Ionized and total magnesium levels in patients with chronic kidney disease: associated factors and outcomes.

Background: The association between hypo- and/or hypermagnesaemia and cardiovascular (CV) outcomes or mortality has shown conflicting results in chronic kidney disease (CKD) and has been conducted on total magnesium (tMg) levels. Thus, the objectives of the present study were to (i) describe the serum ionized Mg (iMg) concentration in patients at various CKD stages, (ii) measure the correlation between iMg and tMg concentrations, (iii) identify their associated factors and (iv) determine whether serum tMg and/or iMg concentrations are associated with major adverse cardiovascular events (MACE) and mortality before kidney replacement therapy in CKD patients. Methods: Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) is a prospective cohort of CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Baseline iMg and tMg serum concentrations were centrally measured. Adjusted cause-specific Cox proportional hazard models were used to estimate hazard ratios (HRs) for first MACE and for mortality. Results: Of the 2419 included patients, median age was 68 years, and the mean eGFR was 34.8 mL/min/1.73 m2. Concentrations of serum iMg and tMg were strongly correlated (r = 0.89, P < .001) and were independently associated with eGFR. The adjusted HR [95% confidence interval (CI)] for MACE associated with the baseline serum tMg level was 1.27 (0.95; 1.69) for patients in Tertile 1 and 1.56 (1.18; 2.06) for patients in Tertile 3, relative to patients in Tertile 2. The HR (95% CI) of death according to serum tMg concentration was increased in Tertile 3 [1.48 (1.11; 1.97)]. The adjusted risk for MACE and mortality (all-cause or CV) associated with the baseline serum iMg level was not significantly different between tertiles. Conclusions: Our analysis of a large cohort of patients with moderate-to-advanced CKD demonstrated that individuals with higher serum tMg concentrations, although still within the normal range, had a greater likelihood of MACE and mortality. However, serum iMg levels were not associated with these outcomes.

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.

CKD-Associated Pruritus and Clinical Outcomes in Nondialysis CKD.

Rationale & Objective: Itching is a frequent symptom experienced by people with chronic kidney disease (CKD). We investigated the associations of CKD-associated pruritus (CKD-aP) with clinical outcomes. Study Design: This was a longitudinal cohort study. Setting & Participants: Patients from Brazil, France, and the United States enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) from 2013 to 2021, an international prospective cohort study of adults with nondialysis dependent CKD, and an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 were included. Exposure: CKD-aP was self-reported by response to the question: "During the past 4 weeks, to what extent were you bothered by itchy skin?" Outcomes: The outcomes were as follows: CKD progression, kidney replacement therapy (KRT) initiation, mortality, hospitalization, cardiovascular events, infection events. Analytical Approach: Associations with time-to-event outcomes were investigated using Cox proportional hazards models adjusted for potential confounders. Results: There were 4,410 patients from 91 clinics with a median age of 69 years and a median eGFR at patient questionnaire completion of 29 (21-38) mL/min/1.73 m2. The proportion of patients not at all, somewhat, moderately, very much, and extremely bothered by itchy skin was 49%, 27%, 13%, 7%, and 3%, respectively. Patients with more advanced stages of CKD, older age, and greater comorbidities reported to be more likely bothered by itchy skin. Among patients at least moderately bothered, 23% were prescribed at least 1 pharmacotherapy (35% in the United States, 19% in France, 4% in Brazil), including antihistamine (10%), gabapentin (6%), topical corticosteroids (4%), pregabalin (3%), or sedating antihistamine (3%). The HR (95% CI) for patients extremely (vs not at all) bothered was 1.74 (1.11-2.73) for all-cause mortality, 1.56 (1.11-2.18) for all-cause hospitalization, and 1.84 (1.22-2.75) for cardiovascular events. As CKD-aP severity increased, patients also had higher rates of infection events (P = 0.04); CKD-aP severity was not associated with KRT initiation (P = 0.20) or CKD progression (P = 0.87). Limitations: The limitations were 25% nonresponse rate, recall bias, and residual confounding factors. Conclusions: These results demonstrate a strong association between severe itch and clinical outcomes, providing the nephrology community new insights into the possible adverse consequences of CKD-aP in individuals with nondialysis CKD, and warrant further exploration. Plain-Language Summary: Chronic kidney disease-associated pruritus (CKD-aP) is a common disturbing symptom of chronic kidney disease (CKD). This article analyzes longitudinal data from the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) to describe prevalence of CKD-aP in 4,410 individuals with nondialysis CKD, and its association with clinical outcomes. We found that 51% of the surveyed population were bothered by pruritus. CKD-aP was more prevalent in those with more advanced stages of CKD, older age, and with more comorbid conditions. Compared to those not at all bothered by pruritus, those who were extremely bothered had a higher risk of all-cause mortality, hospitalizations, and cardiovascular events. Severity of CKD-aP was not associated with CKD progression or initiation of kidney replacement therapy.

