Dialysis-dependent Chronic Kidney Disease Research Articles

Morphological brain alterations in dialysis- and non-dialysis-dependent patients with chronic kidney disease.

To 1) investigate the morphological brain-tissue changes in patients with dialysis- and non-dialysis-dependent chronic kidney disease (CKD); 2) analyze the effects of CKD on whole-brain cortical thickness, cortical volume, surface area, and surface curvature; and 3) analyze the correlation of these changes with clinical and biochemical indices.This study included normal controls (NCs, n = 34) and patients with CKD who were divided into dialysis (dialysis-dependent chronic kidney disease [DD-CKD], n = 26) and non-dialysis (non-dialysis patients who underwent cranial magnetic resonance imaging scans [NDD-CKD], n = 26) groups. Cortical thickness, volume, surface area, and surface curvature in each group were calculated using FreeSurfer software. Brain morphological indicators with statistical differences were correlated with clinical and biochemical indicators.Patients with CKD exhibited a significant and widespread decrease in cortical thickness and volume compared with NCs. Among the brain regions associated with higher neural activity, patients with CKD exhibited more significant morphological changes in the paracentral gyrus, transverse temporal gyrus, and lateral occipital cortex than in other brain regions. Cortical thickness and volume in patients with CKD correlated with blood pressure, lipid, hemoglobin, creatinine, and urea nitrogen levels. The extent of brain atrophy was further increased in the DD-CKD group compared with that in the NDD-CKD group.Patients with CKD potentially exhibit a certain degree of structural brain-tissue imaging changes, with morphological changes more pronounced in patients with DD-CKD, suggesting that blood urea nitrogen and dialysis may be influential factors in brain morphological changes in patients with CKD.

Complications And Effect on Nutritional Status on Increased Creatinine Levels in Dialysis Dependent Chronic Kidney Disease (CKD) Patients with Special Refrence to Bhopal City

Complications And Effect on Nutritional Status on Increased Creatinine Levels in Dialysis Dependent Chronic Kidney Disease (CKD) Patients with Special Refrence to Bhopal City

Diffusion tensor imaging of the brain white matter microstructure in patients with chronic kidney disease and its correlation with cognition.

In individuals with chronic kidney disease (CKD), neurological damage is commonly observed. This neurodegeneration is closely linked to microstructural damage to the brain white matter due to the high incidence of cognitive dysfunction. However, the specific pathogenesis of CKD nephropathy caused by cognitive system developmental disorders remains unclear. This study aimed to examine the correlation between cognitive impairment and diffusion parameters obtained on diffusion tensor imaging (DTI) of abnormal white matter tracts in CKD patients. Sixty-four patients with CKD were divided into the non-dialysis-dependent CKD (NDD-CKD) group (N = 26) and dialysis-dependent CKD (DD-CKD) group (N = 38) according to the estimated glomerular filtration rate, whereas 43 healthy control subjects (normal control [NC]) were included and underwent cranial magnetic resonance imaging during the same period. Differences in the abnormal white matter microstructure and correlations between them and cognitive scores were assessed using several parameters between the groups. There were more extensive peri-lesions and distant white matter microstructural changes in the DD-CKD and NDD-CKD groups than in the NC group. DTI diffusion parameters in abnormal white matter regions were associated with impaired cognitive function in CKD patients. The DD-CKD group had worse cognitive function and more severe microstructural damage in the cerebral white matter than the NDD-CKD group. CKD patients showed cognitive impairment and changes in the brain white matter microstructure; CKD can lead to extensive white matter tract damage. Additionally, diffusion parameters can be used as a complement to describe structural brain damage in CKD patients.

The arteriovenous fistula and the history of a forgotten pioneer.

