Publications by authors named "Marie Metzger"

64 Publications

Water intake and progression of chronic kidney disease: the CKD-REIN cohort study.

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

CESP (Centre de recherche en Epidémiologie et Santé des Populations), INSERM U1018, Université Paris-Saclay, Université Versailles Saint Quentin, Villejuif, France.

Background: Optimal daily water intake to prevent chronic kidney disease (CKD) progression is unknown. Taking kidney 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 per 1.73 m2) from the CKD-REIN cohort (2013-2019), 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 (interquartile range: 1.6-2.6) L total water and 1.5 (1-1.7) L plain water; median urine volume was 1.9 (1.6-2.4) L/24 h, and mean eUosm, 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 below 292 mosm/L. Adjusted HRs for kidney failure associated with plain water intake were 1.88 (95%CI 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 <0.5, 0.6-1.0, 1.6-2.0, and >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.

Conclusion: 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.
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http://dx.doi.org/10.1093/ndt/gfab036DOI Listing
February 2021

Adverse outcomes of proton pump inhibitors in patients with chronic kidney disease: The CKD-REIN cohort study.

Br J Clin Pharmacol 2020 Dec 23. Epub 2020 Dec 23.

Centre for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Paris Sud University, Versailles Saint Quentin University, INSERM, France.

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 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.
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http://dx.doi.org/10.1111/bcp.14713DOI Listing
December 2020

Urinary Sodium-to-Potassium Ratio and Blood Pressure in CKD.

Kidney Int Rep 2020 Aug 2;5(8):1240-1250. Epub 2020 Jun 2.

University Paris-Saclay, UVSQ, University Paris-Sud, Inserm, Clinical Epidemiology team, CESP, Villejuif, France.

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.
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http://dx.doi.org/10.1016/j.ekir.2020.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403539PMC
August 2020

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.

Ann Intern Med 2020 09 14;173(6):426-435. Epub 2020 Jul 14.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (R.R.T.).

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.
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http://dx.doi.org/10.7326/M20-0529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780415PMC
September 2020

Effects of the dialysate calcium concentrations and mineral bone disease treatments on mortality in The French Renal Epidemiology and Information Network (REIN) registry.

PLoS One 2020 6;15(7):e0235135. Epub 2020 Jul 6.

CESP, Centre for Research in Epidemiology and Population Health, Univ Paris-Saclay, Univ Paris Sud, UVSQ, INSERM UMRS, Villejuif, France.

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 <1.5 mmol/l by center and the number of formula used per center were not associated with survival. Depending on the daily dose used, the MBD therapies were associated with survival improvement for calcium, native vitamin D, active vitamin D, sevelamer, lanthanum and cinacalcet in the second and third tertiles of dose.

Conclusion: No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235135PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337343PMC
September 2020

Adverse Drug Reactions in Patients with CKD.

Clin J Am Soc Nephrol 2020 Aug 1;15(8):1090-1102. Epub 2020 Jul 1.

Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.

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<60 ml/min per 1.73 m, 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, and 45% had eGFR<30 ml/min per 1.73 m. 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<30 versus ≥30 ml/min per 1.73 m (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.
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http://dx.doi.org/10.2215/CJN.01030120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409761PMC
August 2020

Prescription patterns of dialysate potassium and potassium binders and survival on haemodialysis-the French Renal Epidemiology and Information Network registry.

Nephrol Dial Transplant 2021 01;36(1):151-159

CESP, Centre for Research in Epidemiology and Population Health, Inserm UMRS 1018, Université Paris-Saclay, Villejuif, France.

Background: Management of potassium disorders in patients on haemodialysis (HD) is complex. We studied prescription patterns of dialysate potassium and potassium binders, and their associations with patient survival.

Methods: This national registry-based study included 25 629 incident adult patients alive after 3 months of HD from 2010 through 2013 and followed-up through 31 December 2014. We used Cox proportional hazard models to estimate multiadjusted mortality hazard ratios (HRs) associated with time-dependent exposure to facility-level dialysate potassium concentrations and patient-level potassium binder exposure.