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.

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.

Arteriovenous access creation and hazards of hospitalization and death in patients starting hemodialysis.

BACKGROUND: Recent evidence suggests overestimation of benefits associated with arteriovenous (AV) fistula versus graft in certain populations. We assessed hazards of all-cause and cause-specific hospitalization and death associated with AV access type in patients who started hemodialysis with a catheter in France, overall and by subgroups of age, sex, and comorbidities. METHODS: From the REIN Registry, we included patients who initiated hemodialysis with a catheter from 2010 through 2018, and identified first-created fistula or graft through the French national health-administrative database. We used joint frailty models to deal with recurrent hospitalizations and potential informative censoring by death, and inverse probability weighting to account for confounding. RESULTS: From the 18 800 patients included (mean age 68 ± 15 years, 35% women), 5% underwent AV graft creation first. Weighted hazard ratio (wHR) of all-cause hospitalization associated with graft was 1.08 (95% CI 1.02 to 1.15), that of vascular access-related hospitalization was 1.43 (95% CI 1.32 to 1.55), and those of cardiovascular- and infection-related hospitalizations were 1.14 (95% CI 1.03 to 1.26) and 1.11 (95% CI 0.97 to 1.28), respectively. Results were consistent for most subgroups, except that the highest hazard of all-cause, cardiovascular-, and infection- related hospitalizations with graft was blunted in patients with comorbidities (i.e. diabetes, wHR 1.01, 95% CI 0.93 -1.10; 1.10, 95% CI 0.96 to 1.26; and 0.94, 95% CI 0.78 to 1.12, respectively). CONCLUSIONS: In patients starting hemodialysis with a catheter, AV graft creation is associated with increased hazard of vascular access-related hospitalizations compared to fistula. This may not be the case for death or other causes of hospitalization.

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

BACKGROUND: 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 3 011 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 third of patients had 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. A better attention to dynamic changes of haemoglobin in CKD should be paid.

Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

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.

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.

Understanding International Variations in Kidney Failure Incidence and Initiation of Replacement Therapy.

Introduction: Incidence of kidney replacement therapy (KRT) varies widely across countries. Its relations to individual characteristics, nephrology practices for slowing chronic kidney disease (CKD) progression, and KRT access remain unclear. Methods: We investigated intercountry differences in kidney failure (KF) rate, defined by a sustained estimated glomerular filtration rate (eGFR) <15 ml/min per 1.73 m2, and separately in KRT incidence, before and after adjusting for risk factors and blood pressure (BP) control or renin-angiotensin-aldosterone system inhibitor (RAASi) prescription practices in the CKD Outcomes and Practice Patterns Study (CKDopps) cohort study. Results: Among 7381 patients with CKD stage 3 to 4 at enrollment, 1297 progressed to KF and 947 initiated KRT over a 3-year follow-up period. Compared to the United States, demographic-adjusted and eGFR-adjusted hazard ratios (HRs) (HRs, 95% confidence intervals [CI]) for a sustained low eGFR were 0.77 (95% CI, 0.57-1.02) in Brazil, 0.90 (95% CI, 0.75-1.08) in France, and 1.03 (95% CI, 0.86-1.03) in Germany. Further adjustment for comorbidities, albuminuria, systolic BP, and RAASi prescription did not substantially change these HRs. In contrast, compared with the United States, the fully-adjusted HR for KRT remained significantly lower in Brazil (0.55, 95% CI 0.39-0.79), higher in Germany (95% CI, 1.36, 1.09-1.69), and similar in France (95% CI, 1.07, 0.81-1.39). Conclusion: Individual risk factors for CKD progression in nephrology patients appeared to explain most intercountry variations in KF but not KRT incidence. This suggests a prominent role for differences in practices related to KRT initiation or access, but not those for slowing disease progression. This study also shows that using KRT as a KF surrogate may bias estimates of associations with CKD progression risk factors.

