The number of nephroprotection targets attained is associated with cardiorenal outcomes and mortality in patients with diabetic kidney disease. The CKD-REIN cohort study.

AIM: The risk of cardiorenal events remains high among patients with diabetes and chronic kidney disease (CKD), despite the prescription of recommended treatments. We aimed to determine whether the attainment of a combination of nephroprotection targets at baseline (glycated haemoglobin <7.0%, urinary albumin-creatinine ratio <300 mg/g, blood pressure <130/80 mmHg, renin-angiotensin system inhibition) was associated with better cardiorenal outcomes and lower mortality. MATERIALS AND METHODS: From the prospective French CKD-REIN cohort, we studied 1260 patients with diabetes and CKD stages 3-4 (estimated glomerular filtration rate: 15-60 ml/min/1.73 m2); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m2. The median follow-up was 4.9 years. RESULTS: In adjusted Cox regression models, the attainment of two nephroprotection targets was consistently associated with a lower risk of cardiorenal events [hazard ratio 0.70 (95% confidence interval 0.57-0.85)], incident kidney failure with replacement therapy [0.58 (0.43-0.77)], four major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure) [0.75 (0.57-0.99)] and all-cause mortality [0.59 (0.42-0.82)] when compared with the attainment of zero or one target. For patients with a urinary albumin-creatinine ratio ≥300 mg/g, those who attained at least two targets had lower hazard ratios for cardiorenal events [0.61 (0.39-0.96)], four major adverse cardiovascular events [0.53 (0.28-0.98)] and all-cause mortality [0.35 (0.17-0.70)] compared with those who failed to attain any targets. CONCLUSIONS: These findings suggest that the attainment of a combination of nephroprotection targets is associated with better cardiorenal outcomes and a lower mortality rate in people with diabetic kidney disease.

Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease.

Background: Kynurenine is a protein-bound uremic toxin. Its circulating levels are increased in chronic kidney disease (CKD). Experimental studies showed that it exerted deleterious cardiovascular effects. We sought to evaluate an association between serum kynurenine levels and adverse fatal or nonfatal cardiovascular events and all-cause mortality in CKD patients. Methods: The CKD-REIN study is a prospective cohort of people with CKD having an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline frozen samples of total and free fractions of kynurenine and tryptophan were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for each outcome. Results: Of the 2406 included patients (median age: 68 years; median eGFR: 25 ml/min/1.73 m2), 52% had a history of cardiovascular disease. A doubling of serum-free kynurenine levels was associated with an 18% increased hazard of cardiovascular events [466 events, HR (95%CI):1.18(1.02,1.33)], independently of eGFR, serum-free tryptophan level or other uremic toxins, cardioprotective drugs, and traditional cardiovascular risk factors. Serum-free kynurenine was significantly associated with non-atheromatous cardiovascular events [HR(95%CI):1.26(1.03,1.50)], but not with atheromatous cardiovascular events [HR(95%CI):1.15(0.89,1.50)]. The association of serum-free kynurenine with cardiovascular mortality was also independently significant [87 events; adjusted HR(95%CI):1.64(1.10,2.40)]. However, the association of serum-free kynurenine with all-cause mortality was no more significant after adjustment on serum-free tryptophan [311 events, HR(95%CI):1.12(0.90, 1.40)]. Conclusions: Our findings imply that serum-free kynurenine, independently of other cardiovascular risk factors (including eGFR), is associated with fatal or nonfatal cardiovascular outcomes, particularly non-atheromatous cardiovascular events; in patients with CKD. Strategies to reduce serum kynurenine levels should be evaluated in further studies.

Haemoglobin trajectories in chronic kidney disease and risk of major adverse cardiovascular events.