Results: Almost all dialysis units used, and generally most often, dialysate potassium concentrations of 2 mmol/L. During this period, use of concentrations <2 mmol/L tended to decrease and those ≥3 mmol/L to increase. In 2014, 9% of units used a single dialysate formula, 41% used two and 50% three or more. The most frequent combinations were 2 and 3 mmol/L (40%), and <2, 2 and 3 mmol/L (37%). Compared with patients on HD in units using only one dialysate formula, those in units using two or three had adjusted mortality HRs of 0.91 [95% confidence interval (CI) 0.82-1.01] and 0.84 (0.75-0.93), respectively. Potassium binders were prescribed for 37% of all patients at baseline. Adjusted mortality HRs associated with doses <4, 4-8 and ≥8 g/day versus none were 1.22 (95% CI 1.04-1.51), 0.6 (0.54-0.66) and 0.25 (0.24-0.33), respectively.

Conclusions: Diversity in facility-level use of dialysate potassium concentrations and potassium binder use at an appropriate dose appear to be associated with better survival in HD patients.
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http://dx.doi.org/10.1093/ndt/gfaa077DOI Listing
January 2021

Letter: how can we reduce mortality in elderly patients with acute severe ulcerative colitis? Authors' reply.

Aliment Pharmacol Ther 2020 06;51(12):1445-1446

Department of Gastroenterology, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris Saclay, Le Kremlin-Bicêtre, France.

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http://dx.doi.org/10.1111/apt.15776DOI Listing
June 2020

Impact of age on cardiovascular drug use in patients with chronic kidney disease.

Clin Kidney J 2020 Apr 10;13(2):199-207. Epub 2019 Jun 10.

Service de Néphrologie-Dialyse, CHU Ambroise Paré, APHP, Boulogne-Billancourt, France.

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 m). 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 <65 years, older age (≥65 years) was associated with greater use of antithrombotic drugs in stroke [adjusted odds ratio (aOR) (95% confidence interval) = 2.83 (1.04-7.73) for patients aged (75-84 years)] and less use of RAS blockers [aOR = 0.39 (0.16-0.89) for patients aged ≥85 years], β-blockers [aOR = 0.31 (0.19-0.53) for patients aged 75-84 years] and lipid-lowering therapy [aOR = 0.39 (0.15-1.02) for patients aged ≥85 years, P for trend = 0.01] in CAD. Older age was not associated with less use of antiplatelet agents in CAD or oral anticoagulants in atrial fibrillation.

Conclusions: In patients with CKD, older age was not associated with the underuse of antithrombotic drugs but was for other major drugs, with a potential impact on cardiovascular outcomes.
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http://dx.doi.org/10.1093/ckj/sfz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147308PMC
April 2020

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

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

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

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

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

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

Conclusion: Beyond 1 year after transplantation, KTRs, who possibly had a longer CKD history, had a significantly greater mortality risk than eGFR-matched CKDps. The excess risk was not associated with CV events.
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http://dx.doi.org/10.1093/ndt/gfaa026DOI Listing
January 2021

Systematic review with meta-analysis: mortality in acute severe ulcerative colitis.

Aliment Pharmacol Ther 2020 01 10;51(1):8-33. Epub 2019 Dec 10.

Hôpital de Bicêtre, Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris and Université Paris Saclay, Le Kremlin-Bicêtre, France.

Background: Acute severe ulcerative colitis (ASUC) is a life-threatening condition. Mortality in ASUC decreased in published series but there is uncertainty as to whether this also applies to the real-life setting.

Aim: To perform a systematic review and meta-analysis of mortality in ASUC in studies from referral centres and in population-based studies, separately and combined. A second aim was to identify risk factors of mortality in ASUC.

Methods: We searched pubmed and embase from 1998 to 2016, to identify studies that reported 3-month or 12-month mortalities of acute UC in adult patients treated in referral centres, and in population-based studies.

Results: Six population-based studies with 741 743 patients and 47 referral centre-based studies with 2556 patients were included. The pooled 3-month and 12-month mortalities were respectively 0.84% and 1.01%. Advanced age was significantly associated with both 3 month and 12 month mortalities (OR = 1.15 per year, 95% CI: 1.10-1.20 and OR = 1.19 per year, 95% CI: 1.15-1.23 respectively). The pooled 3-month and 12-month mortalities were 0.78% and 0.85% in studies with median age of less than 50 and 2.81% and 4.17% in studies with median age of 50 or more, respectively. After adjustment for age, 3-month and 12-month mortalities did not differ between population-based and referral centre-based studies.

