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. CKD-REIN is a French, nationwide, prospective cohort of 3,033 nephrology outpatients with CKD (eGFR < 60 mL/min/1.73 m2). 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). At baseline, 987 of the 3009 patients included in this study (median age: 69; men: 66

Abstract Background and Aims Urate Lowering Therapy (ULT) is frequently prescribed to patients with chronic kidney disease (CKD). However, these prescriptions are often inadequate when considering kidney function. Studies evaluating the appropriateness of ULT in the CKD population are predominantly cross-sectional. Yet, the evolution and reassessment of prescriptions remain unexplored in this context. This study aims to assess the prevalence of inappropriate ULT prescriptions (whether contraindications or inappropriately high doses) with regard to kidney function in patients with CKD. Method We used 5-year longitudinal data from the CKD-REIN cohort, a nationwide sample of 3033 nephrology outpatients with moderate-to-advanced CKD. Prescriptions for colchicine, used in the treatment of acute gout attacks, and ULT, such as allopurinol and febuxostat, were prospectively recorded. An inappropriate prescription was defined as the reported prescription of either a contraindicated drug, an indicated drug at an inappropriately high dose level, or a non-recommended prescription relative to the patient's eGFR, as estimated with de-indexed CKD-EPI equation and according to the European (or French if not available) summary of product characteristics. For patients initiating ULT during follow-up, uric acid levels were compared six months before and after the initiation of ULT. Results At baseline, 987 (33%) out of the 3033 included patients (mean ± standard deviation age 67 ± 13 years, 65% men) were prescribed ULT, with 781 (26%) receiving allopurinol and 206 (7%) receiving febuxostat. Compared to patients without a prescription for ULT, those with a ULT prescription were more frequently male, older, had lower kidney function, higher cardiovascular comorbidities, and were more commonly prescribed diuretics and inhibitors of the renin-angiotensin system. Moreover, their uric acid levels were lower (patients with ULT prescription 377.0 ± 110.4 µmol/L versus without ULT prescription 456.5 ± 116.4 µmol/L, p < 0.001). Notably, 316 (40%) allopurinol prescriptions were prescribed at inappropriately high dosages, while 77 (37%) febuxostat prescriptions were not recommended (resulting in a total of 393 (40%) inappropriate ULT prescriptions at baseline). Of the 54 colchicine prescriptions, one-third (n = 18) were contraindicated according to kidney function and nine were prescribed “on-demand” for crisis anticipation. During a median follow-up of 5.0 [1st-3rd quartile, 4.0–5.1] years, 253 patients were newly prescribed allopurinol and 176 were newly prescribed febuxostat, 54 (21%) out of 253 new allopurinol prescriptions were at inappropriately high dosages, and 68 (39%) out of the 176 new febuxostat prescriptions were not recommended based on the patient's kidney function (Figure). The majority of initially inappropriate ULT prescriptions (n = 393) remained so during follow-up (274 (70%)). Among the 179 patients initiating ULT during follow-up and with available data on uric acid levels, there was a significant decrease in uric acid levels after ULT initiation compared to before initiation (before: 494.5 ± 146.2 µmol/L versus after 408.5 ± 130.9 µmol/L, p < 0.001). A total of 197 patients had initiated colchicine during follow-up, with 61 (31%) receiving contraindicated prescriptions, and 18 (9%) having “on-demand” prescriptions. Conclusion Our findings emphasize the lack of reassessment of ULT prescriptions during the follow-up of patients with CKD. Colchicine prescriptions in case of severe kidney impairment persist despite contraindications. Further evaluation is required to understand the association between ULT prescriptions and the progression of kidney disease.

ABSTRACT 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.