BACKGROUND: The trajectories of haemoglobin in patients with chronic kidney disease (CKD) have been poorly described. In such patients, we aimed to identify typical haemoglobin trajectory profiles and estimate their risks of major adverse cardiovascular events (MACE). METHODS: We used 5-year longitudinal data from the CKD-REIN cohort patients with moderate to severe CKD enrolled from 40 nationally representative nephrology clinics in France. A joint latent class model was used to estimate, in different classes of haemoglobin trajectory, the competing risks of (i) MACE + defined as the first event among cardiovascular death, non-fatal myocardial infarction, stroke or hospitalization for acute heart failure, (ii) initiation of kidney replacement therapy (KRT) and (iii) non-cardiovascular death. RESULTS: During the follow-up, we gathered 33 874 haemoglobin measurements from 3011 subjects (median, 10 per patient). We identified five distinct haemoglobin trajectory profiles. The predominant profile (n = 1885, 62.6%) showed an overall stable trajectory and low risks of events. The four other profiles had nonlinear declining trajectories: early strong decline (n = 257, 8.5%), late strong decline (n = 75, 2.5%), early moderate decline (n = 356, 11.8%) and late moderate decline (n = 438, 14.6%). The four profiles had different risks of MACE, while the risks of KRT and non-cardiovascular death consistently increased from the haemoglobin decline. CONCLUSION: In this study, we observed that two-thirds of patients had a stable haemoglobin trajectory and low risks of adverse events. The other third had a nonlinear trajectory declining at different rates, with increased risks of events. Better attention should be paid to dynamic changes of haemoglobin in CKD.

A New Approach for Cognitive Impairment Pattern in Chronic Kidney Disease.

BACKGROUND AND HYPOTHESIS: Chronic kidney disease (CKD) is associated with an elevated risk of neurocognitive disorders (NCDs). It remains unclear whether CKD-related NCDs have specific cognitive pattern or are earlier-onset phenotypes of the main NCDs (vascular NCDs and Alzheimer's disease). METHODS: We used the Mini Mental State Examination score (MMSE) to assess cognitive pattern in 3003 CKD patients (stage 3 to 4) followed up over 5 years in the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort. After normalizing MMSE scores to a 0-to-100 scale, the associations between the baseline estimated glomerular filtration rate (eGFR, using the CKD-EPI-creatinine formula) and changes in each MMSE domain score were assessed in linear mixed models. RESULTS: Patients (age: 67±13 years old; males: 65%, mean eGFR: 33±12 ml/min/1.73 m²) had a good baseline cognitive functions: the mean MMSE score was 26.9/30 ±2.9. After adjustment for age, sex, educational level, depression (past or present), cardiovascular risk factors, cerebrovascular disease, a lower baseline eGFR (per 10 ml/min/1.73 m²) was associated with a 0.53-point decrement (p<0.001; 95%CI [-0.98,-0.08]) for orientation, a 1.04-point decrement (p=0.03; 95%CI [-1.96,-0.13]) for attention and calculation, a 0.78-point decrement (p=0.003; 95%CI [-1.30,-0.27]) for language, and a 0.94-point decrement (p=0.02; 95%CI [-1.75,-0.13]) for praxis. Baseline eGFR was not, however, associated with significant changes over time in MMSE domain scores. CONCLUSION: A lower eGFR in CKD patients was associated with early impairments in certain cognitive domains: praxis, language and attention domains before an obvious cognitive decline. Early detection of NCD in CKD patients must be perform before clinically cognitive decline using preferably tests assessing executive, attentional functions and language than memory test. This could lead to a better management of cognitive impairment and their consequences on CKD management.

Kidney Function Decline and Serious Adverse Drug Reactions in Patients With CKD.

RATIONALE & OBJECTIVE: Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD. PREDICTORS: Demographic and biological data (including eGFR), medication prescriptions. OUTCOME: ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. ANALYTICAL APPROACH: Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). RESULTS: During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m2 lower baseline eGFR. LIMITATIONS: The results cannot be extrapolated to patients who are not being treated by a nephrologist. CONCLUSIONS: ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents.