Conclusions: Mortality in acute severe ulcerative colitis is approximately 1%; it is higher in older patients. Efforts should be made to improve the care of elderly patients with severe UC.
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http://dx.doi.org/10.1111/apt.15592DOI Listing
January 2020

International variation in the management of mineral bone disorder in patients with chronic kidney disease: Results from CKDopps.

Bone 2019 12 4;129:115058. Epub 2019 Sep 4.

Centre for Research in Epidemiology and Population Health (CESP), UMRS 1018, UVSQ, University Paris-Saclay, Villejuif, France; Department of Nephrology, Ambroise Paré University Hospital, APHP, Boulogne Billancourt/Paris, France. Electronic address:

Background And Objectives: Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3-5 CKD patients.

Design, Setting, Participants, And Measurements: Prospective cohort study of 7658 adult patients with eGFR <60mL/min/1.73m, excluding dialysis or transplant patients, participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, Germany, and the US. CKD-MBD laboratory markers included serum levels of phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25-D). MBD treatment data included phosphate binders and vitamin D (nutritional and active). Nephrologist survey data were collected on target MBD marker levels.

Results: Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60-20mL/min/1.73m and more sharply for eGFR<20. 25-D showed no relation to eGFR. Nephrologist survey data indicated marked variation in upper target P and iPTH levels. Among patients with P>5.5mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%-51%, and use of any (active or nutritional) vitamin D was 60%-87%.

Conclusions: Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.
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http://dx.doi.org/10.1016/j.bone.2019.115058DOI Listing
December 2019

Extracellular fluid volume is associated with incident end-stage kidney disease and mortality in patients with chronic kidney disease.

Kidney Int 2019 10 16;96(4):1020-1029. Epub 2019 Jul 16.

Université de Paris, Paris, France; Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; INSERM U1149, Centre de recherche sur l'inflammation, Paris, France. Electronic address:

Volume overload has been shown to be an independent risk factor for mortality in patients receiving chronic dialysis, but data in non-dialysis patients are scarce. Therefore we evaluated the prognostic value of extracellular fluid (ECF) volume for chronic kidney disease (CKD) progression and mortality in a prospective hospital-based cohort with CKD stage 1-4 (NephroTest Study). ECF (scaled to body surface area) and the measured glomerular filtration rate (mGFR) were determined using the distribution volume and clearance of 51Cr-EDTA, respectively. Cause-specific Cox and linear mixed-effect regression models were used to analyze the association of ECF with end-stage kidney disease (ESKD) and mortality, and with mGFR decline, respectively. The 1593 patients were mean age 58.8 years, 67% were men, mean mGFR of 43.6 mL/min/1.73m and mean ECF 15.1 L/1.73m. After a median follow-up of 5.3 years, ESKD occurred in 324 patients and 185 patients died before ESKD. In multivariable analysis, ECF was significantly associated with the risk of ESKD (hazard ratio per 1L/1.73m increase: 1.14; 95% confidence interval [1.07; 1.21]) and with a faster GFR decline (adjusted mean difference in mGFR slope per 1L/1.73m increase -0.14 [-0.23; -0.05] mL/min/year). The relationship of ECF with mortality was non-linear and not significant (per 1L/1.73m increase 0.92, [0.73; 1.16]), below 15L/1.73m, but significant (1.28; [1.14-1.45]) above 15L/1.73m. Thus, in this large cohort of carefully phenotyped patients with CKD, ECF was an independent risk factor of CKD progression and mortality. Hence, close monitoring and treatment of fluid overload are important for the clinical management of patients with non-dialysis CKD.
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http://dx.doi.org/10.1016/j.kint.2019.06.017DOI Listing
October 2019

Predicting kidney failure from longitudinal kidney function trajectory: A comparison of models.

PLoS One 2019 9;14(5):e0216559. Epub 2019 May 9.

Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Rationale & Objective: Early 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 Design: Prospective cohort.

Setting & Participants: We 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.

Predictors: All models included age, sex, eGFR, and albuminuria, known prognostic markers for ESKD.