Background:People with HIV (PWH) are aging. Frailty is an age-related condition predictive of hospitalization and mortality. Here, we assessed the frequency and factors associated with frailty transitions at 1-year follow-up in elderly PWH. Methods:Five hundred eight PWH aged 70 years or older who were on antiretroviral treatment were included in the French multicenter SEPTAVIH study in 2019-2020. Participants were classified as robust, prefrail, or frail according to Fried frailty phenotype at baseline and at 1 year. Logistic regression models were used to evaluate socioeconomic and medical factors associated with transition between frailty states. Models were adjusted for gender, age at baseline, education, and period of HIV diagnosis (before vs after 1996). Results:Seventeen PWH died during the 1-year follow-up. Of the remaining 491 PWH (median age, 73 years), frailty status worsened for 18% of participants and improved for 14% at 1 year. Advanced age, baseline CD4+ T-cell count <350 cells/mm3, and type 2 diabetes were associated with transition from prefrailty to frailty (adjusted odds ratio [aOR], 1.10 per 1-year positive difference; 95% CI, 1.01-1.20; aOR, 3.05; 95% CI, 1.14-8.18; and aOR, 2.63; 95% CI, 1.05-6.57; respectively). Being female was associated with more frequent improvement from prefrailty to robustness (aOR, 2.50; 95% CI, 1.09-5.55). Conclusions:Preventing frailty in elderly PWH is a long-term problem, beginning with the early diagnosis of HIV infection and the management of comorbidities.

ABSTRACT 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.

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.

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 (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. Study Design Prospective cohort study. Setting & Participants Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. Exposure Sex. Outcomes Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic 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. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD 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 hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. Limitations Cardiovascular biomarkers and sex hormones were not assessed. Conclusion This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

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. Plain-Language Summary: Blood pressure (BP) control remains unattained in most patients with chronic kidney disease (CKD), raising questions about how antihypertensive treatment is managed. Our study highlights dynamic, yet heterogeneous patterns of antihypertensive drug prescriptions in patients with CKD stages 3-4 receiving care from a nephrologist over 5 years of follow-up. Modifiable factors such as high body mass index and poor medication adherence were associated with higher hazard of adding-on an antihypertensive drug class, independently of baseline BP and antihypertensive treatment. Similarly, lower education level was associated with antihypertensive drug withdrawn, as was more frequent visits to primary care physicians, underlining the importance of coordinated care. Sustainable reduction in systolic BP after add-on of a drug class is infrequently achieved and may be related to drug withdrawal and poor treatment adherence.

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 fi ltration 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 identi fi ed 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 -speci fi c 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 1 mL/min/1.73 m(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.

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.

Abstract Background and Aims Timely arteriovenous (AV) access creation in view of starting hemodialysis is challenged by non-linear kidney function decline and the prospect of competing mortality. In addition, some studies have shown slower CKD progression following AV access creation in patients not on dialysis. While pathophysiological mechanisms, such as ischemic preconditioning and improved kidney perfusion, have been put forward to explain the apparent influence of AV access creation on estimated glomerular filtration rate (eGFR) trajectory, it cannot be ruled out that this finding resulted from an artefact induced by the use of models assuming linear (eGFR) decline before and after AV access creation. Our aim was to describe the kinetics of eGFR decline around the period of AV access creation and to identify different trajectory profiles using models relaxing this hypothesis. Method From 2013 through 2016, the CKD-REIN cohort included 3033 patients with CKD stages 3 to 5 from 40 nationally representative outpatient nephrology clinics in France. Participants were followed for 5 years or until initiation of kidney replacement therapy (KRT), death, or loss to follow-up, whichever came first. This study focused on patients who underwent their first AV access creation during follow-up. Linear mixed models with restricted cubic spline functions (two internal knots, one at AV access creation date, the other, one year before) were used to model a potential non-linear eGFR trajectory over time, based on routine labs. Random effects for the intercept and the spline function components allowed us to deal with individual variations in eGFR trajectory. Instantaneous rates of eGFR decline around AV access creation were then extracted. In addition, we performed latent class mixed models (LCMM) to identify distinct eGFR trajectories. Results During a median follow-up of 5.0 years (interquartile range [IQR], 4.6 to 5.2), 415 (14% of the total population) patients underwent a first AV access creation (32% women, 51% with diabetes). The median age at AV access creation was 69 years (IQR, 61 to 76), and the median eGFR, 13 ml/min/1.73 m² (IQR, 11 to 16). The median numbers of eGFR measurements before and after creation were 12 (IQR, 8 to 19) and 3 (IQR, 2 to 6) respectively. The average eGFR decline in the year before and after AV access creation, assuming constant slopes in each period, was 5.2 ml/min/1.73m² (95% confidence interval [CI], 4.8 to 5.5) and 3.4 ml/min/1.73 m² (95% CI, 3.1 to 3.7), respectively, with a mean difference of −1.8 ml/min/1.73m2 (95% CI, −1.4 to −2.1). Analysis of instantaneous rates showed that the slowdown of eGFR decline began 8.3 months on average (95% CI, 7.8 to 8.6) before AV access creation. The LCMM identified two profiles of eGFR trajectories which mostly differed in the rate of eGFR decline (Figure). In both trajectories, the mean time to the slowdown of eGFR decline preceded time of AV access creation, by 9.1 and 7.2 months in the fastest and slowest eGFR decline trajectories, respectively. Conclusion In nondialysis patients, slowdown of kidney function decline appears to occur several months before AV access creation. Our findings do not support a causal biological effect of AV access creation on CKD progression, but favor alternative hypotheses including optimal management before AV access creation, greater inaccuracy in eGFR estimation in advanced CKD due to muscle mass loss, or simply regression to the mean.