Impact of physical activity in non-dialysis CKD patients followed in a multidisciplinary care network on the progression of chronic renal failure ­ PHYSALYS study / Impact de l'activité physique chez les patients insuffisants rénaux non dialysés suivis dans un réseau de santé multidisciplinaire sur la progression de l'insuffisance rénale chronique ­ étude PHYSALYS

Physical activity (PA), has a proven effect on overall health. The study assessed the difference in glomerular filtration rate (GFR) over one year in non-dialysis renal failure patients between those who practiced exercise (P) and those who did not (NP). Patients were categorised as P or not P using the Global Physical Activity Questionnaire (GPAQ2), completed by telephone, at inclusion and at 12 months. Among the 259 patients included, 195 (75.3%) practiced a PA and 64 (24.7%) did not practiced. There was no significant difference in the slope of GFR decline from inclusion to month 12 between the two groups, p = 0.4107. Only the type of kidney seemed to be significantly associated with the slope of GFR decline over the 12 months (p = 0.0039). These results may be explained by a follow-up time too short to identify an effect of behavioural change on the progression of kidney disease.

L'activité physique (AP) a un effet démontré sur l'état de santé global. L'étude évaluait, chez des patients insuffisants rénaux non dialysés, la différence, sur un an, de l'évolution du débit de filtration glomérulaire (eDFG) entre ceux pratiquant une AP (P) et ceux n'en pratiquant pas (NP). Les patients ont été classés comme P ou NP grâce au questionnaire d'AP GPAQ2, passé par téléphone, à l'inclusion et à 12 mois. Parmi les 259 patients inclus, 195 (75,3 %) pratiquaient une AP et 64 (24,7 %) n'en pratiquaient pas. Il n'existe pas de différence significative sur la pente de décroissance du eDFG entre l'inclusion et le 12e mois (p = 0,4107). Le type de néphropathie semblerait associé significativement à cette pente de décroissance au cours des 12 mois (p = 0,0039). Ces résultats peuvent s'expliquer par une durée de suivi trop courte pour mettre en évidence un effet de la modification du comportement sur l'évolution de la maladie rénale.

Chronic kidney disease and nephrological practices in France: lessons from the CKD-REIN cohort, 2013-2023 / Maladie rénale chronique et pratiques néphrologiques en France : leçons de la cohorte CKD-REIN, 2013-2023

Launched in 2013 supported by the Program "Cohorts ­ Investments for the Future", the CKD-REIN (Chronic Kidney Disease ­ Renal Epidemiology and Information Network) study is a prospective cohort that included and followed for 5 years more than 3000 patients with moderate or advanced chronic kidney disease (CKD), from 40 nationally representative nephrology clinics. A large amount of data was collected on CKD and its treatments, patient social characteristics and reported outcomes, and nephrology practices and services. A total of 170,000 blood and urine samples were collected and stored in a central biobank. Coordinated with the CKD outcomes and practice pattern study (CKDopps) and collaborating with the international Network of CKD cohorts (iNETCKD), CKD-REIN contributes to the understanding of CKD and the positioning of France with respect to CKD epidemiology and care in the world. This review highlights major findings from the cohort, and their potential implications for clinical practices and the health system, grouped into the following themes: (1) the complexity of patients with CKD; (2) adherence to clinical guidelines; (3) treatment practices and drug risk; (4) acute on chronic kidney disease; (5) CKD metabolic complications; (6) prediction of kidney failure; (7) sex differences in CKD; (8) patient perspective on CKD; (9) transition to kidney failure and replacement therapy; (10) conservative care.