Analytical Approach: We 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).

Results: The 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.

Conclusion: In 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508737PMC
January 2020

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

Kidney Int 2019 06 5;95(6):1471-1485. Epub 2019 Mar 5.

Laboratoire d'Immunologie et Histocompatibilité Hôpital Saint-Louis, Paris, France; INSERM UMRs 1160, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.

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.
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http://dx.doi.org/10.1016/j.kint.2018.12.029DOI Listing
June 2019

Fasting Urinary Osmolality, CKD Progression, and Mortality: A Prospective Observational Study.

Am J Kidney Dis 2019 05 15;73(5):596-604. Epub 2019 Feb 15.

Sorbonne Université, Inserm UMR_S 1155, Paris, France; Unit of Renal Physiology, AP-HP Hôpital Tenon, Paris, France.

Rationale & Objective: Chronic kidney disease (CKD) characterized by decreased glomerular filtration rate (GFR) is often accompanied by various degrees of impaired tubular function in the cortex and medulla. Assessment of tubular function may therefore be useful in establishing the severity of kidney disease and identifying those at greater risk for CKD progression. We explored reductions in urinary concentrating ability, a well-known feature of CKD, as a risk factor for GFR decline and end-stage renal disease (ESRD).

Study Design: Prospective longitudinal cohort study.

Setting & Participants: 2,084 adult patients with CKD stages 1 to 4 from the French NephroTest Cohort Study.

Predictor: Fasting urinary osmolality measured using delta cryoscopy.

Outcomes: ESRD, mortality before ESRD, and measured GFR (mGFR) assessed using Cr-EDTA renal clearance.

Analytical Approach: Cause-specific hazards models were fit to estimate crude and adjusted associations of urinary osmolality with ESRD and death before ESRD. Linear mixed models with random intercepts were fit to evaluate the association of urinary osmolality with slope of decline in mGFR.

Results: At baseline, mean age was 58.7±15.2 (SD) years with a median mGFR of 40.2 (IQR, 29.1-54.5) mL/min/1.73m and a median fasting urinary osmolality of 502.7±151.7mOsm/kg HO. Baseline fasting urinary osmolality was strongly associated with mGFR (R=0.54; P < 0.001). 380 ESRD events and 225 deaths before ESRD occurred during a median follow-up of 5.9 (IQR, 3.8-8.2) years. Patients with lower baseline fasting urinary osmolality had higher adjusted risk for ESRD but not for mortality (HRs of 1.97 [95% CI, 1.26-3.08] and 0.99 [95% CI, 0.68-1.44], respectively, for the lowest vs highest tertile). Based on a mixed linear model adjusted for baseline mGFR and clinical characteristics, patients in the lowest tertile of baseline urinary osmolality had a steeper decline in kidney function (-4.9% ± 0.9% per year; P < 0.001) compared with patients in the highest tertile.

Limitations: Fasting was self-reported.

Conclusions: Fasting urinary osmolality may be a useful tool, in addition to GFR and albuminuria, for assessing nonglomerular damage in patients with CKD who are at higher risk for CKD progression.
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http://dx.doi.org/10.1053/j.ajkd.2018.12.024DOI Listing
May 2019

Extracellular Fluid Volume Is an Independent Determinant of Uncontrolled and Resistant Hypertension in Chronic Kidney Disease: A NephroTest Cohort Study.

J Am Heart Assoc 2018 10;7(19):e010278

1 Physiology Department Assistance Publique-Hôpitaux de Paris Hôpital Bichat and Inserm U1149 Paris France.

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 Cr-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 m), 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.
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http://dx.doi.org/10.1161/JAHA.118.010278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404875PMC
October 2018

Performance of creatinine-based equations for estimating glomerular filtration rate changes over time.

Nephrol Dial Transplant 2020 05;35(5):819-827

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

Background: Glomerular filtration rate (GFR) is commonly used to monitor chronic kidney disease (CKD) progression, but its validity for evaluating kidney function changes over time has not been comprehensively evaluated. We assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis.

Methods: In the NephroTest cohort study, we measured GFR 5324 times by chromium 51-labeled ethylenediamine tetraacetic acid renal clearance in 1955 adult patients with CKD Stages 1-4 referred to nephrologists (Stages 1-2, 19%) and simultaneously estimated GFR with both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations for isotope dilution mass spectrometry traceable creatinine; absolute and relative GFR slopes were calculated using a linear mixed model.