The radiocephalic arteriovenous fistula (AVF), first introduced by Dr Kenneth Charles Appell, allowed for the provision of hemodialysis for patients with chronic kidney disease (CKD) and remains a reliable method for vascular access today. The purpose of this study is to review the contributions that led to the development of the AVF. We describe the work of Dr Appell, whose procedure bypassed the need for repeated cannulation in achieving vascular access, transforming the management of patients with dialysis-dependent CKD. A literature search was conducted by searching "arteriovenous fistula," "history of surgery," "hemodialysis," "vascular access," "chronic kidney disease," "repeated cannulation," and "Kenneth Charles Appell" on PubMed, Embase, and Web of Science. Only articles written in English were considered. Before the arteriovenous fistula, glass cannulae were used for vascular access, beginning with Abel's "vividiffusion" apparatus in animals and Haas's experimental dialysis on humans. The use of glass cannulae was continued by Kolff, who transitioned from venipuncture needles to glass cannulae. However, these attempts were complicated by thrombosis, excessive bleeding related to heparin use, and damage to vascular access sites from repeated cannulation. Arteriovenous shunts, using polytetrafluoroethylene tubing, were an improvement from previous attempts at vascular access, but were prone to local bleeding, shunt occlusion, phlebitis, cellulitis, and rarely lasted more than a few months. To address these challenges, Dr Appell created an upper extremity AVF, allowing for the provision of maintenance dialysis without externalized devices, repeated cannulation, and extensive anticoagulant administration. Despite Dr Appell's vision and pioneering contributions to vascular surgery, he has received little credit for his work. The enormous contribution by Dr Appell in the development of the AVF that transformed the modern management of patients with CKD is recognized in this review of the history of vascular access surgery for hemodialysis.

Menstrual Abnormalities and Reproductive Lifespan in Females with CKD: A Systematic Review and Meta-Analysis.

Menstrual abnormalities and shortened reproductive lifespan are associated with shorter life expectancy and higher cardiovascular and osteoporosis risk in the general population, although the magnitude of these reproductive factor irregularities in females with CKD is unclear. This systematic review and meta-analysis aimed to summarize the current knowledge regarding menstrual abnormalities and reproductive lifespan among females with CKD. A comprehensive bibliographic search (MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature [CINAHL]) was completed from database inception to February 2022 to identify all original articles reporting on females of reproductive age with nondialysis-dependent/nonkidney transplant CKD, dialysis-dependent CKD, or kidney transplantation and menstruation patterns, age of menarche, and/or menopause. Data extraction and study quality assessment were completed in duplicate. Random effects meta-analyses were used to derive pooled proportions estimates. Forty-six studies were identified, and 35 were meta-analyzed, stratified by KRT modality and reported outcome. Menstrual abnormalities were present in 19%-47% of patients on hemodialysis and 75% of patients on peritoneal dialysis. Kidney transplantation was associated with a 7%-30% decrease in menstrual abnormalities. Reproductive lifespan was 32 years (95% confidence interval, 30 to 34 years). Although significant heterogeneity was present, study quality ranged from fair to good, and no evidence of publication bias was noted. Menstrual abnormalities and shorter reproductive lifespan are common in females with CKD, although kidney transplantation may improve menstrual health.

Abnormal regional homogeneity and amplitude of low frequency fluctuation in chronic kidney patients with and without dialysis.

The study characterizes regional homogeneity (ReHo) and amplitude of low frequency fluctuations (ALFF) in abnormal regions of brain in patients of chronic kidney disease (CKD). A total of 64 patients of CKD were divided into 26 cases of non-dialysis-dependent chronic kidney disease (NDD-CKD), and 38 cases of dialysis-dependent chronic kidney disease (DD-CKD). A total of 43 healthy controls (normal control, NC) were also included. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and ReHo data was processed for monitoring the differences in spontaneous brain activity between the three groups. ALFF and ReHo values of extracted differential brain regions were correlated to the clinical data and cognitive scores of CKD patients. Non-dialysis-dependent group has increased ALFF levels in 13 brain regions while that of DD group in 28 brain regions as compared with NC group. ReHo values are altered in six brain regions of DD group. ALFF is correlated with urea nitrogen and ReHo with urea nitrogen and creatinine. DD group has altered ReHo in two brain regions compared with NDD group. The differences are located in basal ganglia, cerebellar, and hippocampus regions. Abnormal activity in basal ganglia, cerebellar, and hippocampal regions may be involved in the cognitive decline of CKD patients. This link can provide theoretical basis for understanding the cognitive decline.

