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Background: People with chronic kidney disease (CKD) have an elevated risk of cognitive impairment (CI). Medications with anticholinergic activity are recognized for their adverse reactions on central nervous system. The putative association between the anticholinergic burden and CI has not previously been evaluated in patients with CKD. The study aimed to (i) describe prescriptions of medications with anticholinergic activity, (ii) analyze factors associated with these prescriptions, and (iii) evaluate the anticholinergic burden's association with cognitive performance., Methods: CKD-REIN, a prospective cohort study, enrolled nephrology outpatients with a confirmed diagnosis of CKD (eGFR <60 mL/min/1.73m 2 ). Drug prescriptions were recorded prospectively during the 5-year follow-up. Mini Mental State Examination (MMSE) was assessed at baseline and CI was defined as an MMSE score <24/30. For each patient, the anticholinergic burden was determined by summing the Anticholinergic Cognitive Burden (ACB) scores of all prescription drugs at baseline. Multinomial logistic regression was used to analyze factors associated with the ACB score. Logistic regression was used to evaluate the association between the cognitive impairment and the anticholinergic burden at baseline., Results: At baseline, 3007 patients (median age [IQR], 69[60-76]; 65% men) had MMSE data and were included. 1549 (52%) of these patients were taking at least one drug with anticholinergic properties. Most (1092; 70%) had a low anticholinergic burden, 294 (19%) had a moderate anticholinergic burden, and 163 (11%) had a high anticholinergic burden. A history of neurological/psychiatric disorders and a higher number of daily drugs were associated with a greater probability of having a high anticholinergic burden (odds ratio (OR) [95% confidence interval (95% CI)] = 1.88[1.29;2.74] and 1.53[1.45;1.61], respectively). Patients with a high anticholinergic burden had a significantly higher probability of presenting cognitive impairment, compared with patients without an anticholinergic burden (OR[95% CI] = 1.76[1.12;2.75]) after adjustment for sociodemographic factors, comorbidities, laboratory data, and the number of medications taken daily., Conclusions: The results of our study emphasize the need for caution in the prescription of drugs with anticholinergic properties to patients with CKD., (© 2024 The Author(s). Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Hyperuricemia is a hallmark of gout and a suspected risk factor for the progression of chronic kidney disease (CKD). However, the impact of urate-lowering therapy on CKD progression is subject to debate. The objective of the present study was to describe the prevalence of inappropriate urate-lowering therapy prescriptions and evaluate the association between urate-lowering therapy prescription and the progression of kidney disease in patients with CKD., Methods: CKD-REIN is a French, nationwide, prospective cohort of 3,033 nephrology outpatients with CKD (eGFR < 60 mL/min/1.73 m 2 ). Prescriptions of urate-lowering therapy drugs (allopurinol or febuxostat) were recorded prospectively. The appropriateness of each prescription was evaluated according to the patient's kidney function at baseline and during follow-up. Propensity score-matched, cause-specific Cox proportional hazards regression models were used to assess the association between incident urate-lowering therapy use and CKD progression (defined as the initiation of kidney replacement therapy (KRT) but also in other ways)., Results: At baseline, 987 of the 3009 patients included in this study (median age: 69; men: 66%) were receiving urate-lowering therapy; 396 of these 987 patients were receiving an inappropriate prescription with regard to their kidney function. During a 5-year follow-up period, 70% of the 396 urate-lowering therapy prescriptions remained inappropriate. In the propensity score-matched cohort (n = 674), 136 patients started KRT. Compared with non- urate-lowering therapy use, urate-lowering therapy use was not significantly associated with a slowing in CKD progression, regardless of the definition used (HR KRT 0.89, 95% CI 0.67-1.20)., Conclusions: Our real-world data emphasized the lack of reassessment of urate-lowering therapy prescriptions in patients with CKD. Urate-lowering therapy was not associated with a slowing of CKD progression., Competing Interests: Declarations. Conflict of interest: A.M., S.M.L., S.L., O.L., M.L. have nothing to declare. Z.A.M. reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, AstraZeneca, Vifor and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. N.A.P. declares financial support from pharmaceutical companies who are members of the CKD-REIN public–private partnership: Fresenius Medical Care, GlaxoSmithKline, Vifor France, and Boehringer Ingelheim; all grants were made to Paris Saclay University. D.F. has received grants and lecture fees from Astellas, GlaxoSmithKline, Dr Schar, Theradial, and AstraZeneca. Ethical approval: The study protocol was approved by the institutional review board at the French National Institute of Health and medical research (INSERM; reference: IRB00003888). Statement of human and animal rights: This article does not contain any studies with animals. Informed consent to participate: Patients provided informed consent to participate., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: We sought to comprehensively describe drug-related components associated with acute kidney injury (AKI) in patients with chronic kidney disease (CKD), describing the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the 1-year incidences of the recurrence of drug-related AKI, kidney failure, and death., Methods: CKD-REIN is a French national prospective cohort of 3033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR <60 ml/min/1.73 m²). AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital reports, medical records, and patient interviews. Expert nephrologists used the KDIGO criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs)., Results: Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3033 study participants. The drug-related component associated with AKI accounted