Results: Over a median follow-up of 3.4 [interquartile range (IQR) 2.0-5.6] years, the decline in mean absolute and relative measured GFR (mGFR) and CKD-EPI and MDRD estimated GFR (eGFR) was 1.6 ± 1.2, 1.5 ± 1.4 and 1.3 ± 1.3 mL/min/1.73 m2/year and 5.9 ± 5.3, 5.3 ± 5.3 and 4.8 ± 5.2%/year, respectively; 52% and 55% of the patients had MDRD and CKD-EPI eGFR slopes within 30% of mGFR slopes. Both equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and mGFR versus eGFR slope. Other patient characteristics and specific CKD diagnoses had little effect on the performance of the equations in estimating associations.

Conclusions: This study shows little bias, but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. Importantly, bias strongly varied with age, possibly due to variations in muscle mass over time, with implications for clinical care and research.
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http://dx.doi.org/10.1093/ndt/gfy278DOI Listing
May 2020

Prevalence of atheromatous and non-atheromatous cardiovascular disease by age in chronic kidney disease.

Nephrol Dial Transplant 2020 05;35(5):827-836

Service de Néphrologie-Dialyse, CHU Ambroise Paré, APHP, Boulogne-Billancourt, France.

Background: Although chronic kidney disease (CKD) and age are major risk factors for cardiovascular disease (CVD), little is known about the relative proportions of atheromatous and non-atheromatous CVD by age in CKD patients.

Methods: We used baseline data from the French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort of 3033 patients (65% men) with CKD Stages 3-4 to study crude and adjusted associations between age, the estimated glomerular filtration rate (eGFR), atheromatous CVD (coronary artery disease, peripheral artery disease and stroke) and non-atheromatous CVD (heart failure, cardiac arrhythmia and valvular heart disease).

Results: Mean age was 66.8 and mean Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR was 32.9 mL/min/1.73 m2. In the <65, (65-74), (75-84) and ≥85 year age groups, the prevalence was, respectively, 18.7, 35.5, 42.9 and 37.8% for atheromatous CVD, and 14.9, 28.4, 38.1 and 56.4% for non-atheromatous CVD. After adjusting for albuminuria, sex and CVD risk factors, the odds ratio (OR) [95% confidence interval (CI)] for (65-74), (75-84) and ≥85 age groups (compared with the <65 group) was, respectively, 1.99 (1.61-2.46), 2.89 (2.30-3.62), 2.72 (1.77-4.18) for atheromatous CVD and 2.07 (1.66-2.58), 3.15 (2.50-3.97), 7.04 (4.67-10.61) for non-atheromatous CVD. Compared with patients with an eGFR ≥30 mL/min/1.73 m2, those with an eGFR <30 mL/min/1.73 m2 had a higher OR for atheromatous CVD [1.21 (1.01-1.44)] and non-atheromatous CVD [1.16 (0.97-1.38)].

Conclusions: In this large cohort of CKD patients, both atheromatous and non-atheromatous CVD were highly prevalent and more frequent in older patients. In a given age group, the prevalence of atheromatous and non-atheromatous CVD was similar (except for a greater prevalence of non-atheromatous CVD after 85).
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http://dx.doi.org/10.1093/ndt/gfy277DOI Listing
May 2020

Evaluation of the adequacy of drug prescriptions in patients with chronic kidney disease: results from the CKD-REIN cohort.

Br J Clin Pharmacol 2018 12 24;84(12):2811-2823. Epub 2018 Sep 24.

Pharmacology department, Amiens University Hospital, Amiens, France.

Aims: Drug prescription is difficult to manage in patients with chronic kidney disease (CKD). We assessed the prevalence and determinants of inappropriate drug prescriptions (whether contraindications or inappropriately high doses) with regard to kidney function in patients with CKD under nephrology care. We also assessed the impact of the equation used to estimate GFR on the prevalence estimates.