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

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.

Background: Sex differences in cardiovascular disease (CVD) are well-established in the general population, but whether chronic kidney disease (CKD) modifies sex-specific CVD risk, and whether this may differ according to the atheromatous (ACVD) or non-atheromatous (N-ACVD) nature of CVD is unknown. Methods: We assessed sex differences in the risk of ACVD (ischaemic coronary, cerebral, and peripheral artery disease) and N-ACVD (heart failure, haemorrhagic stroke, and arrhythmias) in 1044 women and 1976 men with CKD (median age, 67 vs. 69 years; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m²). Findings: Over 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 men: 2.1 (95%CI: 1.6;2.5) vs 3.6 (3.2;4.0) (P<0.01); that of N-ACVD was not: 5.7 (5.0;6.5) vs 6.4 (5.8;7.0). There was an interaction (p<0.01) between sex and baseline eGFR in ACVD hazard: the hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated as eGFR decreased, reaching 1.00 (0.62;1.63) at 16 mL/min per 1.73m2. In contrast, N-ACVD hazard did not differ between the sexes across the eGFR range studied. Interpretation: This study shows how the beneficial effects of sex hormones in ACVD risk progressively vanish in women with CKD progression. In contrast, the equal risk of N-ACVD between sexes throughout eGFR levels highlights the important contribution of CKD to the development of this cardiovascular complication. Funding: CKD-REIN is funded by the Agence Nationale de la Recherche through the 2010 «Cohortes- Investissements d’Avenir » program (ANR-IA-COH-2012/3731) and by the 2010 national Programme Hospitalier de Recherche Clinique. CKD-REIN is also supported through a public-private partnership with Fresenius Medical Care and GlaxoSmithKline (GSK) since 2012, Sanofi-Genzyme from 2012 to 2015, Baxter and Merck Sharp & Dohme-Chibret (MSD France) from 2012 to 2017, Amgen from 2012 to 2020, Lilly France from 2013 to 2018, Otsuka Pharmaceutical from 2015 to 2020, AstraZeneca from 2018 to 2021, Vifor France from 2018 to 2022, and Boeringher Ingelheim since 2022.Declaration of Interest: AP, ZM, CC, DF, LF, ML, and BS report conflict of interest with the pharmaceutical companies contributing to the public-private partnership which supported the CKD- REIN cohort study (AstraZeneca, Boeringher Ingelheim, Fresenius Medical Care, GSK, Vifor Fresenius).Ethical Approval: The French National Institute of Health and Medical Research (Inserm) institutional review board (IRB00003888) and the Ethics Committee (CCTIRS12.360/CPP) approved the CKD-REIN study. All patients provided written informed consent before inclusion.