Dialysis-dependent Chronic Kidney Disease Patients Research Articles

#1904 Prevalence of osteoporosis in dialysis dependent CKD patients: a cross sectional study from India

Abstract Background and Aims Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. However, the data on prevalence of Osteopenia and osteoporosis in Chronic kidney disease in India is scarce This multicentric, cross sectional study was done to assess the prevalence of osteoporosis in dialysis dependent chronic kidney disease patients. Method This study was conducted in CKD patients on maintenance hemodialysis. Osteoporosis and osteopenia were confirmed on the basis of T-scores using portable- Heel Ultrasound Bone Densitometer. Results A total of 1033 Dialysis patients were screened during August 2022 to December 2022. More than half (56%) of the patients were male. The prevalence of osteoporosis and osteopenia was observed to be 17% and 66%, respectively. Mean T- Score observed in overall population was -1.71 + .0.85, while it was -1.66 + 0.86 and -1.77 + 0.83 in males and females respectively. The maximum T- score observed in males was 2.0 and in females it was 4.0. In females, the minimum T-score was -4.3 while in males it was -2.51. Overall, 16.5% of males and 18% of females were osteoporotic. Among geriatric males (>60 years), average T-score was -1.55 + 0.42 while in geriatric female it was 1.78 + 0.80 Conclusion This data of Osteopenia and osteoporosis should be alarming as osteopenia itself is considered a very serious risk factor for the development of osteoporosis. Early intervention for diagnosis and timely initiation of treatment of osteoporosis is recommended for the CKD population to prevent complications like fractures and falls.

Cataract Surgery and Chronic Kidney Disease: A Hospital-based Prospective Cohort Study.

Objective Cataract and chronic kidney disease (CKD) occur with increasing frequency with age and share common risk factors including smoking, diabetes, and hypertension. We evaluated the risk of incident cataract surgery in patients with non-dialysis-dependent CKD and dialysis-dependent CKD compared to non-CKD patients, while taking into account the competing risk of death. Methods The participants included 1,839 patients from Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016 (54% men; mean age, 69 years). Among these patients, 50%, 44%, and 6% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Results During a median follow-up of 5.6 years (interquartile range, 4.7-7.1), 193 participants underwent cataract surgery [18.7 (95% confidence interval (CI), 16.2-21.5)/1,000 person-years] and 425 participants died without undergoing cataract surgery [41.0 (95% CI, 37.4-45.2)/1,000 person-years]. The cumulative incidence of cataract surgery was the highest in the dialysis-dependent CKD group, followed by the non-dialysis-dependent CKD and non-CKD groups (log-rank p=0.002). After adjusting for potential confounding factors, the dialysis-dependent CKD group [hazard ratio (HR) 2.48; 95% CI 1.43-4.31], but not the non-dialysis-dependent CKD group (HR, 1.01; 95% CI 0.74-1.38), had a higher risk of cataract surgery than the non-CKD group. However, this association was no longer significant according to a competing risk analysis (sub-hazard ratio, 1.67; 95% CI 0.93-3.03). Conclusion Dialysis-dependent CKD patients were found to have an increased risk of cataract surgery; however, the association was attenuated and no longer significant when death was considered a competing risk.

A comparative analysis of serum phosphorus levels and mineral metabolic markers in non-dialysis and dialysis chronic kidney disease patient: a cross-sectional study

Background: Chronic kidney disease is a major public health problem worldwide. As kidney function declines, it leads to several metabolic abnormalities including dysregulation of mineral metabolism. It is also reported that hyperphosphatemia in patients with advanced kidney disease is associated with an increased risk of mortality and cardiovascular events, and is higher in dialysis-dependent chronic kidney disease (CKD) patients compared to non-dialysis CKD. However, data in the Indian context is limited. Objectives were to evaluate and compare serum phosphorus levels and associated factors in non-dialysis and dialysis CKD patients. Also, the impact of dietary phosphate restriction and the use of phosphate binders on serum phosphorus is analysed. Methods: A cross-sectional study was conducted at a tertiary care hospital in Kolkata, India, with 100 CKD patients: 50 non-dialysis CKD patients and 50 dialysis-dependent CKD patients. Relevant demographic, clinical and laboratory parameters including serum phosphorus, calcium, parathyroid hormone (PTH), alkaline phosphatase, albumin and estimated glomerular filtration rate (eGFR) were collected. Data was analyzed using appropriate statistical tests. Results: Mean serum phosphorus was significantly higher in the dialysis CKD group (6.12±0.34 mg/dl) compared to the non-dialysis CKD group (4.56±0.80 mg/dl). Serum calcium and PTH were also higher while eGFR and albumin were lower in the dialysis CKD group. Serum phosphorus levels increased with advancing CKD stages in the non-dialysis group. Phosphate binder helped phosphorus control in dialysis CKD patients. Conclusions: Our study is in confluence with other reports and dietary phosphate restriction and the use of phosphate binders help optimize phosphorus levels in CKD patients.

