Natalia Alencar de Pinho

Aims: Chronic inflammation is associated with cardiovascular disease in the general population, but data on patients with chronic kidney disease (CKD) are limited. We sought to assess whether systemic low-grade inflammation is independently associated with cardiovascular events in CKD patients not yet on kidney replacement therapy, with or without a history of atherosclerotic cardiovascular disease (ASCVD). Methods: The French CKD–Renal Epidemiology and Information Network is a prospective cohort study of adults with CKD stages 2–5, conducted in 40 French nephrology outpatient facilities. Baseline high-sensitivity plasma C-reactive protein (hs-CRP) was centrally measured using an immunoturbidimetric method. Systemic low-grade inflammation was defined as hs-CRP ≥2 mg/L. Cox proportional hazards models estimated cause-specific hazard ratios (HR) and 95% confidence intervals (CI) for major adverse cardiovascular events (MACE; composite of stroke, myocardial infarction, or cardiovascular death) or hospitalization for heart failure (HHF). Results: We included 2078 patients: 67% men, mean (SD) age 67(13) years, mean estimated glomerular filtration rate 36(12) mL/min/1.73 m2, 38% with history of ASCVD, median hs-CRP concentration 2.4 mg/L (inter-quartile range 1.1–5.1). After median follow-up of 5 years, 171 patients had a MACE and 207 had HHF. After controlling for potential confounders, a two-fold increase in hs-CRP was associated with a 12% (95% CI 0–26) higher cause-specific hazard of MACE and a 26% (95% CI 13–40) higher cause-specific hazard of HHF. Conclusion: In CKD patients not yet on kidney replacement therapy, systemic low-grade inflammation, measured through hs-CRP, is associated with occurrence of cardiovascular events independently of traditional risk factors, including a history of ASCVD.

Background: Renin–angiotensin system (RAS) inhibitors are a cornerstone of cardiovascular and kidney risk modification in chronic kidney disease (CKD). Yet, they are often discontinued in advanced CKD to limit adverse effects or to delay kidney replacement therapy (KRT). Methods: From the CKD-Renal Epidemiology and Information Network prospective cohort study, we selected participants with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 and treated with RAS inhibitors. We performed a target trial emulation with parametric g-formula to compare two strategies: to discontinue or to continue RAS inhibitors. Models were adjusted for sociodemographics, clinical and laboratory characteristics, and drug prescriptions. Outcomes were the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, i.e. major cardiovascular events (MACE), and KRT initiation. Results: Among the 1434 patients included (median age 68 years, median eGFR 25 ml/min/1.73 m2, 35% women), 386 (27%) discontinued RAS inhibitors over a median follow-up of 35 months. Very few events related to adverse drug reactions were reported in the 3 months preceding RAS inhibitor discontinuation (n = 23), but their incidence over this period was ∼13-fold higher than that during the entire follow-up. The 3-year adjusted relative risk of MACE associated to discontinuing RAS inhibitors, compared to continuing, was 2.02 (95% Confidence interval (CI), 1.62–2.47), and that of KRT initiation, 1.34 (95% CI, 1.14–1.60). Discussion: RAS inhibitor discontinuation was strongly associated with MACE and KRT risks, major causes of morbidity, and mortality in advanced CKD. Our findings, consistent with prior data, suggest the risk–benefit balance favors continued use with close monitoring.

