Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials

INTRODUCTION: Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. METHODS: Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0–12.0 g/dL)/upper (10.5–13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none). RESULTS: Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug. CONCLUSIONS: This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.GOV IDENTIFIERS: NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348. FUNDING: F. Hoffmann-La Roche Ltd, Basel, Switzerland. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0309-6) contains supplementary material, which is available to authorized users

Renal Cell Carcinoma in Native Kidney After Kidney Transplantation: A Multicenter Case Control Study With a Focus on Screening Strategy

Renal cell carcinoma (RCC) of native kidney is more prevalent after kidney transplantation than in the general population. Risk factors and the value of screening remain unclear. We conducted a multicenter case-control study in kidney transplant recipients transplanted between 1989 and 2017. All patients with RCC were included, and two controls were matched to each case. Two centers performed annual screening (AnS group) and the other two had other strategies (OS group). A total of 125 cancers were found in 113 patients. The majority of cancers were stage T1-T2 (92.0%), 1.6% had metastasis at diagnosis and ten (9.0%) had recurrence after nephrectomy. Men [OR 2.2; IC 95% (1.2–4.4); p = 0.02] and acquired cystic kidney disease [OR 3.2; IC 95% (1.8–5.9); p &lt; 0.01] were associated with cancer in multivariate analysis. The 10-year survival was poorer in cases (65.6% vs. 79.1%, p &lt; 0.001). The AnS group had fewer relapses (5.0% vs. 18.2%, p = 0.02) and a lower rate of cancer-related deaths (16.0% vs. 46.1%, p = 0.04). Survival of patients with RCC is lower than in control patients. Annual screening could improve cancer prognosis, its benefit needs to be evaluated in larger studies

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

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 1 mL/min/1.73 m2 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. © 2023 The Author

Association between free light chain levels, and disease progression and mortality in chronic kidney disease

Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa () and lambda () and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain and levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC and levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC and levels were independently associated with CKD stages and 2 microglobulin levels. Elevated FLC and levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC and levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors

Glomérulonéphrites extra-membraneuses idiopathiques (pronostic et traitement)

La glomérulonéphrite extra-membraneuse idiopathique est l une des causes les plus fréquente de syndrome néphrotique de l adulte. Elle se caractérise par la présence d une protéinurie de débit variable pouvant être responsable d un syndrome néphrotique. Le pronostic est lié à l insuffisance rénale qui peut être sévère et nécessiter le recours à la dialyse. Cette étude rétrospective a comparé les effets du traitement symptomatique versus traitement spécifique chez cinquante-cinq patients. Les deux critères d évaluation principaux étaient la réponse au traitement et la survie rénale. La durée de suivi moyenne était de 50,6 +- 53,1 mois. Tous les patients ont bénéficié d un traitement symptomatique bien conduit. Trente-deux patients ont bénéficié d un traitement spécifique. Les thérapeutiques les plus représentées étaient les agents cytotoxiques (notamment le chlorambucil) et les anti-calcineurines. Le débit de protéinurie semblait être le seul facteur influençant la prescription d un traitement spécifique. Il n a été mis en évidence de supériorité du traitement spécifique sur la réponse au traitement et la survie rénale, de même qu il n a pas été mis en évidence de différence entre les traitements spécifiques utilisés. Seule la réponse au traitement et la survenue d une rémission dans le groupe traitement spécifique semblent être prédictives d une meilleure survie rénale. Les données de la littérature sont actuellement insuffisantes pour qu il puisse être formulé de recommandations quant aux indications de traitement. Il semblerait néanmoins que le traitement spécifique soit à réserver aux patients présentant un ou plusieurs facteurs pronostiques péjoratifs. Une meilleure compréhension de la physiopathologie de la maladie et notamment la mise en évidence d anticorps spécifiques permettra peut-être de proposer dans les années à venir des thérapeutiques ciblées et d améliorer le pronostic de la GEM.Idiopathic membranous nephropathy is a frequent cause of nephrotic syndrome in adults, characterized by proteinuria, usually in a nephrotic range. The prognosis depends on renal failure and membranous nephropathy can progress to end-stage renal disease. This retrospective study compared the results of conservative treatment versus specific treatment with immunosuppresive agents. The primary end-points were clinical response and renal survival.The overall follow-up was 50,6 +- 53 months. All patients had conservative treatment. Thirty-two patients had specific treatment. Among immunosuppressive agents, cytotoxic drugs and cyclosporine were the most employed. Severe proteinuria at presentation could predict the outcome of membranous nephropathy, and could influence clinical practice. There is no good evidence in favor of therapies based on immunosuppresive agents on clinical response and renal survival. In immunosuppresive group, a remission could predict a favorable issue. The litterature is too poor to propose recommandations for the treatment of membranous nephropathy. Specific treatment with immunosuppresive agents might be employed for patients with poor prognosis.A better understanding of physiopathology, as identification of specific antigene, might be promising therapeutic interventions in the near future.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Prédiction de la maladie cardiovasculaire après transplantation rénale (Fibroblast Growth Factor-23 et Fetuin-A)

