Efficacy and safety of direct oral anticoagulants versus vitamin K antagonists in patients on chronic dialysis.

BACKGROUND: Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In a French nationwide registry study of patients on chronic dialysis, we compared the effectiveness and safety of off-label DOAC use vs approved vitamin K antagonist (VKA). METHODS: Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between 1 January 2012 and 31 December 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using propensity score-weighted cause-specific Cox regression, we compared the safety and effectiveness outcomes for DOAC and VKA. RESULTS: A total of 8954 patients received an oral anticoagulant (483 DOAC and 8471 VKA) for the first time after the initiation of dialysis. Over a median (interquartile range) follow-up period of 1.7 (0.8-3.2) years, 2567 patients presented a first thromboembolic event and 1254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA {weighted hazard ratio (wHR) [95% confidence interval (CI)] 0.66 (0.46; 0.94)}. A non-significant trend toward a lower risk of major bleeding events was found in DOAC-treated patients, relative to VKA-treated patients [wHR (95% CI) 0.68 (0.41; 1.12)]. The results were consistent across subgroups and in sensitivity analyses. CONCLUSIONS: In a large group of dialysis patients initiating an oral anticoagulant, the off-label use of DOACs was associated with a significantly lower risk of thromboembolic events and a non-significantly lower risk of bleeding, relative to VKA use. This provides reassurance regarding the off-label use of DOACs in people on dialysis.

Kidney Function Decline and Serious Adverse Drug Reactions in Patients With CKD.

RATIONALE & OBJECTIVE: Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We comprehensively describe ADRs and assess the relationship between estimated glomerular filtration rate (eGFR) and serious ADR risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate to advanced CKD. PREDICTORS: Demographic and biological data (including eGFR), medication prescriptions. OUTCOME: ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. ANALYTICAL APPROACH: Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). RESULTS: During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhage (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death and 22 associated with a life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. The risk of acute kidney injury was 2.2% higher and risk of bleeding ADRs was 8% higher for each 1mL/min/1.73m2 lower baseline eGFR. LIMITATIONS: The results cannot be extrapolated to patients who are not being treated by a nephrologist. CONCLUSIONS: ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease (CKD) have complex clinical presentations, take multiple medications, and often receive inappropriate prescriptions. Using data from a large, prospective CKD cohort, we found a high incidence of serious adverse drug reactions (ADRs). The 2 most common serious ADRs were drug-induced acute kidney injury and bleeding. A large proportion of serious ADRs required hospital admission, and 11% led to death or were life threatening. Lower kidney function was a major risk factor for serious ADRs. Many of these serious ADRs were determined to be partly preventable through greater adherence to prescription guidelines. This report enhances our understanding of the potential toxicity of drugs taken by patients with moderate to advanced CKD. It emphasizes the importance of monitoring kidney function when prescribing drugs, particularly for high-risk medications such as antithrombotic agents.

Statin therapy and the incidence of atherosclerotic cardiovascular events after kidney transplantation.

BACKGROUND: Statins are recommended in kidney transplant recipients (KTRs) - a population with a high risk of major cardiovascular (CV) events. However, the literature data on the effectiveness of statins in KTRs are sparse and inconclusive. The present study's objective was to evaluate the association between statin exposure and atherosclerotic CV events in KTRs and the biochemical effectiveness of statins on the lipid profile. METHODS: 318 consecutive KTRs managed at a single center between 2006 and 2019 were retrospectively included. Those exposed to statins after transplantation were incident users. In all users, statins were indicated for primary CV prevention. Lipid profiles, the occurrence of any atherosclerotic CV events (stroke, myocardial infarction, other atherosclerotic CV events, and atherosclerotic CV deaths) were documented comprehensively. We applied Cox models that included statin exposure as a time-dependent covariate fitted with time-varying inverse probability treatment weighting (IPTW) to assess the effectiveness of statins on atherosclerotic CV events and on all CV events. We built linear mixed models to assess the biochemical effectiveness of statins. RESULTS: During a median [interquartile range] follow-up period of 6.0 [3.9-10.0] years, 27 atherosclerotic CV events occurred in 26 patients. In the Cox models fitted with time-varying IPTW, exposure to statins was not associated with a decrease in atherosclerotic CV events; the hazard ratio (HR) [95% confidence interval (CI)] was 1.16 [0.53-2.53] (p=0.700). In the linear mixed models, statin exposure was associated with significant decrease over time in triglyceride and low-density lipoprotein cholesterol concentrations (p < 0.001). These results were consistent when stratified for the intensity of statin therapy. CONCLUSION: Even though the lipid profile improved, statin exposure was not associated with a decrease in CV events in this real-life, single-center, retrospective, long-term follow-up study of a KTR cohort. Larger, controlled studies are needed to confirm or refute these results.