Methods: The CKD-REIN cohort includes 3033 outpatients with CKD (eGFR between 15 and 60 ml min  1.73 m ). We examined the daily doses of pharmacological agents prescribed at study entry. Inappropriate prescription was defined as the reported prescription of either a contraindicated drug or an indicated drug at an inappropriately high dose level with regard to the patient's GFR, as estimated with the CKD-EPI equation, the de-indexed CKD-EPI equation, or the Cockcroft-Gault (CG) equation. Multivariate logistic regression was used to assess the determinants of inappropriate prescription risk.

Results: At baseline, patients' median [interquartile range] number of drugs prescribed per patient was 8 [5-10]. Half of the patients had been prescribed at least one inappropriate drug. Anti-gout, cardiovascular agents and antidiabetic agents accounted for most of the inappropriate prescriptions. The percentage of inappropriate prescriptions varied from one GFR equation to another: 52% when using the CKD-EPI equation, 47% when using the de-indexed CKD-EPI equation and 41% with the CG equation. A multiple logistic regression analysis showed significantly higher odds ratios [95% confidence interval] for inappropriate prescriptions in male patients (1.28 [1.07; 1.53]), patients with diabetes (1.34 [1.06; 1.70]), those with a high BMI (1.58 [1.25; 1.99]), and those with a low GFR (10.2 [6.02; 17.3]). The risk of having at least one inappropriate prescription increased with the number of drugs per patient (P for trend < 0.0001) and therefore the odds ratio was 5.88 [4.17; 8.28] for those who received at least 11 prescribed medications compared to those who received fewer than 5.

Conclusion: Our results emphasize the complexity of drug management for CKD patients, for whom inappropriate prescription appears to be common.
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http://dx.doi.org/10.1111/bcp.13738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255993PMC
December 2018

Risk profile, quality of life and care of patients with moderate and advanced CKD: The French CKD-REIN Cohort Study.

Nephrol Dial Transplant 2019 02;34(2):277-286

Centre for Research in Epidemiology and Population Health (CESP), UMRS 1018, Université Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France.

Background: The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study was designed to investigate the determinants of prognosis and care of patients referred to nephrologists with moderate and advanced chronic kidney disease (CKD). We examined their baseline risk profile and experience.

Methods: We collected bioclinical and patient-reported information from 3033 outpatients with CKD and estimated glomerular filtration rates (eGFRs) of 15-60 mL/min/1.73 m2 treated at 40 nationally representative public and private facilities.

Results: The patients' median age was 69 (60-76) years, 65% were men, their mean eGFR was 33 mL/min/1.73 m2, 43% had diabetes, 24% had a history of acute kidney injury (AKI) and 57% had uncontrolled blood pressure (BP; >140/90 mmHg). Men had worse risk profiles than women and were more likely to be past or current smokers (73% versus 34%) and have cardiovascular disease (59% versus 42%), albuminuria >30 mg/mmol (or proteinuria > 50) (40% versus 30%) (all P < 0.001) and a higher median risk of end-stage renal disease within 5 years, predicted by the kidney failure risk equation {12% [interquartile range (IQR) 3-37%] versus 9% [3-31%], P = 0.008}. During the previous year, 60% of patients reported one-to-two nephrologist visits and four or more general practitioner visits; only 25% saw a dietician and 75% were prescribed five or more medications daily. Physical and mental quality of life (QoL) were poor, with scores <50/100.

Conclusions: The CKD-REIN study highlights high-risk profiles of cohort members and identifies several priorities, including improving BP control and dietary counselling and increasing doctors' awareness of AKI, polypharmacy and QoL.

Trial Registration: ClinicalTrials.gov identifier: NCT03381950.
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http://dx.doi.org/10.1093/ndt/gfy058DOI Listing
February 2019

Association of a Low-Protein Diet With Slower Progression of CKD.

Kidney Int Rep 2018 Jan 30;3(1):105-114. Epub 2017 Aug 30.

Centre de recherches en Epidémiologie et Santé des Populations, Inserm, University of Paris-Sud, University of Versailles Saint-Quentin, University of Paris-Saclay, Villejuif, France.

Introduction: 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 m, measured by Cr-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 m. 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/m.

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.
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http://dx.doi.org/10.1016/j.ekir.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762958PMC
January 2018

Hypertension Control, Apparent Treatment Resistance, and Outcomes in the Elderly Population With Chronic Kidney Disease.