Abstract 12626: A Systematic Review and Meta-analysis of Factors Associated With Long-Term Mortality in Adults After Coronary Artery Bypass Graft Surgery

Background: With an ageing and increasingly multi-morbid population, the use of coronary artery bypass grafting (CABG) is expected to increase. As short-term CABG mortality rates have decreased, estimating long-term outcomes for patients with specific risk factors has become more relevant. Previous single observational studies have identified risk factors for adverse long-term outcomes, such as older age and diabetes. Purpose: Understanding the pre-operative characteristics that affect late mortality post-CABG can lead to effective risk stratification and enhancement of secondary prevention programmes, thereby aiming to improve long-term prognosis after the procedure. Methods: MEDLINE, Embase, Google Scholar, and Cochrane electronic databases were searched to identify all relevant articles evaluating associations between pre-operative risk factors and long-term mortality (≥5 years ) post-CABG. Studies with <500 patients were excluded. Results: From 1193 potentially eligible articles, 43 studies met the inclusion criteria. A total of 360,481 patients, with an average follow-up of 10 years, were included, representing an approximate cumulative total of 3,604,810 person-years. After pooling adjusted hazard ratios, 6 major risk factors were found to be independently associated with long-term mortality after CABG: age, ischaemia (peripheral vascular disease, prior cerebrovascular accident, left main stem coronary disease), diabetes mellitus, atrial fibrillation, renal impairment (chronic kidney disease and dialysis-dependent chronic kidney disease), and impaired left ventricular function (reduced LV ejection fraction or prior heart failure) (see Table 1). Conclusion: We have identified six groups of risk factors for long-term mortality post-CABG. Further work is needed to assess whether the influence of these risk factors varies over time and if targeted interventions for high-risk groups lead to improved long-term mortality.

Management of anaemia in French dialysis patients: results from a large epidemiological retrospective study.

Limited real-world data are available in Europe, especially France, regarding the therapeutic management of anaemia in patients with dialysis-dependent chronic kidney disease (DD CKD). This retrospective, longitudinal, observational study was based on medical records from the MEDIAL database of not-for-profit dialysis units in France. From January to December 2016, we included eligible patients (≥18 years), with a diagnosis of CKD and receiving maintenance dialysis. Patients with anaemia were followed up for 2 years after inclusion. Patient demographic data, anaemia status, CKD-related anaemia treatments, and treatment outcomes including laboratory test results were evaluated. Of 1632 DD CKD patients identified from the MEDIAL database, 1286 had anaemia; 98.2% of patients with anaemia were receiving haemodialysis at index date (ID). Of patients with anaemia, 29.9% had haemoglobin (Hb) levels of 10-11g/dL and 36.2% had levels of 11-12g/dL at ID. Furthermore, 21.3% had functional iron deficiency and 11.7% had absolute iron deficiency. The most commonly prescribed treatments at ID for patients with DD CKD-related anaemia were intravenous (IV) iron with erythropoietin-stimulating agents (ESAs) (65.1%). Among patients initiating ESA treatment at ID or during follow-up, 347 (95.3%) reached the Hb target of 10-13g/dL and maintained response within the target Hb range for a median duration of 113 days. Despite combined use of ESAs and IV iron, duration within the Hb target range was short, suggesting that anaemia management can be further improved.

Factors associated with self-care behavior in patients with pre-dialysis or dialysis-dependent chronic kidney disease.

Self-care behavior plays a pivotal role in the management of chronic kidney disease. Improved self-care behavior in patients with chronic kidney disease is a key factor in health management and treatment adherence. This study aimed to evaluate the participants’ general and medical condition-related characteristics, physiological indices and the level of health literacy affecting self-care behavior in patients with chronic kidney disease in South Korea. The data of 278 participants were analyzed using t-test, analysis of variance, correlation coefficient, and linear multiple regression analysis. There were significant differences in self-care behavior scores depending on participants’ age and cohabitation status, employment, and smoking status as well as having dialysis due to end-stage kidney disease; number of comorbidities; levels of serum hemoglobin, calcium, and creatinine; and estimated glomerular filtration rate. The results of regression analysis revealed that not currently working, non-smoker, end-stage kidney disease, and positive response to the “actively managing my health” scale of the Health Literacy Questionnaire significantly affected self-care behavior in patients with chronic kidney disease, and the explanatory power of the model was 32.7%. Therefore, it is necessary to identify each patient’s barriers or needs according to individual characteristics, such as age, cohabitation and employment status, and daily life circumstances, including smoking habits, comorbidities, social support, and level of health literacy to develop efficient support strategies for promoting adequate self-care behavior with CKD.

Changes in Iron Availability with Roxadustat in Nondialysis- and Dialysis-Dependent Patients with Anemia of CKD.

Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported. Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa. In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Variaciones de la conductividad y cambios en el sodio plasmático durante hemodiálisis relacionado con el cambio de monitor

IntroductionThe sodium gradient during hemodialysis sessions is one of the key factors in sodium balance in patients with dialysis-dependent chronic kidney disease; however, until the appearance of the new monitors with sodium modules, the differences between prescribed and measured sodium have been understudied. The present study aimed to compare the impact on the measured conductivity and the initial and final plasma sodium after changing the 5008 Cordiax to the new 6008 Cordiax monitor. Material and methods106 patients on hemodialysis were included. Each patient underwent 2 dialysis sessions in which only the monitor was varied. The variables collected were dialysate, sodium and bicarbonate prescribed, real conductivity, initial and final plasma sodium measured, and the calculated sodium gradient (ΔPNa). ResultsThe change of dialysis monitor showed small but statistically significant differences in the initial (138.14 mmol/L with 5008 vs. 138.81 mmol/L with 6008) and final plasma sodium (139.58 mmol/L vs. 140.97 mmol/L), as well as in the actual conductivity obtained (13.97 vs. 14.1 mS/cm). The ΔPNa also increased significantly. ConclusiónThe change from 5008 to 6008 monitor is associated with increased conductivity, leading the patient to end the sessions with higher plasma sodium and ΔPNa. Knowing and confirming this change will allow us to individualize the sodium prescription and avoid possible undesirable effects. It could be the preliminary study to explore the new sodium biosensor incorporated into the new generation of monitors.

Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis.

As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) -0.19, [95% confidence interval (CI), -0.21 to -0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = -0.06, [95% CI, -0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36weeks (MD = 0.02, [95% CI, -0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensatefor the limitations of our study to estimate the vadadustat's value.

Sodium First Approach, to Reset Our Mind for Improving Management of Sodium, Water, Volume and Pressure in Hemodialysis Patients, and to Reduce Cardiovascular Burden and Improve Outcomes.

New physiologic findings related to sodium homeostasis and pathophysiologic associations require a new vision for sodium, fluid and blood pressure management in dialysis-dependent chronic kidney disease patients. The traditional dry weight probing approach that has prevailed for many years must be reviewed in light of these findings and enriched by availability of new tools for monitoring and handling sodium and water imbalances. A comprehensive and integrated approach is needed to improve further cardiac health in hemodialysis (HD) patients. Adequate management of sodium, water, volume and hemodynamic control of HD patients relies on a stepwise approach: the first entails assessment and monitoring of fluid status and relies on clinical judgement supported by specific tools that are online embedded in the HD machine or devices used offline; the second consists of acting on correcting fluid imbalance mainly through dialysis prescription (treatment time, active tools embedded on HD machine) but also on guidance related to diet and thirst management; the third consist of fine tuning treatment prescription to patient responses and tolerance with the support of innovative tools such as artificial intelligence and remote pervasive health trackers. It is time to come back to sodium and water imbalance as the root cause of the problem and not to act primarily on their consequences (fluid overload, hypertension) or organ damage (heart; atherosclerosis, brain). We know the problem and have the tools to assess and manage in a more precise way sodium and fluid in HD patients. We strongly call for a sodium first approach to reduce disease burden and improve cardiac health in dialysis-dependent chronic kidney disease patients.

COVID-19 among Hospitalized Patients with Kidney Disease: Experience at a U.S. Midwestern Academic Medical Center.

In this single-center observational study, we describe 205 patients with acute kidney injury (n=98), dialysis-dependent chronic kidney disease stage 5 (n=54), or kidney transplant (n=53), admitted during the first surge of the local pandemic from March 19 2020, to July 31 2021. Most patients in the cohort were African American (acute kidney injury, 51%; dialysis-dependent chronic kidney disease stage 5, 82%; kidney transplant, 62%), and obesity was common (acute kidney injury, 53%; dialysis-dependent chronic kidney disease stage 5, 44%; kidney transplant 56%). Mechanical ventilation was required in 50% of the acute kidney injury, 22% of the dialysis-dependent chronic kidney disease stage 5, and 13% of the kidney transplant recipients. Nearly half of the acute kidney injury patients (46%) died and 49% required replacement therapy, while in-hospital mortality was 24% in the dialysis-dependent chronic kidney disease stage 5 patients and 9% in the kidney transplant recipients. Logistic regression analysis identified older age and patient group as leading correlates of mortality, with lower death risk in the kidney transplant (24%; odds ratio (OR), 0.17; 95% CI 0.06-0.47) and dialysis dependent chronic kidney disease stage 5 (9%; OR, 0.36; 95% CI 0.16-0.78) patients compared to acute kidney injury patients (46%). Obesity was associated with 5-fold increased mortality risk in the coronavirus disease 2019 patients with acute kidney injury (OR, 5.32; 95% CI 1.41-20.03) but not in dependent dialysis chronic kidney disease stage 5 and kidney transplant patients. During the first surge of the pandemic, kidney patients hospitalized COVID-19 experienced high mortality, especially those with acute kidney injury, older age and obesity. Identifying those at highest risk for adverse outcomes may direct preventative strategies including counseling on vaccination.