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.

Potential Surrogate Outcomes for Kidney Failure in Advanced CKD: Evaluation of Power and Predictive Ability in CKDopps.

RATIONALE & OBJECTIVE: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. STUDY DESIGN: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). SETTING & PARTICIPANTS: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. OUTCOMES: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. ANALYTICAL APPROACH: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. RESULTS: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. LIMITATIONS: Variable visit frequency resulted in variable eGFR measurement frequency. CONCLUSIONS: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.

[CKD care in French nephrology practices]. / Réalité de la prise en charge de la maladie rénale chronique en néphrologie en France : étude de cohorte CKD-REIN.

BACKGROUND: To be able to assess the impact of the bundled payment system on real-life management of patients with chronic kidney disease, an overview of patient-care management before its implementation is needed. PATIENTS AND METHODS: We describe patterns of nephrology care over 3 years in 2835 patients with moderate to severe chronic kidney disease, who were followed-up from 2013 to 2019 in the CKD-REIN cohort study. Compliance with health authority guidelines during this period is also studied. RESULTS: At baseline, patients' mean age was 67 years, 65% were men, and 43% had chronic kidney disease stage 4 or 5. The mean number of nephrology visits increased from 1.1 to 2.7 per year, from chronic kidney disease stage 3A to stage 5. The minimum number of nephrology visits as recommended by health authorities was achieved in 84%, 63%, and 33% of patients with chronic kidney disease stages 3B, 4, and 5, respectively. In chronic kidney disease stages 4 and 5, only 34% and 40% of patients had seen a dietitian, and 33% and 54% had received information about treatment options, respectively. The average waiting time for a first appointment with a nephrologist was longer, 60 days and its duration shorter, 30 vs 38 to 40 minutes, in university hospitals compared with non-university hospitals and private clinics. CONCLUSION: The significant gap between received and recommended care reflects human resources and organizational limits in chronic kidney disease management in the nephrology setting. Improvements with bundled payment are expected.

Adherence to the Kidney Disease: Improving Global Outcomes CKD Guideline in Nephrology Practice Across Countries.

INTRODUCTION: The uptake of the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 chronic kidney disease (CKD) Guideline is not fully described in real-world nephrology practice across the world. METHODS: We used baseline data from the CKD Outcomes and Practice Patterns Study (2013-2017), a 4-country cohort of patients with estimated glomerular filtration rate <60 ml/min per 1.73 m2 recruited from national samples of nephrology clinics, to describe adherence to measures for monitoring and delaying CKD progression. Data were collected as in clinical practice, except laboratory measures per protocol in France. RESULTS: The mean age ranged from 65 years in Brazil to 72 years in Germany. Albuminuria (mostly proteinuria) was measured routinely in 36% to 43% of patients in Brazil, Germany, and the United States. Blood pressure control (≤140/90 mm Hg) ranged from 49% in France to 76% in Brazil; <40% of patients had blood pressure ≤130/80 mm Hg everywhere but Brazil (52%). More than 40% of nephrologists in Brazil reported a systolic blood pressure target ≤130 mm Hg for nondiabetic patients without proteinuria, but only 19% to 24% elsewhere. Prescription of renin-angiotensin aldosterone system inhibitors ranged from 52% in the United States to 81% in Germany. Dietary advice was more frequent for salt than protein intake; dietitian visits were uncommon. In nondiabetic patients, achievement of all 3 targets including blood pressure ≤130/80 mm Hg, renin-angiotensin aldosterone system inhibition, and dietary advice, ranged from 10% in the United States to 32% in Brazil; in treated diabetic patients, this ranged from 6% to 11% after including hemoglobin A1c target. CONCLUSION: Adherence to recommendations to slow CKD progression is low in typical practice settings, and substantial variation among countries for some indicates opportunities for improvement.