Lancée en 2013 grâce au Programme « Cohortes ­ Investissements d'Avenir ¼, l'étude CKD-REIN (Chronic Kidney Disease ­ Renal Epidemiology and Information Network) est une cohorte prospective qui a inclus et suivi pendant cinq ans plus de 3 000 patients avec une maladie rénale chronique (MRC) modérée ou avancée, dans 40 consultations de néphrologie, représentatives nationalement. Un grand nombre de données ont été collectées sur la MRC et ses traitements, les caractéristiques sociales et la santé perçue des patients, les pratiques et l'organisation des services de néphrologie. Une biothèque de 170 000 échantillons de sang et d'urine a été constituée et stockée dans une biobanque centrale. Coordonnée avec l'étude Chronic Kidney Disease outcomes and practice pattern study (CKDopps) et collaborant avec l'International Network of CKD cohorts (iNET-CKD), CKD-REIN contribue à l'avancée des connaissances et au positionnement de la France dans le domaine de l'épidémiologie de la MRC et des pratiques dans le monde. Cette revue fait le point des faits marquants de la cohorte, et de leur implication potentielle pour la clinique et le système de santé, regroupés par thème : (1) la complexité des patients avec une MRC ; (2) l'adhésion aux recommandations cliniques ; (3) les pratiques thérapeutiques et le risque médicamenteux ; (4) l'insuffisance rénale aiguë dans la MRC ; (5) l'évolution des complications métaboliques ; (6) la prédiction de la défaillance rénale ; (7) les différences hommes-femmes ; (8) le point de vue des patients sur la MRC ; (9) la transition vers la défaillance rénale et le traitement de suppléance ; (10) le traitement conservateur.

Proton-Pump Inhibitors and Serum Concentrations of Uremic Toxins in Patients with Chronic Kidney Disease.

Use of proton-pump inhibitors (PPIs) is common in patients with chronic kidney disease (CKD). PPIs and many uremic toxins (UTs) are eliminated by the kidney's tubular organic anion transporter system. In a cross-sectional study, we sought to evaluate the association between PPI prescription and serum concentrations of various UTs. We studied a randomly selected sub-group of participants in the CKD-REIN cohort (adult patients with a confirmed diagnosis of CKD and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) with available frozen samples collected at baseline. PPI prescription was recorded at baseline. Serum concentrations of 10 UTs were measured using a validated liquid chromatography tandem mass spectrometry technique. Multiple linear regression was performed, with the log UT concentration as the dependent variable. Of the 680 included patients (median age: 68 years; median eGFR: 32 mL/min/1.73 m2), 31% had PPI prescriptions at baseline. Patients using PPIs had higher levels of certain UTs in comparison to other patients, including total and free indoxyl sulfate (IS), total and free p-cresylsulfate, total and free p-cresylglucuronide (PCG), phenylacetylglutamine (PAG), free kynurenine, and free hippuric acid. After adjustment for baseline co-morbidities, number of co-prescribed drugs, and laboratory data, including eGFR, associations between PPI prescription and elevated serum concentrations of free and total IS, free and total PCG, and PAG remained significant. Our results indicate that PPI prescription is independently associated with serum UT retention. These findings are interesting to better understand the factors that may modulate serum UT concentration in CKD patients, however, they will need to be confirmed by longitudinal studies.

Longitudinal uric acid has nonlinear association with kidney failure and mortality in chronic kidney disease.

We investigated the shape of the relationship between longitudinal uric acid (UA) and the hazard of kidney failure and death in chronic kidney disease (CKD) patients, and attempted to identify thresholds associated with increased hazards. We included CKD stage 3-5 patients from the CKD-REIN cohort with one serum UA measurement at cohort entry. We used cause-specific multivariate Cox models including a spline function of current values of UA (cUA), estimated from a separate linear mixed model. We followed 2781 patients (66% men, median age, 69 years) for a median of 3.2 years with a median of five longitudinal UA measures per patient. The hazard of kidney failure increased with increasing cUA, with a plateau between 6 and 10 mg/dl and a sharp increase above 11 mg/dl. The hazard of death had a U-shape relationship with cUA, with a hazard twice higher for 3 or 11 mg/dl, compared to 5 mg/dl. In CKD patients, our results indicate that UA above 10 mg/dl is a strong risk marker for kidney failure and death and that low UA levels below 5 mg/dl are associated with death before kidney failure.