Kidney Int Rep 2017 Mar 31;2(2):180-191. Epub 2016 Oct 31.

CESP, Inserm UMR1018 Team 5, University of Paris-Sud, UVSQ, University Paris-Saclay, Villejuif, France.

Introduction: 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 <60 ml/min/1.73m) in 4262 community-dwelling individuals (40% men) more than 65 years of age.

Results: At baseline, 19% had CKD, and 31.2% had controlled hypertension on ≤3 antihypertensive drugs, 62.3% uncontrolled hypertension ≥140/90 mm Hg on ≤2 drugs, and 6.5% apparent treatment-resistant hypertension (aTRH) ≥140/90 mm Hg with ≥3 drugs or use of ≥4 drugs regardless of level. There were 1115 deaths (305 total cardiovascular deaths) and 274 incident nonfatal or fatal strokes or coronary events. Compared to the reference group (controlled hypertension and no CKD), participants without CKD and with uncontrolled hypertension or aTRH had adjusted hazard ratios for all-cause mortality of 0.86 (0.74-1.01) and 1.09 (0.82-1.46), and those with CKD and controlled or uncontrolled hypertension, or aTRH, of 1.33 (1.06-1.68), 1.14 (0.93-1.39), and 1.34 (0.98-1.85), respectively. Participants with aTRH and CKD had a risk of coronary death more than 3 times higher than that of the reference group; participants with aTHR, with or without CKD, had a risk of stroke more than twice as high, and those with CKD but controlled hypertension a 2 times higher risk for cardiovascular deaths from other causes.

Discussion: CKD does not appear to amplify the risk of stroke and coronary events associated with aTRH in this older population. The reasons for excess cardiovascular mortality from other causes associated with controlled hypertension require further study.
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http://dx.doi.org/10.1016/j.ekir.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678838PMC
March 2017

Association of plasma potassium with mortality and end-stage kidney disease in patients with chronic kidney disease under nephrologist care - The NephroTest study.

BMC Nephrol 2017 Sep 12;18(1):295. Epub 2017 Sep 12.

FCRIN INI-CRCT, Paris, France.

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 (P) and glomerular filtration rate (GFR) measured (mGFR) by Cr-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/1.73m; prevalence of low P (<4 mmol/L) was 26.5%, and of high P (>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 < 10 mL/min/1.73m or lost to follow-up, 459 ESKD events and 236 deaths before ESKD (83 CV deaths) occurred during a median follow-up of 5 years. Compared to patients with P within [4, 5] mmol/L at baseline, those with low P had hazard ratios (HRs) [95% CI] for all-cause and CV mortality before ESKD, and for ESKD of 0.82 [0.58-1.16], 1.01 [0.52-1.95], and 1.14 [0.89-1.47], respectively, with corresponding figures for those with high P of 0.79 [0.48-1.32], 1.5 [0.69-3.3], and 0.92 [0.70-1.21]. Considering time-varying P did not materially change these findings, except for the HR of ESKD associated with high P, 1.39 [1.09-1.78]. Among 1190 patients with at least two visits, P had normalized at the second visit in 39.9 and 54.1% respectively of those with baseline low and high P. Among those with low P that normalized, ARB or ACEi use increased between the visits (68.3% vs 81.8%, P < .0001), and among those with high P that normalized, potassium-binding resin and bicarbonate use increased (13.0% vs 37.0%, P < .001, and 4.4% vs 17.4%, P = 0.01, respectively) without decreased ACEi or ARB use.

Conclusion: In these patients under nephrology care, neither low nor high P was associated with excess mortality.
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http://dx.doi.org/10.1186/s12882-017-0710-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596852PMC
September 2017

Predictors of nonfunctional arteriovenous access at hemodialysis initiation and timing of access creation: A registry-based study.

PLoS One 2017 27;12(7):e0181254. Epub 2017 Jul 27.

Renal and Cardiovascular Epidemiology Team, CESP, INSERM U1018, Paris-Sud Univ, UVSQ, Paris Saclay University,Villejuif, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531527PMC
September 2017

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

Sci Rep 2017 04 28;7:45040. Epub 2017 Apr 28.

Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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http://dx.doi.org/10.1038/srep45040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408227PMC
April 2017

High Evening Cortisol Level Is Associated With Low TBS and Increased Prevalent Vertebral Fractures: OsteoLaus Study.

J Clin Endocrinol Metab 2017 07;102(7):2628-2636

Center for Bone Diseases, Rheumatology Unit, Bone and Joint Department, Lausanne University Hospital, CH-1011 Lausanne, Switzerland.

Context: Increased evening cortisol levels have been implicated in bone mineral density (BMD) loss. The effect on bone microarchitecture and fracture risk has never been studied.

Objective: To study the relationship between salivary cortisol circadian rhythm and (1) trabecular bone score (TBS) and (2) fracture prevalence.

Design, Setting, Patients, And Interventions: Cross-sectional study including 608 women >50 years old (mean = 65.5) from the OsteoLaus cohort. Data included the FRAX© questionnaire, BMD, TBS and vertebral fracture (VFx) assessment by dual X-ray absorptiometry, and measures of salivary cortisol (awakening, 30 minutes thereafter, 11 am, and 8 pm).

Results: In the multivariate model, participants in the highest tertile of 8 pm salivary cortisol (sc-8 pm) (mean = 5.7 ± 2.5 nmol/L) vs lowest tertile (1.7 ± 0.4 nmol/L) had lower TBS values (1.27 vs 1.29; P = 0.02), more prevalent VFx grades 2 and 3 (odds ratio = 5.34; P = 0.012), low-trauma fractures (odds ratio = 1.80; P = 0.036), and major osteoporotic fractures (odds ratio = 1.96; P = 0.042), without difference in lumbar spine BMD (0.91 vs 0.92 g/cm2; P = 0.431). VFx prevalence was associated with sc-8 pm and TBS independently of each other and of other risk factors. The cut-point for sc-8 pm correlating with the presence of >1 VFx was 3.62 nmol/L (sensitivity 0.74, specificity 0.66).

Conclusions: High sc-8 pm is associated with low TBS and an increased prevalence of radiologic VFx independently of other risk factors. Measurement of sc-8 pm may add relevant information in the assessment of fracture risk.
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http://dx.doi.org/10.1210/jc.2016-3804DOI Listing
July 2017

Vascular access conversion and patient outcome after hemodialysis initiation with a nonfunctional arteriovenous access: a prospective registry-based study.

BMC Nephrol 2017 02 22;18(1):74. Epub 2017 Feb 22.

Paris Saclay University, Paris-Sud Univ, UVSQ, CESP, INSERM, Renal and Cardiovascular Epidemiology Team, Villejuif, France.

Background: Little is known about vascular access conversion and outcomes for patients starting hemodialysis with nonfunctional arteriovenous (AV) access. We assessed mortality risk associated with nonfunctional AV access at hemodialysis initiation, taking subsequent changes in vascular access into account.

Methods: We studied the 53,092 incident adult hemodialysis patients included in the French REIN registry from 2005 through 2012. AV access placed predialysis was considered nonfunctional when dialysis began with a central venous catheter. Information about vascular access changes was obtained from treatment modality updates.

Results: At hemodialysis initiation, AV access was functional for 47% of patients and nonfunctional for 9%; 44% had a catheter alone. After a 3-year follow-up, 63% of patients beginning hemodialysis with a nonfunctional AV access had changed to a functional one, 4% had had a transplant, 19% had died before any vascular access change, and 13% still used a catheter. Cox proportional hazard models with vascular access treated as a time-dependent variable showed an adjusted mortality hazard ratio (95% confidence interval) for patients with nonfunctional AV access who subsequently converted to functional access of 0.95 (95% CI 0.89-1.03) compared with the reference group with functional AV access since first hemodialysis, versus 1.43 (95% CI 1.31-1.55) for those who did not convert.

Conclusions: Among patients starting hemodialysis with a nonfunctional AV access, a substantial percentage may never experience successful vascular access conversion. Poor survival seems to be limited to these patients, while those who subsequently convert to functional AV access have similar mortality risk compared to patients with such access since hemodialysis initiation. Every effort should be made to obtain functional AV access in all suitable patients.
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http://dx.doi.org/10.1186/s12882-017-0492-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320699PMC
February 2017