for 236 cases, and 28% were judged to be preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. A history of cardiovascular events, diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥5 drugs taken daily were associated with a greater risk of drug-related AKI. Full recovery was not attained in 64 (27%) of the 236 cases of drug-related AKI. The 1-year cumulative incidences of recurrence of drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI., Conclusions: Drug-related AKI is prevalent among patients with CKD. Even though a substantial proportion of these events were classified as stage 1, our findings point to a poor prognosis., Competing Interests: S.M.L., S.L., J.V., V.G.C., and J.M. have nothing to declare. Z.A.M. reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Sanofi- Genzyme, Lilly, Otsuka, AstraZeneca, Vifor and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. N.A.P. declare financial support from pharmaceutical companies integrating the public-private partnership of the CKD-REIN cohort: Fresenius Medical Care, GlaxoSmithKline (GSK), Vifor France, and Boeringher Ingelheim; all grants are made to Paris Saclay University., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Rationale & Objective: Sex differences in cardiovascular disease (CVD) are well established, but whether chronic kidney disease (CKD) modifies these risk differences and whether they differ between atheromatous CVD (ACVD) and nonatheromatous CVD (NACVD) is unknown. Assessing this interaction was the principal goal of this study., Study Design: Prospective cohort study., Setting & Participants: Adults enrolled in the CKD-REIN (CKD-Renal Epidemiology and Information Network) cohort, a nationally representative sample of 40 nephrology clinics in France, from 2013 to 2020., Exposure: Sex., Outcomes: Fatal and nonfatal composite ACVD events (ischemic coronary, cerebral, and peripheral artery disease) and composite NACVD events (heart failure, hemorrhagic stroke, and arrhythmias)., Analytical Approach: Multivariable cause-specific Cox proportional hazards models., Results: 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs 69y; mean estimated glomerular filtration rate [eGFR], 32±12 vs 33±12mL/min/1.73m 2 ) were studied. During a median follow-up of 5.0 (IQR, 4.8-5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than in men, at 2.1 (95% CI, 1.6-2.5) versus 3.6 (3.2-4.0; P<0.01), whereas the NACVD rate was not, at 5.7 (5.0-6.5) versus 6.4 (5.8-7.0; P=0.55). NACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted HR for women versus men was 0.42 (0.25-0.71) at 45mL/min/1.73m 2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62-1.63) at 16mL/min/1.73m 2 . In contrast, the NACVD hazard did not differ between sexes across the eGFR range studied., Limitations: Cardiovascular biomarkers and sex hormones were not assessed., Conclusions: This study shows how the lower risk of ACVD among women versus men attenuates fully with kidney disease progression. The equal risk of NACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type., Plain-Language Summary: Sex differences in the risks of atheromatous and nonatheromatous cardiovascular disease (CVD) are well established in the general population. If or how chronic kidney disease (CKD) might modify these risks is unknown. In this large cohort of 3,010 patients with CKD, women had a lower risk than men of atheromatous CVDs such as coronary artery disease or stroke when they were at an early stage of CKD. This advantage, partly due to women's better cardiovascular risk profile, tended to attenuate as CKD progressed to kidney failure. In contrast, the risk of nonatheromatous CVDs such as heart failure for women with CKD appeared similar to that of men with CKD at all kidney function levels., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Blood pressure (BP) control is essential for preventing cardiorenal complications in chronic kidney disease (CKD), but most patients fail to reach BP target. We assessed longitudinal patterns of antihypertensive drug prescription and systolic BP., Study Design: Prospective observational cohort study., Setting & Population: In total, 2,755 hypertensive patients with CKD stages 3-4, receiving care from a nephrologist, from the French CKD-Renal Epidemiology and Information Network (CKD-REIN cohort study)., Exposure: Patient factors, including sociodemographic characteristics, medical history, and laboratory data, and provider factors, including number of primary care physician and specialist encounters., Outcomes: Changes in antihypertensive drug-class prescription during follow-up: add-on or withdrawal., Analytical Approach: Hierarchical shared-frailty models to estimate hazard ratios (HR) to deal with clustering at the nephrologist level and linear mixed models to describe systolic BP trajectory., Results: At baseline, median age was 69 years, and mean estimated glomerular filtration rate was 33 mL/min/1.73 m². In total, 66% of patients were men, 81% had BP ≥ 130/80 mm Hg, and 75% were prescribed ≥2 antihypertensive drugs. During a median 5-year follow-up, the rate of changes of antihypertensive prescription was 50 per 100 person-years, 23 per 100 for add-ons, and 25 per 100 for withdrawals. After adjusting for risk factors, systolic BP, and the number of antihypertensive drugs, poor medication adherence was associated with increased HR for add-on (1.35, 95% confidence interval [CI], 1.01-1.80), whereas a lower education level was associated with increased HR for withdrawal (1.23, 95% CI, 1.02-1.49) for 9-11 years versus ≥12 years. More frequent nephrologist visits (≥4 vs none) were associated with higher HRs of add-on and withdrawal (1.52, 95% CI, 1.06-2.18; 1.57, 95% CI, 1.12-2.19, respectively), whereas associations with visit frequency to other physicians varied with their specialty. Mean systolic BP decreased by 4 mm Hg following drug add-on but tended to increase thereafter., Limitations: Lack of information on prescriber and drug dosing., Conclusions: In patients with CKD and poor BP control, changes in antihypertensive drug prescriptions are common and relate to clinician preferences and patients' tolerability. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved., (© 2024 The Authors.)