Introduction: Hyperkalemia is a life-threatening disorder in chronic kidney disease (CKD), yet the contribution of key factors including age, sex, body mass index, and proteinuria remain controversial. We aimed to identify factors associated with chronic hyperkalemia in a large cohort of patients with gold-standard measured glomerular filtration rate (GFR) and standardized plasma potassium measurements. Methods: This cross-sectional study of 5,046 adults with non-dialysis CKD referred for kidney workup, including radio-isotopic measured GFR, defined hyperkalemia as a plasma potassium concentration ≥5.0 mmol/L or the use of potassium binders. We analyzed demographic, clinical, pharmacological, and biochemical risk factors for hyperkalemia using logistic regression models. Results: Mean measured GFR was 59 ± 26 mL/min/1.73 m2, mean age was 52 ± 15 years, 42% were women, 22% were of sub-Saharan African ancestry, 25% had diabetes, and 36% were kidney transplant recipients. The prevalence of hyperkalemia was 6.4% and increased with declining measured GFR, from 1% in CKD stages 1–2–8% in CKD stage 3 and 21% in stages 4–5. In the multivariable model, measured GFR remained strongly associated with hyperkalemia (OR 1.65 [1.51–1.81] per 10 mL/min/1.73 m2 decrease), an effect amplified in renin-angiotensin-aldosterone system inhibitor (RAASi) users (1.82 [1.61–2.07]) (p for interaction 0.036). Other independently associated factors were diabetes (OR 1.67 [1.38–2.17]), RAASi and calcineurin inhibitor (OR 2.30 [1.72–3.11] and 1.39 [1.06–1.83] respectively), higher urinary albumin-to-creatinine ratio, and lower venous bicarbonate level, whereas female sex (OR 0.71 [0.55–0.92]), sub-Saharan African ancestry (HR 0.68 [0.48–0.94]), and loop diuretics (OR 0.71 [0.51–0.98]) were protective, and age and body mass index showed no independent association. Conclusion: In this large cohort, across the entire range of gold-standard measured GFR, hyperkalemia is driven primarily by reduced kidney function, diabetes, and RAASi, whereas protective factors were female sex, sub-Saharan African ancestry, and loop diuretic therapy. These robust findings, based on unbiased GFR assessment, identify key contributors for individualized prevention of hyperkalemia in CKD.

Background: Chronic kidney disease (CKD) leads to the accumulation of uremic toxins (UTs), including tryptophan-derived metabolites such as kynurenine (KYN), indoxyl sulfate (IS), and indole-3-acetic acid (IAA). IS has been identified as a potential contributor to cognitive impairment (CI), whereas less is known about the other tryptophan metabolites. We aimed to evaluate the association between these toxins related to tryptophan metabolism and CI in patients with CKD. Methods: Three thousand thirty-three patients with CKD stages 2–5 enrolled in CKD–Renal Epidemiology and Information Network (CKD-REIN) cohort. Patients with both UT measurement and cognitive function screening [with mini-mental state examination (MMSE)] were included. CI was defined as an MMSE score ≤ 26/30. Logistic regression was used to assess the association between the studied UTs and MMSE. Results: Of the 2389 included patients [mean (SD) age: 66.5 (12.8) years, 66% males, mean (SD) estimated glomerular filtration rate (eGFR) 34.8 (13.4) ml/min/1.73 m2], 858 patients (35.9%) had an MMSE score ≤26/30. After adjustment for sociodemographic factors, cardiovascular risk factors, cerebrovascular disease, current depression, eGFR, urinary albumin-to-creatinine ratio, and UTs known to be associated with CI, no significant association was found between KYN or IAA and MMSE ≤26/30, whereas IS was significantly associated [Odds Ratio (OR), 95% confidence interval: 1.11 (1.00–1.21)]. Conclusion: Among tryptophan-derived metabolites studied, IS was associated with CI in patients with CKD, in contrast to KYN and IAA. Despite sharing a common origin, the UTs studied follow distinct metabolic pathways with different effects, highlighting the need for further investigation of the tryptophan pathway on CI in CKD.

Background: Dialysate composition is crucial for managing secondary hyperparathyroidism (SHPT) in patients on hemodialysis. Acetate‐based dialysates elevate serum acetate and trigger adverse effects, while citrate and hydrochloric acid formulations might offer distinct clinical benefits. Methods: In this longitudinal observational real-life study, 876 adult patients on hemodialysis were classified by acid component of the dialysate (acetic acid, citric acid, or hydrochloric acid). Monthly pre-dialysis parathyroid hormone (PTH) and bone-mineral biomarkers were measured. A linear mixed model (LMM), adjusted for baseline PTH, demographics, and clinical covariates, evaluated PTH trajectories over two years. The significance of the main effect of dialysate and its interaction with time was assessed using likelihood-ratio tests (LRT). Results: At baseline, serum PTH was significantly higher in the acetate group. The LMM confirmed significant influence of dialysate type (p < 0.001) and its interaction with time (p = 0.048) on PTH trajectories. Over two years, acetate showed a modest, non-significant PTH reduction of 2.9% (95% CI: −8.8% to +3.4%), whereas hydrochloric acid resulted in a significant cumulative PTH reduction of 10.9% (95% CI: −15.7% to −0.2%), with a significantly different yearly slope versus acetate (p = 0.044). Citrate showed a modest, non-significant change compared to acetate (−2.3%; 95% CI: −6.7% to +8.4%). Baseline PTH, phosphate, prior hypercalcemia, and dialysate calcium concentration were major predictors in the model. Conclusions: In adjusted longitudinal analyses, hydrochloric acid–based bicarbonate dialysate was associated with a steeper decline in pre-dialysis PTH over two years compared with acetate, while citrate did not differ from acetate. Prospective studies are needed to confirm whether buffer composition influences PTH control under standardized calcium-bath strategies.