#6829 DIFFERENTIAL LIPIDIC PROFILE WITH THE USE OF CITRATE OR ACETATE DIALYSATES

Abstract Background and Aims Unlike other high-cardiovascular-risk populations, the efficacy obtained from lipid-lowering therapy remains uncertain in dialysis-dependent chronic kidney disease (DD-CKD) patients. This is probably given to the exclusion in clinical trials of patients with very high LDL levels, their population's heterogeneity, accompanying cardiovascular morbidities, and the higher mortality risk explained partly by chronic inflammation. The latter has been associated with the accumulation of uremic toxins, membrane biocompatibility, and acetate-based dialysates, which promote inflammation. Different dialysate weak acidifying agents such as lactic, pyruvic, hydrochloric, or citric acids have surged as less-inflammatory alternatives to acetate. This study aims to evaluate the effects of the metabolism of acetate and citrate in the lipidic profile of DD-CKD patients. Method In a unicentric, cross-over, prospective study, we compared the lipidic profile by assessing the plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), high-density (HDL) and very low-density (VLDL) lipoprotein cholesterol, and lipoprotein (a) [Lp(a)] comparing the use of citrate (CD) vs. acetate (AD) as dialysate buffers, after twelve sessions with each one. Prealbumin was also measured to rule out malnutrition as a potential confounding factor. Prevalent (i.e., dialysis vintage ≥3 months) adult patients on maintenance hemodialysis were included. The dialysis prescription parameters and additional medical treatments remained unchanged during their sessions with both dialysates. Quantitative variables are reported with mean and standard deviation. Normal distribution was assessed with the Shapiro-Wilk test, and the comparisons were made with the Student's paired T-test or Wilcoxon's signed-rank test, accordingly. A two-sided p-value ≤0,05 was considered statistically significant. Results After twelve dialysis sessions with CD, compared to AD, there was a statistically significant decline in TG and HDL and an increase in LDL. There was also a notable but non-significant reduction in VLDL (Table 1). Conclusion There were noteworthy differences in the lipid profile that can only be attributed to the change of dialysis fluid, as we avoided inter-individual (with a cross-over design) and intra-individual (different inflammatory or nutritional profiles would not be expected with this short-term setting) variabilities. Further studies must elucidate if the short-term changes induced in the lipidic profile of DD-CKD patients by the dialysate's weak acid translate into clinical implications.

Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors versus erythropoiesis-stimulating agents on iron metabolism and inflammation in patients undergoing dialysis: A systematic review and meta-analysis

AimsThis study aimed to evaluate the effects of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) on iron metabolism and inflammation in dialysis-dependent chronic kidney disease (DD-CKD) patients. MethodsPubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov websites were searched for randomized controlled trials (RCTs) investigating HIF-PHIs versus ESAs for DD-CKD patients. Key findingsTwenty studies with 14,737 participants were included in the meta-analysis, which demonstrated no significant difference in the effect of transferrin saturation and ferritin between HIF-PHIs and the ESAs group (MD, 0.65; 95%CI, −0.45 to 1.75; very low certainty; SMD, −0.03; 95% CI, −0.13 to 0.07; low certainty). However, HIF-PHIs significantly increased the iron (MD, 2.30; 95% CI, 1.40 to 3.20; low certainty), total iron-binding capacity (SMD, 0.82; 95% CI, 0.66 to 0.98; low certainty), and transferrin (SMD, 0.90; 95%CI, 0.74 to 1.05; moderate certainty) levels when compared with the ESAs group. In contrast, the hepcidin level and dosage of intravenous iron were significantly decreased in the HIF-PHIs group compared with the ESAs group (MD, −15.06, 95%CI, −21.96 to −8.16; low certainty; MD, −18.07; 95% CI, −30.05 to −6.09; low certainty). The maintenance dose requirements of roxadustat were independent of baseline CRP or hsCRP levels with respect to the effect on inflammation. SignificanceHIF-PHIs promote iron utilization and reduce the use of intravenous iron therapy. Furthermore, HIF-PHIs, such as roxadustat, maintain the erythropoietic response independent of the inflammatory state. Thus, HIF-PHIs may be an alternative treatment strategy for anemia in DD-CKD patients, where ESA is hyporesponsive due to iron deficiency and inflammation.

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.

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.

POSC199 A Retrospective Database Analysis of Erythropoiesis-Stimulating Agent Treatment Patterns and Associated Healthcare Resource Use in Non–Dialysis-Dependent Chronic Kidney Disease Patients with Anaemia in Japan

The purpose of this study was to use real-world, longitudinal data to evaluate clinical characteristics, treatment patterns, and healthcare resource use (HCRU) for Japanese non–dialysis-dependent (NDD) chronic kidney disease (CKD) patients with anaemia.

