The Medical Device Regulation (MDR) was adopted in 2017 to replace the Medical Device Directive. Key changes included more rigorous clinical evidence requirements, increased scrutiny of notified bodies and improved traceability of medical devices, with the overarching aim to improve their safety and quality. For chronic haemodialysis, the impact of the MDR on devices has been substantial, resulting in niche devices being no longer available, and critical shortages, especially in paediatric nephrology. The EuDial board discussed these developments and concluded that the MDR has had a clear negative impact on innovation. In conjunction with other emerging economic macro-trends, this development heightens the potential for disruptions within critical supply chains. We offer actionable recommendations to optimize the benefits of the MDR and to minimize unintended consequences.

Oxidative phosphorylation is the main source of cellular ATP production and depends on proteins encoded by both mitochondrial and nuclear DNA. Pathogenic variants affecting this dual genetic control cause primary mitochondrial disorders, which follow either maternal inheritance when they affect mitochondrial DNA or autosomal inheritance when they affect nuclear-encoded mitochondrial proteins. Once considered predominantly paediatric conditions, these disorders are increasingly recognized in adults where their clinical presentation is heterogeneous and frequently underdiagnosed, requiring the involvement of various medical specialties.Because of their high energy requirements, kidneys are particularly vulnerable to primary mitochondrial disorders. Tubular epithelial cells rely on oxidative phosphorylation for solute transport, while podocytes require sustained ATP production to preserve the glomerular filtration barrier. Although kidney involvement in adult primary mitochondrial disorders has long been regarded as rare, emerging data indicate that primary mitochondrial-disorders–associated nephropathy (MIDAN) is more common than previously appreciated, yet remains under-recognized, as a cause of adult kidney disease. Renal manifestations include a broad spectrum of glomerular disorders—predominantly focal segmental glomerulosclerosis, often associated with diabetes mellitus and sensorineural hearing impairment—as well as tubulo-interstitial nephritis, which may present as an isolated renal phenotype or as part of a multisystemic disorder.Advances in next-generation sequencing, including mitochondrial genome sequencing and exome or whole-genome sequencing, are transforming the diagnostic approach to MIDAN. Improved recognition of mitochondrial etiologies in adults with unexplained glomerular or tubulo-interstitial kidney disease is essential to optimize diagnosis, management, and genetic counseling.

The transition from advanced chronic kidney disease (CKD) to kidney failure requires comprehensive management to optimize patient outcomes. This crucial period, in practical terms defined by CKD stages G4 and G5, involves complex decision-making regarding kidney replacement therapy, pre-emptive kidney transplantation and conservative kidney management. Patient preferences, quality of life, and comorbidities, especially cardiovascular disease, are essential considerations when making treatment decisions. Importantly, nephroprotective therapies should be continued even at advanced stages of CKD to stabilize kidney function and prevent cardiovascular events. Pre-emptive kidney transplantation, when feasible, offers the best outcomes and should be prioritized. Dialysis initiation should be based on clinical symptoms and shared decision-making with the patient, rather than laboratory values alone. For some, particularly older, patients with substantial comorbidities, conservative kidney management, emphasizing symptom management without kidney replacement therapy, might be preferred. Considerable disparities in access to care exist globally, especially in low- and middle-income countries, highlighting the need for tailored strategies. Registry and cohort studies have provided most of the scientific understanding in this area, but more randomized clinical trials are needed to guide advanced CKD management.

Background:Real-world practices for managing anemia and iron deficiency in chronic kidney disease appear heterogeneous and sometimes controversial. This study aimed to describe the prescribing preferences and habits of French nephrologists in this area. Methods:All nephrologists seeing patients at one of the 40 centers participating in the Chronic Kidney Disease – Renal Epidemiology and Information Network (CKD-REIN) cohort were invited to participate in two waves (2015–2016 and 2019–2020) of a practice survey. The self-administered questionnaires collected information on nephrologists’ characteristics and their management strategies for anemia and iron deficiency in patients with stage 4–5 CKD. Results:A total of 137 nephrologists participated in the first wave and 60 in the second wave. Most reported initiating treatment with erythropoiesis-stimulating agents (ESAs) when hemoglobin levels were between 9.5 and 10.5 g/dL (85% in the first wave and 96% in the second). In patients with anemia and iron deficiency, the thresholds for initiating iron therapy varied widely: for oral iron, transferrin saturation (TSAT) ranged from 10% to more than 35% and ferritin from 50 to 500 μg/L; for intravenous iron, TSAT ranged from 10 to 30% and ferritin from 50 to 500 μg/L. Conclusion:Between 2015–2016 and 2019–2020, French nephrologists’ practices for ESA management were relatively homogeneous and in line with current recommendations. In contrast, approaches to iron deficiency varied greatly among practitioners.