La maladie rénale chronique (MRC) affecte environ 10% de la population adulte et est associée à un risque élevé de progression vers l’insuffisance rénale terminale (IRT), d’événements cardiovasculaires et de décès précoce. Des mesures sont recommandées pour prévenir la progression et les complications de la MRC, mais elles sont souvent basées sur un niveau de preuve faible ou sur la seule opinion d’experts. Dans cette thèse, nous avons utilisé des données observationnelles pour évaluer les pratiques cliniques dans deux domaines clés de la MRC : les abords artérioveineux (AV) en hémodialyse et le contrôle de l’hypertension artérielle (HTA) dans la MRC non terminale. Avec le registre national REIN des traitements de suppléance de l'IRT, nous avons montré que seuls 56% des 53 092 patients adultes incidents en hémodialyse de 2005 à 2013 avaient une voie d’abord AV (fistule ou pontage) créée, telle que recommandée, avant le démarrage de la dialyse, dont 16% étaient non fonctionnelles, nécessitant l'utilisation d'un cathéter associé à une sur-mortalité. La conversion en abord AV fonctionnel était associée à un meilleur pronostic, mais concernait dans les trois premières années de dialyse moins de deux patients sur trois ayant démarré sur cathéter. Dans l’étude de cohorte CKD-REIN, chez 1658 patients avec une MRC modérée à sévère, nous avons mis en évidence un moins bon contrôle de l'HTA et des niveaux de pression artérielle systolique plus élevés en lien avec des apports élevés en sodium, mais pas avec des apports faibles en potassium, évalués sur échantillon urinaire ponctuel. Le ratio sodium/potassium urinaire n'était pas plus discriminant que le sodium seul. Enfin, grâce au réseau International Network of Chronic Kidney Disease cohorts (iNET-CKD), qui inclut 17 cohortes sur 4 continents (N=34 602 patients avec un débit de filtration glomérulaire estimé < 60 mL/min/1,73 m2) nous avons mis en lumière le contrôle médiocre de l’HTA en général dans la MRC au regard des recommandations, avec d'importantes variations entre pays (27 à 61% de pression artérielle ≥140/90 mm Hg) expliquées en partie par les caractéristiques des patients et associées à des profils de traitements antihypertenseurs très différents. En conclusion, cette thèse pointe des écarts importants aux recommandations dans la prise en charge de la MRC en vie réelle et des pistes de prévention des complications liées aux abords AV et un meilleur contrôle de l'HTA.

Background: The Kidney Failure Risk Equation (KFRE) is a widely used tool to estimate the 2- and 5-year risk of progression to kidney failure in patients with chronic kidney disease (CKD). The choice of estimated glomerular filtration rate (eGFR) equation and biomarker may influence its prognostic performance. We aimed at comparing the predictive performance of the KFRE when used with different eGFR equations [CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) vs. EKFC (European Kidney Function Consortium)] and biomarkers (creatinine, cystatin C, or both) in a large French CKD cohort. Methods: We analyzed 2168 patients with CKD stages G3–G5 from the prospective Chronic Kidney Disease Renal Epidemiology and Information Network cohort. Eight eGFR equations were evaluated in combination with both the four- and eight-variable KFRE models. Prognostic performance was assessed at 2 and 5 years using the time-dependent area under the receiver operating characteristic curve (AUROC), Brier scores, calibration plots, and decision curve analysis. Subgroup analyses were performed by age and sex. Results: Discrimination was uniformly high (AUROC > 0.89), but calibration patterns and decision curve analyses differed between equations. The creatinine-based CKD-EPI 2009 equation demonstrated robust and consistent performance across models and time horizons. EKFC equations—especially when using creatinine alone—showed slightly improved clinical utility at the 40% decision threshold. Cystatin C-based equations did not improve KFRE predictions compared to creatinine-based ones. Conclusions: In this French CKD cohort, both CKD-EPI 2009 and EKFC creatinine-based equations supported accurate risk prediction using the KFRE. These findings support the use of EKFC in European clinical practice and reinforce the importance of aligning eGFR equations with the population context when applying prognostic models.