Liquid chromatography-tandem mass spectrometry methods for quantification of roxadustat (FG-4592) in human plasma and urine and the applications in two clinical pharmacokinetic studies

Roxadustat (FG-4592) can inhibit the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes that are responsible for targeting and regulating HIF for ubiquitination and proteasomal degradation. It has been approved in China as an anti-anemia drug for treating the anemia in dialysis-dependent CKD (chronic kidney disease) patients, and is also under regulatory review in Japan. Some studies are also investigating the clinical pharmacokinetics and pharmacodynamics of roxadustat in CKD patients. To support clinical investigations, a rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method, with a concentration range from 1 to 5000 ng/mL, was designed for the quantification of roxadustat in human plasma and urine. Liquid-liquid extraction (LLE) was applied to sample clean-up followed by a chromatographic separation conducted on a Waters XTerra Phenyl column with isocratic elution. The mixture consisting of acetonitrile/water/formic acid (60:40:0.1[%], v/v/v) was employed as the mobile phase (flow rate: 1.0 mL/min) with 60% post-column split. The quantitation was employed in multiple reactions monitoring (MRM) mode based on positive electrospray ionization (ESI). This proposed method was fully validated and applied to the pharmacokinetic (PK) and pharmacodynamic (PD) study of roxadustat among healthy subjects in China.

Stroke incidence and chronic kidney disease: A hospital-based prospective cohort study.

This prospective cohort study aimed to (i) examine stroke incidence and stroke subtypes by chronic kidney disease (CKD) stage, (ii) examine whether CKD patients with or without proteinuria have a high risk of stroke independent of traditional cardiovascular risk factors, and (iii) determine precise estimates of stroke risk by CKD stage while accounting for competing mortality risk. Participants were 2023 patients enrolled in the Project in Sado for Total Health between June 2008 and December 2016 (55% men; mean age, 69 years), of whom 52% had CKD (stage 1-2, 10%; G3a, 48%; G3b, 17%; G4-5, 11% and G5D, 14%). During a median follow-up of 5.7 years, 157 participants developed stroke and 448 died without developing stroke. Most stroke cases were ischaemic among non-dialysis-dependent CKD participants, but the relative frequency of ischaemic stroke was near that of intracerebral haemorrhage among dialysis-dependent CKD participants. After adjustment, stage 1-2 (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.60-5.51) and stage G3-5 participants with proteinuria (HR, 2.50; 95% CI, 1.56-4.02), but not stage G3-5 participants without proteinuria (HR, 0.64; 95% CI, 0.38-1.08), had a higher stroke risk compared to non-CKD participants. In competing risk analyses, the association was attenuated but remained significant. Although the distribution of stroke subtypes differed, CKD participants with proteinuria and those with CKD stage 5D had a 2- and 4-times higher risk of stroke, respectively, than that of non-CKD participants, after accounting for competing mortality risk and traditional risk factors.

MO536: Cardiovascular Events in Patients With Anemia Associated With Non–Dialysis-Dependent Chronic Kidney Disease: Regional Analysis of Patients not Previously Treated With Erythropoiesis-Stimulating Agents in The PRO2TECT Trial