Worldwide Disparity in the Relation Between CKD Prevalence and Kidney Failure Risk.

INTRODUCTION: The incidence of kidney replacement therapy (KRT) for kidney failure varies internationally much more than chronic kidney disease (CKD) prevalence. This ecologic study investigated the relation of CKD prevalence to KRT and mortality risks by world region. METHODS: We used data from Global Burden of Disease and KRT registries worldwide with linear models to estimate the percentages of variance in KRT incidence and all-cause mortality explained by age-adjusted prevalence of CKD stages 3 to 5, overall and by gender, in 61 countries classified in 3 regions: high income (n = 28), Eastern and Central Europe (n = 15), and other (n = 18). RESULTS: The incidence of KRT ranged from 89 to 378 per million population in high-income regions, 32 to 222 per million population in Central and Eastern Europe, and 22 to 493 per million population in the other region; age-adjusted CKD prevalence ranged from 5.5% to 10.4%, 7.6% to 13.7%, and 7.4% to 13.1%, respectively. The relation between these indicators was positive in high-income countries, negative in Central and Eastern Europe, and null in the other region. Age-adjusted CKD prevalence explained 40% of the variance in KRT incidence (P < 0.001) in high-income countries. The explained variance of age-adjusted mortality was close to 0 in high-income countries and positive at 19% (P = 0.10) in Central and Eastern Europe and at 11% (P = 0.17) in the other region. Results were consistent by gender. CONCLUSION: This study raises awareness on the significant part of the gaps in KRT incidence across countries not explained by the number of individuals with CKD, even in high-income countries where access to KRT is not limited.

Practice patterns of dialysis access and outcomes in patients wait-listed early for kidney transplantation.

BACKGROUND: Early kidney transplantation (KT) is the best option for patients with end-stage kidney disease, but little is known about dialysis access strategy in this context. We studied practice patterns of dialysis access and how they relate with outcomes in adults wait-listed early for KT according to the intended donor source. METHODS: This study from the REIN registry (2002-2014) included 9331 incident dialysis patients (age 18-69) wait-listed for KT before or by 6 months after starting dialysis: 8342 candidates for deceased-donor KT and 989 for living-donor KT. Subdistribution hazard ratios (SHR) of KT and death associated with hemodialysis by catheter or peritoneal dialysis compared with arteriovenous (AV) access were estimated with Fine and Gray models. RESULTS: Living-donor candidates used pretransplant peritoneal dialysis at rates similar to deceased-donor KT candidates, but had significantly more frequent catheter than AV access for hemodialysis (adjusted OR 1.25; 95%CI 1.09-1.43). Over a median follow-up of 43 (IQR: 23-67) months, 6063 patients received transplants and 305 died before KT. Median duration of pretransplant dialysis was 15 (7-27) months for deceased-donor recipients and 9 (5-15) for living-donor recipients. Catheter use in deceased-donor candidates was associated with a lower SHR for KT (0.88, 95%CI 0.82-0.94) and a higher SHR for death (1.53, 95%CI 1.14-2.04). Only five deaths occurred in living-donor candidates, three of them with catheter use. CONCLUSIONS: Pretransplant dialysis duration may be quite long even when planned with a living donor. Advantages from protecting these patients from AV fistula creation must be carefully evaluated against catheter-related risks.