Cognitive performance is associated with glomerular filtration rate in patients with chronic kidney disease: results from the CKD-REIN cohort.

BACKGROUND: Chronic kidney disease (CKD) is associated with cognitive impairment in general population. We assessed the association between kidney and cognitive functions in patients with CKD and the influence of cardiovascular (CV) risk factors, and depression on this association. METHODS: The CKD-Renal Epidemiology and Information Network cohort included 3033 patients with CKD stages 3-4, followed for 5 years. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and estimated glomerular filtration rate (eGFR) with the CKD-Epidemiology Collaboration equation-creatinin formula. Evolution of the MMSE score over time and its association with baseline eGFR were investigated with linear mixed models. We assessed the risk of incident cognitive outcome (hospitalisation or death with relevant International Classification of Disease-10 codes), with a Cox proportional hazard model. RESULTS: The mean age was 66.8, the mean eGFR was 33 mL/min/1.73 m2 and 387 patients (13.0%) had an MMSE score below 24 at baseline. A 10 mL/min/1.73 m2 decrement of baseline eGFR was associated with a mean MMSE decrease of 0.12 (95% CI 0.04 to 0.19) after adjustment for demographic characteristics, depression, CV risk factors and disease; but baseline eGFR was not associated with MMSE temporal evolution. HR for cognitive outcome during follow-up (median 2.01 years) associated with a 10 mL/min/1.73 m2 decrement of baseline eGFR was 1.35 (1.07, 1.70) (p=0.01) after adjustment. CONCLUSIONS: In patients with CKD, lower eGFR was associated with worse cognitive performance and incident cognitive events, independently of demographics, CV risk factors and depression. TRIAL REGISTRATION NUMBER: NCT03381950.

Five-Year Symptom Trajectories in Nondialysis-Dependent CKD Patients.

BACKGROUND AND OBJECTIVES: Late stages of CKD are characterized by significant symptom burden. This study aimed to identify subgroups within the 5-year trajectories of symptom evolution in patients with CKD and to describe associated patient characteristics and outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2787 participants (66% men) with eGFR <60 ml/min per 1.73 m2 enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort study from July 2013 to May 2016, we assessed symptoms annually using the Kidney Disease Quality of Life-36 (KDQOL-36) questionnaire until December 2020. A total of 9121 measures were reported over follow-up; all participants had symptoms scored for at least one time point. We used a joint latent class-mixed model to distinguish profiles of symptom trajectories. RESULTS: Patient mean age (±SD) at baseline was 67±13 years, and mean eGFR was 33±13 ml/min per 1.73 m2. The prevalence of each symptom ranged from 24% (chest pain) to 83% (fatigue), and 98% of participants reported at least one symptom. After a median (interquartile range) follow-up of 5.3 (3.4-6.0) years, 690 participants initiated KRT, and 490 died before KRT. We identified two profiles of symptom trajectories: a "worse symptom score and worsening trajectory" in 31% of participants, characterized by a low initial symptom score that worsened more than ten points over time, and a "better symptom score and stable trajectory" in 69% of participants, characterized by a high initial score that remained stable. Participants in the worse symptom score and worsening trajectory group had more risk factors for CKD progression at baseline, worse quality of life, and a higher risk of KRT and death before KRT than other participants. CONCLUSIONS: This study highlights a significant worsening of symptoms in about one third of the participants, whereas the majority reported low symptom severity throughout the study.

Point of care creatinine derived eGFR measurement in capillary blood for identifying patients at risk.