Introduction:Chronic kidney disease (CKD) is associated with systemic inflammation and elevated pro-inflammatory cytokines. While interleukin (IL)-8 has shown harmful cardiovascular effects in preclinical studies, its role in CKD remains underexplored. The study aimed to (i) determine serum IL-8 concentrations across CKD stages, (ii) identify factors associated with IL-8 concentrations, and (iii) evaluate its association with major adverse cardiovascular events (MACEs) and all-cause mortality. Methods:The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) prospective cohort includes CKD patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² not on kidney replacement therapy. Baseline serum IL-8 concentrations were centrally measured. MACE was defined as any cardiovascular death, myocardial infarction, stroke and hospital admission for heart failure. Multivariable linear regression was used to identify factors associated with IL-8 concentrations. Adjusted cause-specific Cox proportional hazard models were used to estimate hazard ratios [hazard ratio (HR) (95% confidence interval)] for the first MACE and for mortality. Results:Among 2389 included patients (66% men; median age 68 years; mean eGFR 34.8 mL/min/1.73 m²), median serum IL-8 concentration was 12.2 pg/mL. Higher IL-8 levels correlated with more advanced CKD (P < .001), and were independently associated with lower eGFR, diabetes, prior cardiovascular disease, anemia, elevated C-reactive protein, more medications and lower serum albumin. Elevated baseline IL-8 was associated with a greater adjusted hazard of MACEs in women [HR for 1-unit change in log(IL-8): 1.75 (1.26; 2.43)] but not in men [HR 1.16 (0.93; 1.45)]. The adjusted HR for all-cause mortality was 1.70 (1.40; 2.06), with no difference between men and women. Conclusion:In a large cohort of patients with moderate-to-advanced CKD, higher IL-8 levels were associated with a greater risk of MACEs in women (but not in men) and higher mortality in both sexes. Further research is needed to assess the potential of IL-8 as a cardiovascular risk biomarker, clarify the clinical significance of the sex difference observed here and determine whether targeting IL-8 could reduce cardiovascular risk in CKD.

Introduction:Chronic kidney disease (CKD) leads to the accumulation of uremic toxins (UTs). Studies have suggested that UTs are associated with cognitive impairment (CI) in patients with CKD. Recently, studies reported that phenylacetylglutamine (PAG) contributes to the association between CKD and CI. However, this association has not been investigated in nondialysis-dependent adults with CKD. Methods:The CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort study included 3033 patients with CKD stages 2 to 5. This cross-sectional analysis included those with a PAG measurement and a mini-mental state examination (MMSE) score within 3 months of each other. CI was defined as an MMSE score ≤ 26 out of 30. Logistic regression was used to assess the association between PAG and CI. Results:Of the 2590 patients included (mean [SD] age: 67 [13] years, mean [SD] estimated glomerular filtration rate [eGFR]: 34 [13] ml/min per 1.73 m2, median [interquartile range, IQR] PAG level: 2.1 [1.2-3.6] mg/l), 908 (35%) presented an MMSE score ≤ 26 out of 30. After adjustment for sociodemographic factors (age, male sex, and educational level), cardiovascular risk factors, cerebrovascular disease, current depression, eGFR, urinary albumin-to-creatinine ratio (uACR), and UTs known to be associated with CI risk, a 2-fold increase in the PAG level was associated with CI (odds ratio [OR] [95% confidence interval]: 1.12 [1.01-1.23]). Conclusion:This study shows that a higher serum PAG level was associated with CI in nondialysis-dependent adults with CKD and highlight a new UT associated with CI in patients with CKD. Further studies are needed to confirm the causal nature of the association and to explore strategies for reducing serum PAG levels to protect cognition.