Urea levels and cardiovascular disease in patients with chronic kidney disease.

BACKGROUND: Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic 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 to 15.1, and T3 ≥ 15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or nonatheromatous 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) eGFR 33.5(11.6) mL/min/1.73 m²), 54% had a history of cardiovascular disease. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular 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 cardiovascular outcomes beyond CV risk factors including eGFR.

Adverse outcomes of proton pump inhibitors in patients with chronic kidney disease: The CKD-REIN cohort study.

AIMS: Long-term use of proton pump inhibitors (PPIs) has been associated with adverse kidney events in the general population, but their impact among chronic kidney disease (CKD) patients is unclear. We studied the prevalence and incidence (new users) of PPI prescriptions and their relation to kidney outcomes and mortality in CKD patients. METHODS: We collected drug prescriptions prospectively in a cohort of 3023 nephrology outpatients with CKD stages 2-5 at inclusion. Hazard ratios (HR, 95% confidence intervals [95% CI]) for acute kidney injury (AKI), end-stage kidney disease (ESKD), and mortality associated with new PPI prescriptions as a time-dependent variable were estimated with cause-specific Cox models in 1940 non-users with eGFR ≥ 15 mL/min/1.73 m2 at baseline, adjusted for comorbidities, laboratory data and drugs. RESULTS: There were 981/3023 (32%) prevalent users (67 ± 13 years, 65% men) at baseline, and 366/3023 (12%) were prescribed PPI (new users) over a median follow-up of 3.9 years (interquartile range, 3-4.2). Among these new users, their median cumulative duration of prescription was 1 year (interquartile range: 0.4-2.3). During follow-up, 354 patients developed ESKD and 216 died before ESKD. The adjusted HRs associated with PPI prescription were 1.74 (95% CI, 1.26-2.40) for ESKD and 2.42 (95% CI, 1.73-3.39) for all-cause mortality. Over the first 3 years of follow-up, 211 AKI events had occurred. The adjusted HR for AKI associated with PPI prescription was 2.89 (95% CI, 1.91-4.38). CONCLUSIONS: Long-term PPI prescription was common in CKD patients. Our results call attention to its potential risks of both acute and chronic kidney failure.

Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease.

BACKGROUND: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. METHODS: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). RESULTS: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2-5.1] and 2.5 [1.3-4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. CONCLUSION: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but-at least in our study setting-not in transplanted patients.

Evaluation of the adequacy of drug prescriptions in patients with chronic kidney disease: results from the CKD-REIN cohort.

AIMS: Drug prescription is difficult to manage in patients with chronic kidney disease (CKD). We assessed the prevalence and determinants of inappropriate drug prescriptions (whether contraindications or inappropriately high doses) with regard to kidney function in patients with CKD under nephrology care. We also assessed the impact of the equation used to estimate GFR on the prevalence estimates. METHODS: The CKD-REIN cohort includes 3033 outpatients with CKD (eGFR between 15 and 60 ml min-1  1.73 m-2 ). We examined the daily doses of pharmacological agents prescribed at study entry. Inappropriate prescription was defined as the reported prescription of either a contraindicated drug or an indicated drug at an inappropriately high dose level with regard to the patient's GFR, as estimated with the CKD-EPI equation, the de-indexed CKD-EPI equation, or the Cockcroft-Gault (CG) equation. Multivariate logistic regression was used to assess the determinants of inappropriate prescription risk. RESULTS: At baseline, patients' median [interquartile range] number of drugs prescribed per patient was 8 [5-10]. Half of the patients had been prescribed at least one inappropriate drug. Anti-gout, cardiovascular agents and antidiabetic agents accounted for most of the inappropriate prescriptions. The percentage of inappropriate prescriptions varied from one GFR equation to another: 52% when using the CKD-EPI equation, 47% when using the de-indexed CKD-EPI equation and 41% with the CG equation. A multiple logistic regression analysis showed significantly higher odds ratios [95% confidence interval] for inappropriate prescriptions in male patients (1.28 [1.07; 1.53]), patients with diabetes (1.34 [1.06; 1.70]), those with a high BMI (1.58 [1.25; 1.99]), and those with a low GFR (10.2 [6.02; 17.3]). The risk of having at least one inappropriate prescription increased with the number of drugs per patient (P for trend < 0.0001) and therefore the odds ratio was 5.88 [4.17; 8.28] for those who received at least 11 prescribed medications compared to those who received fewer than 5. CONCLUSION: Our results emphasize the complexity of drug management for CKD patients, for whom inappropriate prescription appears to be common.