Introduction: The aim of the study was to assess the clinical reliability of eGFR values estimated with a creatinine measurement from a point of care (StatSensor®) compared with measured GFR (mGFR) by a gold standard method. Methods: We prospectively included 113 patients undergoing renal function assessment. We compared eGFR using creatinine from capillary blood or venous blood measured by StatSensor® and measured GFR (mGFR) by Passing Bablok regression. Performance of eGFR was estimated by biais, precision and accuracy. Results: A total of 113 subjects were included. Median eGFR values were 59 (10-132), 52 (10-123) and 51 (10-131) ml/min/1.73 m2 for enzymatic, capillary and venous measurements, respectively. There was no difference between P30 and P10 for the three eGFR values (p = 0.11 and p = 0.1 respectively). StatSensor® eGFR tended to be underestimated compared to mGFR. For CKD stage 4/5 patients, concordance was 79 and 84% for eGFR with capillary creatinine and venous creatinine respectively. For mGFR< 60 ml/min/1.73 m2, concordance was 84 and 88% with capillary creatinine and venous creatinine respectively. Conclusion: The use of a handheld blood creatinine monitoring system with eGFR calculation provides a good estimation of GFR and allow to identify patients at high risk of acute kidney injury.

Urea levels and cardiovascular disease in patients with chronic kidney disease.

BACKGROUND: Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. METHODS: CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous cardiovascular (CV) events, and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data, and medications. FINDINGS: Of the 2507 included patients (median [interquartile range (IQR)] age: 69[61-77]; mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patient in T1 (n events = 451, HR[95%CI]: 1.93[1.39-2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31[0.97; 1.76] and 1.73[1.22; 2.45] for patients T2 and those in T3, respectively. INTERPRETATION: Our data suggested that urea is a predictor of cardiovascular outcomes beyond CV risk factors including eGFR.

Probiotic Intake and Inflammation in Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort.

Background and Aims: Little is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD. Methods: We performed a cross-sectional study of 888 patients with stage 3-5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily). Results: The 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers. Conclusion: We observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship. Clinical Trial Registration: [https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].

3-methylhistidine and clinical outcomes in maintenance haemodialysis patients.

BACKGROUND: Chronic kidney disease is an important contributor to morbidity and mortality. 3-methylhistidine (3-MH) is the by-product of actin and myosin degradation reflecting skeletal muscle turnover. Markedly elevated 3-MH levels have been documented in uraemic patients, but the interpretation of high 3-MH concentration in maintenance haemodialysis (MHD) patients remains unclear. Indeed, it is not known whether elevated serum 3-MH levels are a marker of excessive muscle catabolism or a better lean tissue mass. Here, we evaluated the association between serum 3-MH levels and clinical outcomes in these patients. METHODS: Serum 3-MH concentration was measured by reverse-phase liquid chromatography/tandem mass spectrometry in a cohort of MHD patients. We analysed the relationships between various clinical/laboratory indices, lean tissue mass measured by bioimpedance spectroscopy, mortality and cardiovascular (CV) events. RESULTS: Serum 3-MH concentration was positively correlated with serum albumin, normalized protein catabolic rate (nPCR), simplified creatinine index (SCI) and lean tissue mass. Of 291 MHD patients, during a mean follow-up of 847 days, 91 patients died and 101 patients experienced a CV event. Survival was significantly better in patients with high 3-MH concentrations (P = .002). A higher level of 3-MH was also associated with a lower CV mortality and lower incidence of CV events (P = .015 and P < .001, respectively). Low serum 3-MH levels remained significantly associated with CV events but not with mortality after adjustment for demographic, metabolic and CV risk factors. CONCLUSION: Elevated serum 3-MH concentration appears to be a marker of better lean tissue mass and nutritional status. Low serum 3-MH is a robust and independent predictor of CV events in the MHD population.

Barriers to conservative care from patients' and nephrologists' perspectives: the CKD-REIN study.

