographics, mGFR and several other factors: 2.1 (1.04-4.3). Their crude ESRD risk was not higher: HR: 0.95 (0.65-1.4), and even tended to be lower after adjusting for mGFR and log-proteinuria: HR: 0.70 (0.45-1.1). Adjustment for eGFR instead of mGFR reversed this relationship: HR: 1.7 (1.1-2.7). In early stage CKD, low UCr is associated with higher risk for mortality, but not for ESRD. Using creatinine-based equation to adjust for GFR may bias the relationship of UCr with ESRD risk. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    No preview · Article · Mar 2015 · Nephrology Dialysis Transplantation
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    ABSTRACT: Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1-4. All patients had measured glomerular filtration rate (mGFR) by (51)Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m(2). Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06-3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98-3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes.Kidney International advance online publication, 11 March 2015; doi:10.1038/ki.2015.52.
    No preview · Article · Mar 2015 · Kidney International
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    ABSTRACT: In 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. This 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 (GFR<15 mL/min/1.73 m2, n = 282 observed) and death (n = 168). For 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. This 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.
    Full-text · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.Kidney International advance online publication, 10 December 2014; doi:10.1038/ki.2014.361.
    Full-text · Article · Dec 2014 · Kidney International
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    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 51Cr-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 <15 mL/min/1.73 m2, and from 9.6±1.9 to 7.6±2.5 (0.16±0.03 to 0.12±0.03) in women. In addition to mGFR, an older age, diabetes, and lower levels of body mass index, proteinuria, and protein intake assessed by urinary urea were associated with lower mean urinary creatinine excretion at baseline. Mean annual decline in mGFR was 1.53±0.12 mL/min/1.73 m2 per year and that of urinary creatinine excretion rate, 0.28±0.02 mmol/24 h per year. Patients with fast annual decline in mGFR of 5 mL/min/1.73 m2 had a decrease in urinary creatinine excretion more than twice as big as in those with stable mGFR, independent of changes in urinary urea as well as of other determinants of low muscle mass. Conclusions Decrease in 24-hour urinary creatinine excretion rate may appear early in CKD patients, and is greater the more mGFR declines independent of lowering protein intake assessed by 24-hour urinary urea. Normalizing urine analytes for creatininuria may overestimate their concentration in patients with reduced kidney function and low muscle mass.
    Full-text · Article · Nov 2014 · PLoS ONE

Publication Stats

3k Citations
657.18 Total Impact Points


  • 2016
    • Université Paris-Saclay
      Lutetia Parisorum, Île-de-France, France
  • 2015
    • Université de Versailles Saint-Quentin
      Versailles, Île-de-France, France
  • 2008-2015
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 1990-2015
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2014
    • Université du Droit et de la Santé Lille 2
      Lille, Nord-Pas-de-Calais, France
  • 1998-2014
    • French Institute of Health and Medical Research
      • Center for Research in Epidemiology and Population Health CESP
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Hôpital Paul-Brousse – Hôpitaux universitaires Paris-Sud
      Villejuif, Île-de-France, France
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
  • 2012
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • University of Bordeaux
      Burdeos, Aquitaine, France
  • 2009
      Lutetia Parisorum, Île-de-France, France
  • 2006
    • INRS
      Lutetia Parisorum, Île-de-France, France