Update and Perspectives in the Personalized Management of Sodium, Water, Volume and Hemodynamic Disorders of Dialysis Patients

Sodium and water-related disorders are major components of chronic kidney disease (CKD) and contribute significantly to cardiovascular (CV) complications and mortality. Usually, they are marked by gradual accumulation of sodium, water and have hemodynamic consequences (i.e., fluid overload, hypertension and cardiac disorders) along with the progression of kidney failure culminating in end stage kidney disease. Renal replacement therapy which is then required to sustain life is intended to restore sodium, fluid and pressure disorders along with the objective of reducing the uremic toxin load. Unfortunately, the intermittent nature of conventional short hemodialysis relying on a so called ‘dry weight’ probing approach, only partially restores the sodium-water overload related disorders, thereby exposing patients to further multi-organ damage through the resultant dialysis-induced systemic stress (DISS). Fluid volume management in dialysis patients has emerged as a very challenging condition that requires further attention and more precise tools. Furthermore, recent findings indicate that the physiology of sodium is more complex than that previously summarized by the kidney-centric two-compartment model (volemia and Interstitium) linked to osmotically active sodium (water-bound sodium). A third tissue compartment (skin, muscle) of sodium has now been identified, taking the form of free-water sodium [glycosaminoglycans (GAGs) or gel-like component] with newly-identified pathophysiologic metabolic consequences. All these findings suggest that restoration of sodium homeostasis in dialysis-dependent chronic kidney disease patients should encompass a more holistic approach to improve cardiac health and reduce cardiovascular burden in this highly vulnerable population. In this context, new tools for monitoring and managing dialysis patients to ensure a more precise and personalized control of their sodium and water homeostasis, volemic and hemodynamic disorders are needed. Several monitoring and management tools (e.g., bioimpedance, lung ultrasound, blood volume control, thermal balance control) are already available with potential value. The conductivity measurement-based automated sodium control module represents the latest and very appealing addition to this list of innovative tools. Although establishing the clinical value of these tools requires further outcome-based studies, current clinical use of this new tools has shown promising indications towards the goal of reducing CV morbidity and mortality in kidney dialysis patients. A brief review of these new pathophysiologic findings as well as clinical interests of these new tools is provided in this narrative review.

The efficacy of Roxadustat for the treatment of anemia in dialysis dependent chronic kidney disease patients: an updated systematic review and meta-analysis of randomized clinical trials.

BackgroundAnemia is a common complication in chronic kidney disease (CKD) with increased morbidity and mortality. Recently published RCTs were conducted to compare the effect of the new medication roxadustat (ROX) with erythropoiesis-stimulating agent (ESA) in dialysis-dependent CKD (DD-CKD) patients. Our article aimed to meta-analyze published RCTs to investigate the efficacy and safety of ROX for anemia in DD-CKD patients and update the effect of the new studies on overall analysis with subsequent impact on management.MethodsElectronic databases (PubMed, EMBASE, Scopus, Web of Science, Cochrane Central, and Google Scholar) were searched systematically from inception to July 2021 by using this search term (Roxadustat OR ASP1517 OR FG4592 OR “FG-4592”) AND (kidney OR renal) AND (Anemia). We only included randomized control trials (RCTs) that reported the primary outcome of change in hemoglobin (Hb) level and iron utilization parameters, including ferritin, serum iron, TSAT, TIBC, transferrin, and hepcidin.ResultsTen RCTs were finally included with 3031 patients in the ROX group and 2737 patients in the control group. ROX was associated with increase in Hb level (SMD: 0.2; 95% CI: 0.02, 0.39; P=0.03), TIBC (SMD: 0.79; 95% CI: 0.61, 0.98; P<0.00001), serum iron (SMD: 0.27; 95% CI: 0.18, 0.36; P<0.00001), transferrin (SMD: 0.98; 95% CI: 0.81, 1.15; P<0.00001) and decrease in hepcidin (SMD: −15.53; 95% CI: −28.07, −3.00; P<0.02) when compared with control group. There was no difference between ROX and the control group regarding ferritin level and TSAT. Sensitivity analysis by removing the most recent studies, Chen et al. or Hou et al. did not show significant difference in regard to change in Hb level. There was no difference between both groups regarding the serious side effects. However, ROX showed higher TEAEs when compared to the control group (RR: 1.03; 95% CI: 1.01, 1.05; P=0.002).DiscussionOur updated meta-analysis concluded that ROX increased Hb level and improved iron utilization parameters in DD-CKD patients, but ROX was associated with higher TEAEs. Our results support the use of ROX for DD-CKD patients with anemia. However, higher-quality RCTs are still needed to confirm the results of our review.