BACKGROUND: Conservative care is increasingly considered an alternative to kidney replacement therapy for kidney failure management, mostly among the elderly. We investigated its status and the barriers to its implementation from patients' and providers' perspectives. METHODS: We analysed data from 1204 patients with advanced chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2] enrolled at 40 nationally representative nephrology clinics (2013-16) who completed a self-administered questionnaire about the information they received and their preferred treatment option, including conservative care, if their kidneys failed. Nephrologists (n = 137) also reported data about their clinics' resources and practices regarding conservative care. RESULTS: All participating facilities reported they were routinely able to offer conservative care, but only 37% had written protocols and only 5% had a person or team primarily responsible for it. Overall, 6% of patients were estimated to use conservative care. Among nephrologists, 82% reported they were fairly or extremely comfortable discussing conservative care, but only 28% usually or always offered this option for older (>75 years) patients approaching kidney failure. They used various terminology for this care, with conservative management and non-dialysis care mentioned most often. Among patients, 5% of those >75 years reported receiving information about this option and 2% preferring it. CONCLUSIONS: Although reported by nephrologists to be widely available and easily discussed, conservative care is only occasionally offered to older patients, most of whom report they were not informed of this option. The lack of a person or team responsible for conservative care and unclear information appear to be key barriers to its implementation.

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

BACKGROUND: Acute-on-chronic kidney disease (ACKD) is poorly understood and often overlooked. We studied its incidence, circumstances, determinants and outcomes in patients with CKD. METHODS: We used the Kidney Disease: Improving Global Outcomes criteria to identify all-stage acute kidney injury (AKI) events in 3033 nephrology outpatients with CKD Stages 3-5 participating in the CKD-Renal Epidemiology and Information Network cohort study (2013-20), and cause-specific Cox models to estimate hazard ratios [HRs; 95% confidence intervals (CIs)] of AKI-associated risk factors. RESULTS: At baseline, 22% of the patients [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] had a history of AKI. Over a 3-year follow-up, 443 had at least one AKI event: 27% were Stage 2 or 3 and 11% required dialysis; 74% involved hospitalization including 47% acquired as hospital inpatients; and a third were not reported in hospital discharge reports. Incidence rates were 10.1 and 4.8/100 person-years in patients with and without an AKI history, respectively. In 2375 patients without this history, male sex, diabetes, cardiovascular disease, cirrhosis, several drugs, low eGFR and serum albumin levels were significantly associated with a higher risk of AKI, as were low birth weight (<2500 g) (adjusted HR 1.98; 95% CI 1.35-2.91) and haemoglobin level (HR 1.21; 1.12-1.32 per 1 g/dL decrease). Within 1 year, only 63% of the patients had recovered their previous kidney function, 13.7% had started kidney replacement therapy and 12.7% had died. CONCLUSIONS: The study highlights the high rate of hospital-acquired AKI events in patients with CKD, and their underreporting at hospital discharge. It also reveals low birth weight and anaemia as possible new risk factors in CKD patients.

Natriuretic Peptides as Predictors of Protein-Energy Wasting in Hemodialysis Population.

OBJECTIVE: Imbalance between anabolism and catabolism is linked to cachexia and protein-energy wasting (PEW), especially in frail populations such as patients with chronic kidney disease. PEW is responsible of poor outcomes with increased morbidity and mortality. Several causes are involved in PEW such as insulin resistance, acidosis, or hyperparathyroidism. Natriuretic peptides (NPs) have recently been described as activators of resting energy expenditure through the induction of browning of white adipose tissue in rodents with chronic kidney disease. The present study was therefore implemented to investigate whether NPs could be associated with PEW criteria and predict clinical outcomes. METHODS: We quantified serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a prospective cohort of 231 patients undergoing maintenance hemodialysis and atrial natriuretic peptide in a subgroup of 35 patients. Body composition parameters were measured with bioimpedance spectroscopy. RESULTS: NT-proBNP was inversely associated with serum albumin, prealbumin, and body mass index and, conversely, positively associated with age and C-reactive protein. NT-proBNP as well as atrial natriuretic peptide were significantly higher in patients with PEW criteria. NT-proBNP was negatively associated with body fat mass. In multiple linear regression, NT-proBNP remained associated with body mass index. Kaplan-Meier analysis revealed a significant correlation between serum NT-proBNP concentrations and all-cause mortality and cardiovascular events. This association remained significant after multivariable Cox regression models adjusted for demographic factors and cardiovascular risk factors. CONCLUSION: Accumulation of NPs seems to be associated with poor nutritional status and reduced survival among hemodialysis patients. Further studies are needed to confirm this association using resting energy expenditure measurement and adipose tissue biopsy.