Background: The prevalence of impaired kidney function (eGFR<60mL/min/1·73m2) is higher in People Living with HIV (PLHIV) compared to the general population. We aimed to quantify differences in estimated glomerular filtration rates (eGFR) between PLHIV and HIV-negative individuals in the French population-based CONSTANCES cohort, considering socioeconomic and lifestyle factors, HIV-related history, and potentially nephrotoxic/eGFR-modifying drug use.Methods: We analyzed baseline data (2012-2021) from the prospective French national cohort study CONSTANCES (questionnaire data, medical examination results, and healthcare utilization data from the national medico-administrative database SNDS), including 220,000 participants aged 18-69. PLHIV were identified through linkage to the SNDS and 1:4 matched with same-sex HIV-negative people, on age, year of enrollment, examination center, Sub-Saharan African origin, and sexual orientation (in men). Missing data were handled using multiple imputation by chained equations, separately by sex. eGFR levels were compared by HIV status using linear regression models in each imputed dataset. Multivariable models were adjusted for sociodemographic and lifestyle factors, and treatment with potentially nephrotoxic/eGFR-modifying drugs.Results: The study population included 2,195 men (439 PLHIV, 1,756 HIV-negative) and 365 women (73 PLHIV, 292 HIV-negative). PLHIV had lower education levels, belonged to lower socio-professional categories, and reported more often high-risk substance use than HIV-negative people. In both sexes, living with HIV was associated with lower kidney function. In men, the mean difference in eGFR levels was -7·0mL/min/1·73m2, 95%CI[-8·5mL/min/1·73m2; -5·5mL/min/1·73m2] in the fully adjusted model (p<0·0001). In women, it was -4·9mL/min/1·73m2, 95%CI[-8·8mL/min/1·73m2; -0·9mL/min/1·73m2] (p=0·015). Overall, the prevalence of impaired kidney function was 5·6% in PLHIV vs. 1·0% in HIV-negative people, adjusted OR=5·0, 95%CI[2·5-9·9].Interpretation: Living with HIV is associated with lower eGFR levels after comprehensive adjustment for many confounders. Our findings emphasize the need for regular kidney function assessments and for reducing the use of nephrotoxic drugs among PLHIV.

Urinary albumin-creatinine ratio (UACR) and urinary protein-creatinine ratio (UPCR) are both used in clinical practice to diagnose and monitor chronic kidney disease (CKD). Which measure exhibits stronger associations with clinical outcomes and whether this varies by patient characteristics are unknown. To assess and compare the performance of UACR and UPCR across CKD-related clinical outcomes. Individual patient-level meta-analysis. 38 research and clinical cohorts. 148 994 participants with same-day measurements of UACR and UPCR. We quantified the associations of UACR and UPCR with subsequent clinical outcomes, including kidney failure and cardiovascular events, using Cox proportional hazards regression. Analyses were done in each cohort, followed by random-effects meta-analysis. Subgroups included those based on severity of proteinuria, type 2 diabetes, estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m², and glomerular disease. There were 148 994 participants and 9773 kidney failure events during a median of 3.8 years of follow-up. Higher UACR and UPCR both had a log-linear association with increased risk for kidney failure. The association with kidney failure was somewhat stronger for UACR (adjusted hazard ratio [HR] per SD increment, 2.55 [95% CI, 2.36 to 2.74]) than UPCR (HR, 2.40 [CI, 2.28 to 2.53]; P for comparison2, diabetes, and glomerular disease. Associations between UACR and UPCR were generally similar for cardiovascular outcomes but favored UACR in subgroups with moderately to severely elevated UACR. Assessment of UACR and UPCR in spot urine samples. Overall, UACR was more strongly associated with kidney failure than UPCR (particularly in subgroups with higher UACR), supporting the use of UACR rather than UPCR to diagnose and risk-stratify patients. National Kidney Foundation and National Institute of Diabetes and Digestive and Kidney Diseases.