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

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

Medication-overuse headache: A pharmacovigilance study in France.

BACKGROUND: Overusing medication for primary headaches or other medical conditions can lead to dependency and medication-overuse headache (MOH) as an adverse drug reaction (ADR). OBJECTIVES: To analyse reports of ADRs associated with MOH recorded in the French national pharmacovigilance database (FPVD). METHODS: This retrospective study selected all MOH cases reported in the FPVD from January 2000 to June 2023. A search of the High-Level Group Term "headache" was performed for drugs classified under ATC codes for the musculoskeletal and nervous systems. Specific keywords were searched in report narratives to further reduce their number. Voluntary intoxication reports were excluded. Only MOH cases according to the International Classification of Headache Disorders or with a medical diagnosis of MOH were considered. RESULTS: Among the 2674 reports associated with the HLGT "headache", for 649 ATC drug codes, only 234 reports correspond to MOH, primarily notified by physicians. The median age was 45 years (IQR: 32-56), with 74.4% females and approximately 61.0% having pre-existing primary headaches. In all, 53.4% of the reports were classified as serious. Among patients, 84.2% had an isolated "headache" as the ADR. One drug was suspected in 47.4% of cases, two drugs in 29.1%, and three or more in 23.5%. In total, 473 suspected drugs, corresponding to 104 active ingredients, were involved, including analgesics (63.0%), in particular, acetaminophen-containing drugs, opioids, triptans and ergots, and non-steroidal anti-inflammatory drugs (12.7%). Antiepileptics and psycholeptics were found in 6.6% and 6.1% of cases, respectively. Drug withdrawal was successful in 84.6% of drug-discontinuation cases. Warnings about MOH are mentioned in the summary of product characteristics (SmPCs) for triptans, ergots, and certain acetaminophen-containing drugs, but not other drug classes. CONCLUSIONS: Certain drug classes show a high reporting rate of MOH and caution should be exercised when prescribing these drugs. Notably, warnings about MOH must be mentioned in the SmPC of all concerned drug classes.

De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease.

Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73 m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs). Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR <60 mL/min/1.73 m2. The inclusion criteria for this study were the use of OADs and the availability of data on weight, height and serum creatinine. We compared data for three BMI subgroups (group 1 <30 kg/m2; group 2 30-34.9 kg/m2; group 3 ≥35 kg/m2). Inappropriate prescriptions (contraindicated or over-dosed drugs) were assessed with regard to the summary of product characteristics and the patient's kidney function estimated with the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the 2021 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) equation, the European Kidney Function Consortium (EKFC) equation, their deindexed estimates, and the Cockcroft-Gault (CG) formula. The impact of deindexing the equations was evaluated by assessing 1) the difference between the indexed and deindexed eGFRs, and 2) the difference in the proportion of patients with at least one inappropriate OAD prescription between the indexed and deindexed estimates. Results: At baseline, 694 patients were receiving OADs. The median BMI was 30.7 kg/m2, the mean BSA was 1.98 m2, and 90% of patients had a BSA >1.73 m2. Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively -4% and -10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs. Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI.

Urea Level and Depression in Patients with Chronic Kidney Disease.

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 (ß = 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.

Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease.