Depression is common in patients with chronic kidney disease (CKD). Experimental studies suggest the role of urea toxicity in depression. We assessed both the incidence of antidepressant prescriptions and depressive symptoms (measured by CESD (Center for Epidemiologic Depression) scale) in 2505 patients with CKD (Stage 3-4) followed up over 5 years in the Chronic Kidney Disease Renal Epidemiology and Information Network (CKD-REIN) cohort. We used a joint model to assess the association between the serum urea level and incident antidepressant prescriptions, and mixed models for the association between the baseline serum urea level and CESD score over the 5-year follow-up. Among the 2505 patients, 2331 were not taking antidepressants at baseline. Of the latter, 87 started taking one during a median follow-up of 4.6 years. After adjustment for confounding factors, the hazard ratio for incident antidepressant prescription associated with the serum urea level (1.28 [95%CI, 0.94,1.73] per 5 mmol/L increment) was not significant. After adjustment, the serum urea level was associated with the mean change in the CESD score (β = 0.26, [95%CI, 0.11,0.41] per 5 mmol/L increment). Depressive symptoms burden was associated with serum urea level unlike depression events. Further studies are needed to draw firm conclusions and better understand the mechanisms of depression in CKD.

Background: Recent evidence suggests an overestimation of the 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: We performed a target trial emulation including patients who initiated hemodialysis with a catheter from 2010 through 2018 and were followed by the REIN Registry. We 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. The weighted hazard ratio (wHR) of all-cause hospitalization associated with graft was 1.08 [95% confidence interval (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 to 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 with fistula. This may not be the case for death or other causes of hospitalization., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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/1.73m 2 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 m 2 ); 69% were men, and at inclusion, mean ± SD age: 70 ± 10 years; estimated glomerular filtration rate: 33 ± 11 ml/min/1.73 m 2 . 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., (© 2024 John Wiley & Sons Ltd.)

Background: Chronic kidney disease (CKD) is associated with an elevated risk of neurocognitive disorders (NCDs). It remains unclear whether CKD-related NCDs have a 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 patterns in 3003 CKD patients (stage 3-4) 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 Chronic Kidney Disease Epidemiology Collaboration 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 and cerebrovascular disease, a lower baseline eGFR (per 10 mL/min/1.73 m2) was associated with a 0.53-point decrement [P < .001; 95% confidence interval (CI) (-0.98, -0.08)] for orientation, a 1.04-point decrement [P = .03; 95% CI (-1.96, -0.13)] for attention and calculation, a 0.78-point decrement [P = .003; 95% CI (-1.30, -0.27)] for language, and a 0.94-point decrement [P = .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 performed before clinically cognitive decline using preferably tests assessing executive, attentional functions and language, rather than memory tests. This early cognitive screening could lead to a better management of cognitive impairment and their consequences on CKD management., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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 m 2 . 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 m 2 . 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., Competing Interests: M.P., S.M.L., S.L., S.K. and M.M. have nothing to declare. Z.A.M. reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merrck Sharp & Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, AstraZeneca, Vifor and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline. N.A.P. declare financial support from pharmaceutical companies integrating the public–private partnership of the CKD-REIN cohort: Fresenius Medical Care, GlaxoSmithKline (GSK), Vifor France and Boeringher Ingelheim; all grants are made to Paris Saclay University., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

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 m 2 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 m 2 . 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., (© 2023 The Authors.)