BACKGROUND:Chronic pain is common in patients with chronic kidney disease (CKD), yet pain management in non-dialysis-dependent CKD (NDD-CKD) is underexplored. Inappropriate analgesic use poses significant risks in this population. OBJECTIVE:To evaluate patterns of analgesic use-specifically opioids and NSAIDs-and associated clinical characteristics in patients with NDD-CKD. METHODS:A systematic review was conducted following PRISMA 2020 guidelines. Databases including PubMed and ClinicalTrials.gov were searched in December 2024 using MeSH terms related to CKD, analgesics, opioids, and NSAIDs. Inclusion criteria targeted NDD-CKD patients with reported analgesic use. Data extraction and risk of bias assessments were performed independently by two reviewers. RESULTS:Nine studies encompassing 3,674,959 patients were included. Opioid use was reported in 324,111 patients (22.8%), while NSAIDs were used in 1,095,052 (77.1%). Opioid use increased with CKD severity and pain intensity, but was associated with higher mortality, especially in frail or comorbid patients. NSAID use was prevalent in early-stage CKD and associated with nephrotoxic risk and may occur without clinician oversight. Regional variation and inconsistent prescribing practices were noted. No study directly compared opioid vs. NSAID outcomes. CONCLUSION:Analgesic use in NDD-CKD is widespread and varies by region, CKD stage, and pain severity. Inadequate pain control is common. Standardized guidelines tailored to CKD patients are urgently needed to optimize pain management while minimizing harm.

Background:Chronic pain significantly impacts health-related quality of life (HRQOL) in patients with non-dialysis chronic kidney disease (ND-CKD), yet the management of pain in this population is challenging. We hypothesized that analgesic prescription practices vary internationally, influencing the pain experience and HRQOL of patients with stage 3-5 ND-CKD. Methods:This descriptive, observational, multinational cohort study utilized data from the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps), enrolling adult patients from nephrology practices in Brazil, France and the USA between 2013 and 2020. Analgesic prescriptions within 6 months before HRQOL assessment were categorized as non-steroidal anti-inflammatory drugs (NSAIDs), opioids or other analgesics. HRQOL was measured using the Kidney Disease Quality of Life Short Form, assessing multiple subdomains. Results:Among 3945 patients, analgesics were most frequently prescribed in the USA across all CKD stages, with opioids prescribed nearly twice as often compared with Brazil and France. NSAIDs are frequently prescribed in Brazil, including in advanced CKD stages, contrasting sharply with practices in France and the USA. Higher reported pain intensity consistently correlated with poorer outcomes across all HRQOL subdomains. Conclusions:This study identifies considerable international variability in pain reporting and analgesic prescription patterns in patients with stage 3-5 ND-CKD. Randomized controlled trials evaluating the efficacy and safety of analgesics are warranted to improve key patient-reported outcomes such as pain in patients with ND-CKD.

Haemodialysis (HD) is a life-saving therapy for individuals with kidney failure. Post-filter haemodiafiltration (HDF) and high-flux HD are the most widely used treatment modalities. To date, five randomized controlled trials (RCTs) have been performed that compare all-cause and cardiovascular (CV) mortality between HDF and low- or high-flux HD in adults receiving maintenance dialysis for at least 1 year. RCTs, meta-analyses and pooled individual patient data analyses have been published on this topic. However, all of them are limited by the heterogeneity of inclusion criteria and significant methodological shortcomings, including informative selection bias and the exclusion of poorly performing patients from the HDF arm after randomization. Given this background, the European Dialysis Working Group of the European Renal Association presents a Consensus Statement on HDF and high-flux HD, addressing three key outcomes: survival, health-related quality of life, and biochemical endpoints. A separate section is dedicated to paediatric patients. We searched five large electronic databases to identify parallel or cross-over RCTs comparing HDF with high-flux HD on pre-defined outcome measures. Using a mini-Delphi method, we developed 22 key consensus points by combining meta-analyses, clinical experience, and expert opinion. They aim to inform and assist in decision making and are not intended to define a standard of care. The key summary point is that HDF appears to be associated with improved overall and CV survival, provided high convection volumes are achieved. The generalizability of these findings to the entire dialysis population depends on the patient's overall health and requires further study.