Background: Kynurenine is a protein-bound uremic toxin. Its circulating levels are increased in chronic kidney disease (CKD). Experimental studies showed that it exerted deleterious cardiovascular effects. We sought to evaluate an association between serum kynurenine levels and adverse fatal or nonfatal cardiovascular events and all-cause mortality in CKD patients. Methods: The CKD-REIN study is a prospective cohort of people with CKD having an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline frozen samples of total and free fractions of kynurenine and tryptophan were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for each outcome. Results: Of the 2406 included patients (median age: 68 years; median eGFR: 25 ml/min/1.73 m2), 52% had a history of cardiovascular disease. A doubling of serum-free kynurenine levels was associated with an 18% increased hazard of cardiovascular events [466 events, HR (95%CI):1.18(1.02,1.33)], independently of eGFR, serum-free tryptophan level or other uremic toxins, cardioprotective drugs, and traditional cardiovascular risk factors. Serum-free kynurenine was significantly associated with non-atheromatous cardiovascular events [HR(95%CI):1.26(1.03,1.50)], but not with atheromatous cardiovascular events [HR(95%CI):1.15(0.89,1.50)]. The association of serum-free kynurenine with cardiovascular mortality was also independently significant [87 events; adjusted HR(95%CI):1.64(1.10,2.40)]. However, the association of serum-free kynurenine with all-cause mortality was no more significant after adjustment on serum-free tryptophan [311 events, HR(95%CI):1.12(0.90, 1.40)]. Conclusions: Our findings imply that serum-free kynurenine, independently of other cardiovascular risk factors (including eGFR), is associated with fatal or nonfatal cardiovascular outcomes, particularly non-atheromatous cardiovascular events; in patients with CKD. Strategies to reduce serum kynurenine levels should be evaluated in further studies.

Fetal and Neonatal Adverse Drug Reactions Associated with Biologics Taken During Pregnancy by Women with Autoimmune Diseases: Insights from an Analysis of the World Health Organization Pharmacovigilance Database (VigiBase®).

INTRODUCTION: Published data on the safety of biologics other than tumor necrosis factor (TNF) inhibitors during pregnancy are limited. OBJECTIVE: The aim was to detect pharmacovigilance signals for fetal and neonatal adverse drug reactions (ADRs) to biologics taken by pregnant women with autoimmune diseases. METHODS: We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database from 1968 to June 1, 2021. Data were collected in June 2021. By using terms for different hierarchical levels of the Medical Dictionary for Regulatory Activities, we selected the following fetal or neonatal ADRs: stillbirth, premature birth, low birth weight, small for gestational age, and congenital malformations. The frequency of all identified ADRs for biologics of interest (adalimumab, infliximab, golimumab, certolizumab, etanercept, anakinra, canakinumab, tocilizumab, sarilumab, ustekinumab, guselkumab, secukinumab, ixekizumab, belimumab, abatacept, and rituximab) was compared with that of all other reports for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval]. Reports with known concomitant use of teratogenic drugs were excluded from the main analysis. Other analyses included ROR stratifications by therapeutic indication in the periods 1968-2021 and 2001-2021, and an analysis after excluding reports with steroids. RESULTS: In the main analysis, the RORs were particularly high for musculoskeletal malformations with anakinra (7.18 [3.50-14.73]), canakinumab (19.54 [12.82-29.79]), and abatacept (5.09 [2.77-9.33]), and for immune system disorders with canakinumab (347.88 [217.9-555.50]) and rituximab (9.27 [2.95-29.15]). After the exclusion of reports with steroids, the ROR was significant for neonatal infections with belimumab (28.49 [5.75-141.25]). CONCLUSION: We identified possible associations with some adverse fetal and neonatal outcomes, suggesting that vigilance is required when prescribing certain biologics during pregnancy.

Drugs associated with incident fragility fractures in kidney transplant recipients.

Background: The risk of fragility fractures is high in kidney transplant recipients, and steroids are reportedly a major cause. Other drugs known to induce fragility fractures have been studied in the general population but not in kidney transplant recipients. Here, we investigated the association between exposure over time to drugs that can injure bone (namely vitamin K antagonists, insulin, loop diuretics, proton pump inhibitors, opioids, selective serotonin reuptake inhibitors, antiepileptics and benzodiazepines) and incident fractures and changes over time in T-scores in this population. Methods: A total of 613 consecutive kidney transplant recipients were included between 2006 and 2019. Drug exposures and incident fractures during the study period were comprehensively documented, and dual-energy X-ray absorptiometry was performed regularly. The data were analyzed using Cox proportional hazards models with time-dependent covariates and linear mixed models. Results: Incident fractures occurred in 63 patients, giving a fracture incidence of 16.9 per 1000 person-years. Exposures to loop diuretics [hazard ratio (95% confidence interval) 2.11 (1.17-3.79)] and opioids [5.94 (2.14-16.52)] were associated with incident fractures. Exposure to loop diuretics was associated with a decrease over time in the T-score for the lumbar spine (P = .022) and for the wrist (P = .028). Conclusions: This study suggests that the exposure to loop diuretics and opioids increases the risk of fracture in kidney transplant recipients.