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.

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 m 2 ), 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., Competing Interests: C.E.C., I.A.L., N.A.D.P., O.L., C.C., D.F., L.F., C.J., M.L., S.La., C.L., J.-C.A. and S.Li. declare no conflict of interest. Z.A.M. reports having received grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Sanofi- Genzyme, Lilly, Otsuka, AstraZeneca, Vifor and the French government, as well as fees and grants to charities from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. The sponsors had no role in the design, execution, interpretation, or writing of the study., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

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 (R 2 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., (© 2023 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

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.

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 m 2 and 387 patients (13.0%) had an MMSE score below 24 at baseline. A 10 mL/min/1.73 m 2 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 m 2 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., Competing Interests: Competing interests: BS reports grants for the CKD-REIN cohort study from Amgen, AstraZeneca, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, and Vifor France. ZAM reports grants for CKD-REIN and other research projects from Amgen, Baxter, Fresenius Medical Care, GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka and the French government, as well as fees and grants to charities from Astellas, Baxter, Daichii and Sanofi-Genzyme; these sources of funding are not necessarily related to the content of the present manuscript. DF reports grants for other research projects from Fresenius Kabi and Sanofi.The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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 m 2 ) 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 m 2 ), 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.

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 m 2 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 m 2 . 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., (Copyright © 2022 by the American Society of Nephrology.)

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 m 2 , 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., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

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 m 2 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 m 2 (interquartile range, 21-36 mL/min/1.73 m 2 ) 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 m 2 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 m 2 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., (© 2021 The Authors.)

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., (Copyright © 2021 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

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 m 2 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., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

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., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

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.

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., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background and Objectives: Cancer survival is improving along with an increase in the potential for adverse kidney effects from antineoplastic treatments or nephrectomy. We sought to describe recent trends in the incidence of kidney failure related to antineoplastic treatments and urinary tract cancers and evaluate patient survival and kidney transplantation access., Design, Setting, Participants, & Measurements: We used the French Renal Epidemiology and Information Network registry to identify patients with kidney failure related to antineoplastic treatments or urinary tract cancer from 2003 to 2015. We identified 287 and 1157 cases with nephrotoxin- and urinary tract cancer-related kidney failure, respectively. The main study outcomes were death and kidney transplantation. After matching cases to two to ten controls ( n =11,678) with other kidney failure causes for age, sex, year of dialysis initiation, and diabetes status, we estimated subdistribution hazard ratios (SHR) of each outcome separately for patients with and without active malignancy., Results: The mean age- and sex-adjusted incidence of nephrotoxin-related kidney failure was 0.43 (95% CI, 0.38 to 0.49) per million inhabitants and 1.80 (95% CI, 1.68 to 1.90) for urinary tract cancer-related kidney failure; they increased significantly by 5% and 2% annually, respectively, during 2006-2015. Compared with matched controls, age-, sex-, and comorbidity-adjusted SHRs for mortality in patients with nephrotoxin-related kidney failure were 4.2 (95% CI, 3.2 to 5.5) and 1.4 (95% CI, 1.0 to 2.0) for those with and without active malignancy, respectively; for those with urinary tract cancer, SHRs were 2.0 (95% CI, 1.7 to 2.2) and 1.1 (95% CI, 0.9 to 1.2). The corresponding SHRs for transplant wait-listing were 0.19 (95% CI, 0.11 to 0.32) and 0.62 (95% CI, 0.43 to 0.88) for nephrotoxin-related kidney failure cases and 0.28 (95% CI, 0.21 to 0.37) and 0.47 (95% CI, 0.36 to 0.60) for urinary tract cancer cases. Once on the waiting list, access to transplantation did not differ significantly between cases and controls., Conclusions: Cancer-related kidney failure is slowly but steadily increasing. Mortality does not appear to be increased among patients without active malignancy at dialysis start, but their access to kidney transplant remains limited., (Copyright © 2020 by the American Society of Nephrology.)

Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m 2 and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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.

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.