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

BACKGROUND: Optimal daily water intake to prevent chronic kidney disease (CKD) progression is unknown. Taking the kidney's urine-concentrating ability into account, we studied the relation of kidney outcomes in patients with CKD to total and plain water intake and urine volume. METHODS: Including 1265 CKD patients [median age 69 years; mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] from the Chronic Kidney Disease-Renal Epidemiology and Information Network cohort (2013-19), we assessed fluid intake at baseline interviews, collected 24-h urine volumes and estimated urine osmolarity (eUosm). Using Cox and then linear mixed models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney failure and eGFR decline associated with hydration markers, adjusting for CKD progression risk factors and eUosm. RESULTS: Patients' median daily intake was 2.0 L [interquartile range (IQR) 1.6-2.6] for total water and 1.5 L (1-1.7) for plain water, median urine volume was 1.9 L/24 h (IQR 1.6-2.4) and mean eUosm was 374 ± 104 mosm/L. Neither total water intake nor urine volume was associated with either kidney outcome. Kidney failure risk increased significantly with decreasing eUosm ˂292 mosm/L. Adjusted HRs (95% CIs) for kidney failure associated with plain water intake were 1.88 (1.02-3.47), 1.59 (1.06-2.38), 1.76 (0.95-3.24) and 1.55 (1.03-2.32) in patients drinking <0.5, 0.5-1.0, 1.5-2.0 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. CONCLUSIONS: In patients with CKD, the relation between plain water intake and progression to kidney failure appears to be U-shaped. Both low and high intake may not be beneficial in CKD.

Effectiveness and Tolerance of Renin-Angiotensin System Inhibitors With Aging in Chronic Kidney Disease.

OBJECTIVES: Renin-angiotensin system inhibitors (RASi) are recommended for slowing chronic kidney disease (CKD) progression to kidney failure. Their effectiveness and tolerance as patients age remain uncertain because older patients have often been excluded from clinical trials. DESIGN: CKD-REIN cohort study. SETTING AND PARTICIPANTS: We studied 2762 patients with CKD stages 3 and 4 and a clinical indication for RASi enrolled between 2013 and 2016 in 40 nephrology clinics nationally representative in France. METHODS: The primary outcome was the occurrence of kidney failure or death. The secondary outcomes were the occurrence of cardiovascular events and hospitalizations with acute kidney injury (AKI) or hyperkalemia. A propensity score analysis was performed. We used Cox models to estimate hazard ratios (HRs) for each outcome associated with RASi prescription and tested interactions with age. RESULTS: Patients' mean age was 67 years, including 841 (30%) aged 75 years and older; 2178 (79%) were prescribed RASi's. During a median follow-up of 4.6 years, 33% of patients reached kidney failure or died. RASi prescription was associated with a lower risk of kidney failure or death (HR 0.79, 95% CI 0.66, 0.95), an association not modified by age (P for interaction = .72). It was not significantly associated with cardiovascular events. During the first 3 years of follow-up, 14% of patients were hospitalized with AKI or hyperkalemia, but risk was not higher among those prescribed RASi's (HR 0.75, 95% CI 0.55-1.02) and age did not modify its effect (P for interaction = .28). CONCLUSIONS AND IMPLICATIONS: This study shows that aging does not appear to modify either RASi's beneficial effects on major CKD outcomes or their potential adverse effects.