Chronic kidney disease and nephrological practices in France: lessons from the CKD-REIN cohort, 2013-2023 / Maladie rénale chronique et pratiques néphrologiques en France : leçons de la cohorte CKD-REIN, 2013-2023

Launched in 2013 supported by the Program "Cohorts ­ Investments for the Future", the CKD-REIN (Chronic Kidney Disease ­ Renal Epidemiology and Information Network) study is a prospective cohort that included and followed for 5 years more than 3000 patients with moderate or advanced chronic kidney disease (CKD), from 40 nationally representative nephrology clinics. A large amount of data was collected on CKD and its treatments, patient social characteristics and reported outcomes, and nephrology practices and services. A total of 170,000 blood and urine samples were collected and stored in a central biobank. Coordinated with the CKD outcomes and practice pattern study (CKDopps) and collaborating with the international Network of CKD cohorts (iNETCKD), CKD-REIN contributes to the understanding of CKD and the positioning of France with respect to CKD epidemiology and care in the world. This review highlights major findings from the cohort, and their potential implications for clinical practices and the health system, grouped into the following themes: (1) the complexity of patients with CKD; (2) adherence to clinical guidelines; (3) treatment practices and drug risk; (4) acute on chronic kidney disease; (5) CKD metabolic complications; (6) prediction of kidney failure; (7) sex differences in CKD; (8) patient perspective on CKD; (9) transition to kidney failure and replacement therapy; (10) conservative care.

Lancée en 2013 grâce au Programme « Cohortes ­ Investissements d'Avenir ¼, l'étude CKD-REIN (Chronic Kidney Disease ­ Renal Epidemiology and Information Network) est une cohorte prospective qui a inclus et suivi pendant cinq ans plus de 3 000 patients avec une maladie rénale chronique (MRC) modérée ou avancée, dans 40 consultations de néphrologie, représentatives nationalement. Un grand nombre de données ont été collectées sur la MRC et ses traitements, les caractéristiques sociales et la santé perçue des patients, les pratiques et l'organisation des services de néphrologie. Une biothèque de 170 000 échantillons de sang et d'urine a été constituée et stockée dans une biobanque centrale. Coordonnée avec l'étude Chronic Kidney Disease outcomes and practice pattern study (CKDopps) et collaborant avec l'International Network of CKD cohorts (iNET-CKD), CKD-REIN contribue à l'avancée des connaissances et au positionnement de la France dans le domaine de l'épidémiologie de la MRC et des pratiques dans le monde. Cette revue fait le point des faits marquants de la cohorte, et de leur implication potentielle pour la clinique et le système de santé, regroupés par thème : (1) la complexité des patients avec une MRC ; (2) l'adhésion aux recommandations cliniques ; (3) les pratiques thérapeutiques et le risque médicamenteux ; (4) l'insuffisance rénale aiguë dans la MRC ; (5) l'évolution des complications métaboliques ; (6) la prédiction de la défaillance rénale ; (7) les différences hommes-femmes ; (8) le point de vue des patients sur la MRC ; (9) la transition vers la défaillance rénale et le traitement de suppléance ; (10) le traitement conservateur.

Proton-Pump Inhibitors and Serum Concentrations of Uremic Toxins in Patients with Chronic Kidney Disease.