Abstract BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1,2]. In a prespecified subgroup analysis of the PRO2TECT trials, no difference in cardiovascular safety was observed in the USA, but a higher risk of MACE was found for patients treated with vadadustat outside the USA.1 We investigated regional differences in MACE in patients previously untreated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trial. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial not treated with ESAs within 8 weeks of enrollment (correction trial; NCT02648347) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-USA/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1748 ESA-untreated patients receiving ≥1 dose of study drug were enrolled in the PRO2TECT trial, including 1058 patients in the USA, 139 in Europe and 551 outside the USA and Europe. Patients in the non-USA/non-European countries were younger and had a lower mean eGFR than patients in the USA or Europe. Furthermore, 34.7% of patients randomized to vadadustat had a baseline eGFR &amp;lt;10 mL/min/1.73 m2 versus 24.0% of patients randomized to darbepoetin alfa in the non-USA/non-European countries. The hazard ratio for MACE in the overall population for vadadustat versus darbepoetin alfa was 1.16 [95% confidence interval (CI) 0.96–1.41]. When analyzed by region, higher event rate for MACE was observed in the vadadustat arm in the non-USA/non-European countries compared with the USA and Europe (Table 1). The higher event rates for MACE in the non-USA/non-European countries were driven by 21 excess MACEs reported in the vadadustat group. Many deaths in the non-USA/non-European countries were related to kidney failure (n = 25/43 in the vadadustat group; n = 20/30 in the darbepoetin alfa group; Table 2), and were concentrated in Brazil and South Africa, countries that enrolled a higher proportion of patients with end-stage kidney failure who may not have had access to dialysis. The adverse event profiles for vadadustat and darbepoetin alfa were similar across regions. CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were not previously treated with ESAs and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT trial. The higher event rate in the vadadustat group in non-USA/non-European countries may have been related to randomization imbalances and/or design and methodological issues. These findings should help inform care providers as they assess the overall safety of vadadustat for the treatment of anemia associated with NDD-CKD.

MO532: Cardiovascular Events in Patients With Non–Dialysis-Dependent Chronic Kidney Disease and Anemia: Regional Analysis of Patients Previously Treated With Erythropoiesis-Stimulating Agents in the PRO2TECT Trial

Abstract BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for the treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1, 2]. In a prespecified subgroup analysis of the PRO2TECT trials, a difference in the relative safety between vadadustat and darbepoetin alfa was observed between the US and non-US regions [1]. We investigated regional differences in MACE in patients with NDD-CKD-administered vadadustat and darbepoetin alfa who were previously treated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trials. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial who were actively maintained on ESAs at study entry with ≥1 dose received within 6 weeks before or during screening (Conversion trial; NCT02680574) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-US/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1723 ESA-treated patients were randomized in the conversion trial of the PRO2TECT program and received ≥1 dose of study drug, including 665 patients in the USA, 444 in Europe, and 614 outside the USA and Europe. Europe had a lower proportion of patients with diabetes and more patients who had received intravenous (IV) iron, while patients in the non-US/non-European region were younger and had a lower prevalence of cardiovascular (CV) disease. A higher proportion of patients in Europe were using darbepoetin alfa at baseline than in other regions (59%–63% versus 14%–28%), though ESA dose was lower (57–61 versus 93–149 IV epoetin equivalent U/kg/week). The hazard ratio for MACE in the overall population for vadadustat versus darbepoetin alfa was 1.16 (95% CI 0.93–1.45). Across regions, event rates were similar in the vadadustat groups, but event rates in the darbepoetin alfa group were lower in Europe compared with the US and non-US/non-Europe (Table 1), which was driven by fewer total deaths (non-CV and CV) reported in Europe in the darbepoetin alfa arm (n = 24/220) compared with the vadadustat arm (n = 38/224) (Table 2). Additional post hoc analyses of MACE accounting for several baseline characteristics, including ESA dose, did not alter the outcomes of the study. CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were treated with ESA and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT program. It remains unclear if the lower risk of MACE observed in Europe with the darbepoetin alfa group was related to differences in unobserved baseline characteristics, regional treatment practices, methodological reasons or chance.

MO525: Iron absorption and phosphate-lowering effects of ferric citrate hydrate are not influenced by gastric secretion inhibitors in patients with chronic kidney disease