Furosemide is commonly prescribed to patients with CKD but may impair the kidney's excretion of uraemic toxins (UTs) via the organic anion transporters 1 and 3 (OAT1/OAT3). We evaluated the association between furosemide prescription (status and dose) and free serum levels of OAT1/3-inhibiting UTs in patients with CKD. We included 2,342 patients with CKD (stages 2–5) from the CKD-REIN cohort and with centralized serum UT assay data at baseline. The UT levels were measured using liquid chromatography tandem mass spectrometry. Furosemide prescriptions from any medical doctor were collected by clinical research associates based on the anatomical therapeutic chemical (ATC) code (ATC C03CA01), as were patients’ demographic, clinical, and laboratory characteristics. The OAT1/3-inhibiting UTs identified in a literature review included indoxyl sulphate (IS), kynurenine (Kyn), p-cresyl sulphate (PCS), and indole-3-acetic acid (IAA). Multiple linear regression was used to assess fractions of each UT or their sum (ΣUTsfree) as the dependent variable. Patients prescribed furosemide (n = 799, 34%) were older and had a lower estimated glomerular filtration (eGFR) rate, a higher C-reactive protein level, more comorbidities (cardiovascular (CV) disease, diabetes, acute kidney injury (AKI) history), and more co-prescribed medications than patients not prescribed furosemide. After adjustment for age, sex, the total number of co-prescribed medications, the number of potential OAT1/3 inhibitor drugs, history of AKI and CV disease, serum CRP and albumin levels, diabetes, body mass index, smoking status, urine albumin-creatinine ratio, and eGFR, furosemide prescription was positively associated with ΣUTsfree (+7.0%) and free levels of UTs, Kyn (+5.9%), and PCS (+14.3%). Patients prescribed >120 mg furosemide had significantly higher serum levels of ΣUTsfree (+19.1%), IS (+31.9%), Kyn (+9.3%), PCS (+29.3%) and IAA (+16.9%) than patients not prescribed furosemide. In patients with CKD, furosemide (particularly at doses >120 mg) is independently associated with higher free serum UT levels. Our findings suggested that drug-UT competition contributes to UT accumulation. Submission supported by / on behalf of: CKD-REIN study group

Chronic kidney disease (CKD) is associated to increased inflammation and elevated cytokine levels. Interleukins, a group of cytokines, play a crucial role in immune system development and activity, serving as key effectors and signalling molecules. In CKD patients, pro-inflammatory interleukins tend to be elevated. While interleukin 6 (IL-6) has been extensively studied in the context of CKD, other interleukins, such as interleukin 8 (IL-8), deserve further attention. IL-8 is a chemoattractant cytokine primarily involved in neutrophil activation, which is produced by a wide range of cell types, mainly monocytes and macrophages. IL-8 is produced early in the inflammatory response but can persist for prolonged periods, even days or weeks. Despite experimental data suggesting its potential harmful effects, notably in cardiovascular disease, IL-8 has been poorly studied in patients with CKD. Thus, the objectives of the present study were to (i) describe the serum IL-8 concentration in patients at various CKD stages, (ii) assess the correlation between the estimated glomerular filtration rate (eGFR) and IL-8 concentration, (iii) identify the factors associated with IL-8 levels, and (iv) explore the association between IL-8 levels and the risk of major adverse cardiovascular event (MACE). CKD-REIN is a French, prospective, nationally representative cohort of 3,033 patients with stage 3 to 5 CKD (eGFR <60 mL/min/1.73 m²), recruited from 40 nephrology facilities. Participants were neither on maintenance dialysis nor had received a kidney transplant, and were followed-up for 5 years. Baseline IL-8 serum concentrations were measured centrally using an ELISA method. Since IL-8 concentration was not normally distributed in this population, it was log-transformed for analysis. IL-8 levels were compared across CKD stages using analysis of variance. Multivariate linear regression was performed to identify factors associated with serum IL-8 concentrations (log-transformed). Cox proportional hazards model was used to estimate hazard ratio (HR) for the first major adverse cardiovascular event (MACE, defined as a composite of nonfatal stroke, nonfatal myocardial infarction, hospitalization for heart failure, and cardiovascular death). The models were adjusted for baseline comorbidities, laboratory data and medications. Among the 2,389 patients included, 66% were men, with a median age of 68 [Q1–Q3: 60–76] years, and a mean (SD) eGFR of 34.8 (13.4) mL/min/1.73 m². The median serum IL-8 concentration was 12.2 [Q1–Q3: 8.0-17.7] pg/mL. IL-8 concentrations were significantly inversely correlated with eGFR (r=−0.21, P < 0.001). IL-8 levels varied across CKD stages, with higher concentrations observed in advanced stages (P < 0.001). Serum IL-8 concentration was independently and positively associated with decreasing eGFR, diabetes, history of cardiovascular disease, anaemia, C-reactive protein (CRP) levels, and proton pump inhibitor use. It was negatively associated with serum albumin. CRP (eβCRP = 1.01), eGFR (eβeGFR = 0.99), albumin (eβalbumin = 0.98), and diabetes (eβdiabetes = 1.16) were the strongest predictors of IL-8 levels. The risk of MACE increased with higher baseline serum IL-8 concentrations (HR [95% Confidence Interval] for 1-unit change in log(IL-8), 1.30 [1.09; 1.56]), after adjusting for age, sex, smoking status, history of diabetes, cardiovascular disease, anaemia, eGFR, pulse pressure, body mass index, C-reactive protein, serum albumin, serum urea, urinary albumin-to-creatinine ratio, and baseline prescriptions for proton pump inhibitors, diuretics, statins, and antithrombotic agents. Decline of kidney function was associated with an increase in serum IL-8 levels in patients with moderate-to-advanced CKD. Higher levels of IL-8 were associated to higher risk of MACE, independently of eGFR. These results suggest that IL-8 may serve as a potential biomarker for cardiovascular risk in CKD patients. Further studies are needed to evaluate whether targeting IL-8 could mitigate the risk of cardiovascular outcomes in CKD.