Introduction : La transplantation rénale est grevée par la survenue d évènements cardiovasculaires, liés aux anomalies phosphocalciques induites par l insuffisance rénale, où le fibroblast growth factor-23 (FGF-23) joue un rôle clé et à la diminution des inhibiteurs de la calcification, telle que la fetuin-A. L objectif principal de cette étude était d évaluer si le taux de FGF-23 ou de fetuin-A pouvait prédire la survenue d évènements cardiovasculaires après la transplantation. Patients et méthodes : Les 81 patients transplantés au CHU d Amiens en 2008 ont été étudiés rétrospectivement, avec un suivi de 3,5 ans. Un dosage de FGF-23 et de fetuin-A a été fait le jour de la transplantation, à 4 mois et à 1 an. Les évènements cardiovasculaires (mort subite, syndrome coronarien, accident vasculaire cérébral, maladie vasculaire périphérique) ont été répertoriés. Résultats : Les patients avec un taux de FGF-23 supérieur à la médiane ou un taux de fetuin-A dans le quartile inférieur à 4 mois ont présentés plus d évènements cardiovasculaires, respectivement 22% contre 5% et 33% contre 9% (p<0,05). Ces taux permettaient respectivement de prédire le retour en dialyse ou le débit de filtration glomérulaire. Discussion : L évolution lors des premiers mois après transplantation des taux de FGF-23 et de fetuin-A semble prédictive de la survenue d évènements cardiovasculaires et du devenir de la fonction du greffon. La durée d étude était trop courte pour évaluer l impact de ces deux marqueurs sur la survie. Conclusion : Un taux élevé de FGF-23 et bas de fetuin-A après une transplantation rénale sont des facteurs prédictifs des complications cardiovasculaires et de la survie du greffon.Objectives: Kidney transplantation is characterized by cardiovascular events. They are due to disruption of phosphocalcic metabolism associated with chronic kidney disease and to the decrease of calcification inhibitors. FGF-23 and fetuin-A have a key role in these disturbances. The aim of this study was to evaluate whether the rate of FGF-23 or fetuin-A could predict the occurrence of cardiovascular events after transplantation. Study design: In 81 patients transplanted at the University Hospital of Amiens in 2008, a dosage of FGF-23 and fetuin-A was made retrospectively at the day of transplantation, 4 months and 1 year. Cardiovascular events (sudden death, coronary syndrome, stroke, peripheral vascular disease) were identified. Follow-up was 3.5 years. Results: At 4 months, patients with a rate of FGF-23 higher than the median rate or a rate of fetuin-A in the bottom quartile have shown more cardiovascular events, 22% against 5% and 33% against 9 % (p <0.05). Moreover, the rate of FGF-23 predicted graft survival and the rate of fetuin-A predicted the glomerular filtration rate. Conclusions: High levels of FGF-23 and low levels of fetuin-A after renal transplantation are predictive of cardiovascular complications and graft survival. The study duration was too short to assess the impact of these two markers on survival.AMIENS-BU Santé (800212102) / SudocSudocFranceF