Use of proton-pump inhibitors (PPIs) is common in patients with chronic kidney disease (CKD). PPIs and many uremic toxins (UTs) are eliminated by the kidney's tubular organic anion transporter system. In a cross-sectional study, we sought to evaluate the association between PPI prescription and serum concentrations of various UTs. We studied a randomly selected sub-group of participants in the CKD-REIN cohort (adult patients with a confirmed diagnosis of CKD and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) with available frozen samples collected at baseline. PPI prescription was recorded at baseline. Serum concentrations of 10 UTs were measured using a validated liquid chromatography tandem mass spectrometry technique. Multiple linear regression was performed, with the log UT concentration as the dependent variable. Of the 680 included patients (median age: 68 years; median eGFR: 32 mL/min/1.73 m2), 31% had PPI prescriptions at baseline. Patients using PPIs had higher levels of certain UTs in comparison to other patients, including total and free indoxyl sulfate (IS), total and free p-cresylsulfate, total and free p-cresylglucuronide (PCG), phenylacetylglutamine (PAG), free kynurenine, and free hippuric acid. After adjustment for baseline co-morbidities, number of co-prescribed drugs, and laboratory data, including eGFR, associations between PPI prescription and elevated serum concentrations of free and total IS, free and total PCG, and PAG remained significant. Our results indicate that PPI prescription is independently associated with serum UT retention. These findings are interesting to better understand the factors that may modulate serum UT concentration in CKD patients, however, they will need to be confirmed by longitudinal studies.

Serum Calcification Propensity Represents a Good Biomarker of Vascular Calcification: A Systematic Review.

Vascular calcification contributes to cardiovascular morbidity and mortality. A recently developed serum calcification propensity assay is based on the half-transformation time (T50) from primary calciprotein particles (CPPs) to secondary CPPs, reflecting the serum's endogenous capacity to prevent calcium phosphate precipitation. We sought to identify and review the results of all published studies since the development of the T50-test by Pasch et al. in 2012 (whether performed in vitro, in animals or in the clinic) of serum calcification propensity. To this end, we searched PubMed, Elsevier EMBASE, the Cochrane Library and Google Scholar databases from 2012 onwards. At the end of the selection process, 57 studies were analyzed with regard to the study design, sample size, characteristics of the study population, the intervention and the main results concerning T50. In patients with primary aldosteronism, T50 is associated with the extent of vascular calcification in the abdominal aorta. In chronic kidney disease (CKD), T50 is associated with the severity and progression of coronary artery calcification. T50 is also associated with cardiovascular events and all-cause mortality in CKD patients, patients on dialysis and kidney transplant recipients and with cardiovascular mortality in patients on dialysis, kidney transplant recipients, patients with ischemic heart failure and reduced ejection fraction, and in the general population. Switching from acetate-acidified dialysate to citrate-acidified dialysate led to a longer T50, as did a higher dialysate magnesium concentration. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with a lower serum calcification propensity. Serum calcification propensity is an overall marker of calcification associated with hard outcomes but is currently used in research projects only. This assay might be a valuable tool for screening serum calcification propensity in at-risk populations (such as CKD patients and hemodialyzed patients) and, in particular, for monitoring changes over time in T50.

Effectiveness and Tolerance of Renin-Angiotensin System Inhibitors With Aging in Chronic Kidney Disease.

OBJECTIVES: Renin-angiotensin system inhibitors (RASi) are recommended for slowing chronic kidney disease (CKD) progression to kidney failure. Their effectiveness and tolerance as patients age remain uncertain because older patients have often been excluded from clinical trials. DESIGN: CKD-REIN cohort study. SETTING AND PARTICIPANTS: We studied 2762 patients with CKD stages 3 and 4 and a clinical indication for RASi enrolled between 2013 and 2016 in 40 nephrology clinics nationally representative in France. METHODS: The primary outcome was the occurrence of kidney failure or death. The secondary outcomes were the occurrence of cardiovascular events and hospitalizations with acute kidney injury (AKI) or hyperkalemia. A propensity score analysis was performed. We used Cox models to estimate hazard ratios (HRs) for each outcome associated with RASi prescription and tested interactions with age. RESULTS: Patients' mean age was 67 years, including 841 (30%) aged 75 years and older; 2178 (79%) were prescribed RASi's. During a median follow-up of 4.6 years, 33% of patients reached kidney failure or died. RASi prescription was associated with a lower risk of kidney failure or death (HR 0.79, 95% CI 0.66, 0.95), an association not modified by age (P for interaction = .72). It was not significantly associated with cardiovascular events. During the first 3 years of follow-up, 14% of patients were hospitalized with AKI or hyperkalemia, but risk was not higher among those prescribed RASi's (HR 0.75, 95% CI 0.55-1.02) and age did not modify its effect (P for interaction = .28). CONCLUSIONS AND IMPLICATIONS: This study shows that aging does not appear to modify either RASi's beneficial effects on major CKD outcomes or their potential adverse effects.

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins.

Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota's activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.