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

Introduction L'anémie, définie par une hémoglobine (Hb) inférieure à 13 g/dL chez les hommes et 12 g/dL chez les femmes, est une complication très fréquente de la maladie rénale chronique (MRC). Dans cette population, plusieurs études ont rapporté une association entre Hb et morbi-mortalité cardiovasculaire (CV) mais n'ont pas considéré les mesures répétées d'Hb, ni étudié l'association selon le sexe et l’âge. Méthodes Nous avons utilisé les données de CKD-REIN, cohorte prospective nationale de sujets présentant une MRC, ni dialysés, ni greffés, et pour cette étude, non traités par agents stimulant l’érythropoïèse (ASE). Toutes les mesures d'Hb ont été analysées de l'inclusion jusqu’à la fin du suivi ou le début d'un traitement par ASE ou la survenue d'un premier évènement parmi 1/ événement cardiovasculaire majeur (ECVM) défini par le décès de cause CV, l'infarctus du myocarde, l'accident vasculaire cérébral et l'hospitalisation pour insuffisance cardiaque, 2/ initiation d'un traitement de suppléance rénale, ou 3/ décès de cause non CV. Nous avons utilisé, pour chaque sous-groupe préalablement défini (femme ≤70 ans et >70 ans, hommes ≤70 ans et >70 ans), un modèle de Cox cause-spécifique ajusté sur des variables sélectionnées par un graphe acyclique orienté. La valeur courante de l'Hb était modélisée en variable dépendante du temps, par une fonction spline si nécessaire, et était préalablement estimée par un modèle conjoint multivarié à effets aléatoires partagés estimé par une approche Bayesienne. Résultats Au total, 2742 patients (551 femmes ≤70 ans, 349 femmes >70 ans, 1009 hommes ≤70 ans et 833 hommes >70 ans) ont été inclus dans l'analyse soit un total de 28 423 mesures d'hémoglobine (médiane 12,9 g/dL). Le suivi médian était de 5,0 ans et 362 ECVM ont été recensés. Aucune association statistiquement significative n'a été trouvée entre la valeur courante d'Hb et le risque instantané d'ECVM chez les hommes. Chez les femmes on retrouvait une courbe en J inversé avec une augmentation prononcée du risque instantané pour des valeurs courantes d'Hb inférieures à 12 g/dl chez les femmes de >70 ans (Fig. 1). Conclusion Chez les patients présentant une MRC et ne recevant pas de traitement par ESA, l'anémie est associée à la survenue d'un ECVM chez les femmes, en particulier celles âgées de plus de 70 ans. Ces résultats appellent à prendre en compte une spécificité liée au sexe et à l’âge dans l'interprétation des valeurs basses d'hémoglobine dans la population MRC.