Abstract BACKGROUND AND AIMS Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in chronic kidney disease (CKD) patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with CKD not on dialysis. Ingested iron is dissolved at a low pH of the secreted gastric acid in the stomach, which is an important process for its effective absorption [1]. Patients taking gastric acid secretion inhibitors (GASI), such as proton pump inhibitors and histamine-2 receptor antagonists, showed decreased iron absorption and increased risk of iron deficiency, which were dose- and treatment-duration-dependent [2]. The increase in the intragastric pH by concomitantly use of GASI might be affected on FC's iron absorption effect. METHOD We have conducted a retrospective study using data from two previous clinical studies to investigate FC in CKD patients with hyperphosphatemia. A 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study in non–dialysis-dependent (ND) CKD patients (FC, n = 60, ; placebo, n = 30) (CTI-111 435) [3], and a 52-week, phase 3, multicenter, open-label, dose-titration study in CKD patients undergoing hemodialysis (HD) (FC, n = 180) (CTI-111 437) [4] were divided into with or without GASI, and levels of iron and phosphate related parameters were analyzed. RESULTS In ND patients, approximately 25% in FC (n = 14) and 50% (n = 14) in placebo used GASI. Mean [standard deviation (SD)] changes from baseline to end of treatment (EOT) in serum ferritin (ng/mL) were 109.83 (104.46) in FC with GASI, 142.68 (94.28) in FC without GASI, −22.49 (74.85) in placebo with GASI, and −3.43 (43.58) in placebo without GASI (Fig. 1a). Those in transferrin saturation (TSAT, %) were 16.64 (30.13) in FC with GASI, 17.07 (17.56) in FC without GASI, 2.86 (14.68) in placebo with GASI, and 1.31 (9.75) in placebo without GASI (Figure 1b). The mean (SD) dose of FC with or without GASI were 3240 mg/day (approximately 778 mg ferric iron) with GASI (n = 14) and 3445 mg/day (approximately 827 mg ferric iron) without GASI (n = 46), respectively. In HD patients, approximately 50% (n = 95) used GASI. Mean changes (SD) from baseline to EOT in serum ferritin (ng/mL) were 166.32 (153.70) with GASI and 155.16 (139.47) without GASI, and in TSAT (%) were 16.60 (19.44) with GASI and 16.02 (18.81) without GASI, respectively. The mean (SD) dose of FC with or without GASI were 2619 mg/day (approximately 629 mg of ferric iron) with GASI (n = 95) and 2854 mg/day (approximately 685 mg or ferric iron) without GASI (n = 85), respectively. In both studies, there were no differences in the changes from baseline to EOT in serum phosphate between with or without GASI. CONCLUSION GASI did not interfere with iron absorption and phosphate-lowering effects of FC in CKD patients with hyperphosphatemia.

MO519: Ferric Citrate Hydrate Improves Levels of Transferrin Saturation in Hemodialysis Patients With Lower Levels of Transferrin Saturation

Abstract BACKGROUND AND AIMS Iron deficiency identified by transferrin saturation (TSAT) is reported as a risk factor for all-cause mortality and cardiovascular events in non-dialysis dependent (NDD) chronic kidney disease (CKD) [1, 2] and for all-cause mortality in hemodialysis patients [3]. Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in CKD patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan in 2021. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with NDD-CKD. FC or ferric citrate increased TSAT in patients with NDD-CKD and IDA [4]. However, a few data show that whether FC or ferric citrate has the similar effect in hemodialysis patients whose TSAT is &amp;lt;20%. Considering the additional indication of IDA in Japan, we investigated the FC's effect on TSAT by using the data obtained from the ASTRIO study [5], which was conducted in Japanese hemodialysis (HD) patients. METHOD We conducted a retrospective study using the data of ASTRIO study [5], which is a randomized, prospective, open-label, multicenter 24-week study to investigate the FC's effect on anemia management compared with non-iron-based phosphate binders (PBs) in Japanese HD patients with hyperphosphatemia. Ninety-three patients taking non-iron-based PBs were randomized 1:1 to continue PBs (control) or switch to FC. During 24-week study, serum phosphate and hemoglobin were controlled, 3.5–6.0 mg/dL and 10–12 g/dL, respectively. From 93 patients (FC, n = 48; control, n = 45), we extracted 41 patients (FC, n = 21; control, n = 20) whose TSAT at baseline was &amp;lt;20% and compared the levels of TSAT and other iron related parameters between FC group and control group. RESULTS In the ASTRIO study, the mean (SD) levels of TSAT (%) was 14.3 (4.0) at baseline and rapidly increased to 25.0 (11.1) at 4 weeks in the FC group. After that, the levels of TSAT were almost unchanged in the FC group, whereas, in the control group, the mean (SD) levels of TSAT were almost unchanged during the 24-week study. The mean (SD) levels of serum ferritin gradually increased until week 12 and subsequently showed to be stabilized in the FC group, whereas, in the control group, these were almost unchanged during the 24-week study (Table 1). CONCLUSION In Japanese HD patients whose TSAT was &amp;lt;20%, FC rapidly increased TSAT compared with control. We will also investigate the FC's effect on TSAT in HD patients from the post-marketing surveillance study, the prospective, multicenter and observational, up to maximum 2 years treatment.