The Impact of Intravenous Iron on Renal Injury and Function Markers in Patients With Chronic Kidney Disease and Iron Deficiency Without Anemia

The Impact of Intravenous Iron on Renal Injury and Function Markers in Patients With Chronic Kidney Disease and Iron Deficiency Without Anemia

Current status of the assessment of sarcopenia, frailty, physical performance and functional status in chronic kidney disease patients.

Low physical function, frailty, and sarcopenia are common complications of chronic kidney disease (CKD). In this article, we review the epidemiology and pathogenesis of low physical function, as well as its associations with adverse outcomes in CKD patients. Additionally, we present various traditional and novel methods for assessment of physical function in CKD patients. In nondialysis dependent (NDD) and dialysis-dependent CKD patients, the prevalence of low physical function, frailty, and sarcopenia are substantially higher than in the general population. The potential mechanisms of low physical function, frailty, and sarcopenia in CKD patients are due to various factors including underlying kidney disease, co-existing comorbidities, and certain therapeutic interventions utilized in CKD. Increasing evidence has also uncovered the ill effects of impaired physical function on clinical outcomes in CKD patients. Routine assessment of physical function is an under-utilized yet important component in the management of CKD patients. Future studies are needed to determine how prescription of exercise and increased daily physical activity can be tailored to optimize the health and well-being of NDD and dialysis-dependent CKD patients in pursuit of successful aging.

Title: Efficacy and Safety of Ferric Derisomaltose for Treatment of Anemia in Chronic Kidney Disease Patients: A Systematic Review

BackgroundAnemia in chronic kidney disease (CKD) patients develop primarily due to iron and erythropoietin deficiency, factors contributing to this include uremia induced inhibition of erythropoiesis, shortened red cell survival and nutritional deficiency. Erythropoietin stimulating agents (ESA) used in CKD increases iron demand for the production of new red blood cells (RBCs). Oral iron does not provide a reliable route to meet the demand of the iron required and poses the risk of side effects. The intravenous formulation provides the fastest route, although multiple intravenous formulations are available they require multiple dosing and still carry a risk of an adverse event. Ferric derisomaltose/iron isomaltoside (IIM) is an intravenous formulation of iron recently approved by the Food and drug administration (FDA) for patients intolerant to oral iron and non-dialysis dependent CKD patients. FDI is administered in high dose usually in a single administration. In this systematic review, we evaluated the published literature for the efficacy and safety of ferric derisomaltose in both dialysis-dependent and dialysis independent patients.Material/MethodsA literature search was done using the following databases: PubMed, Cochrane, Embase, Clinical trials.gov, and Web of Science. The search was completed without using any filter and we used the Mesh Terms for “anemia”, “iron deficiency anemia” “chronic kidney disease” and “ferric compounds”. Total of 316 which were further screened and we included 2 trials, and 2 prospective studies. Case reports, preclinical trials, meta-analyses, and review articles were excluded. We followed the PRISMA guidelines for literature search and selection of studies. We only included the trial studies that were completed. We excluded the studies that did not report efficacy and safety.ResultsIn total, amongst the four studies, 1558 CKD patients received ferric derisomaltose in a single dose. Patients in all stages of CKD were studied but most patients were between stages I to stage III CKD, stage IV and V(dialysis-dependent) were studied by Kalra et al (2020). A single dose of 1000 mg/dl of IIM, was administered intravenously. The mean pre-treatment haemoglobin level varied from 9.6g/dl to 10.6 g/dl. The mean serum ferritin ranged from 82.4 µg/L to 161.9 µg/L and the mean transferrin saturation ranged in patients from 15.8% to 18.51%. IIM receiving patients were compared with iron sucrose receiving patients by Bhandari et al, and oral iron by Kalra et al (2015). The remaining two studies compared single IIM with multiple IIM dosages. The results are summarised in the table below.Efficacy: The increase in haemoglobin ranged between 0.9 g/dL to 6.58 g/dL from baseline measured at 8 weeks. At the same time, serum ferritin showed an increase in baseline serum ferritin from 104 µg/L to 277 µg/L and transferrin saturation (TSAT) increased in the range of 5.3%-11.4 %. All markers of iron deficiency showed significant improvement. It achieved a greater Hb response irrespective of ESA treatment in both haemodialysis dependent and non-dependent patients. In the comparison group by Bhandari et al, iron sucrose receiving patients also had similar efficacy as IIM. On the other hand, those receiving oral iron in the study by Kalra et al (2015) had much poorer efficacy as compared to IIMSafety: Severe adverse effect was seen in a total of 10 (0.6%) patients who developed hypersensitivity reaction, acute myocardial infarction and injection site-related adverse effects with hypersensitivity being the most common. 15 (0.9%) patients discontinued the treatment. 21 (1.3%) died, and the death was attributed to end-stage renal disease.ConclusionFerric derisomaltose is an effective parenteral iron therapy to treat iron deficiency when compared to oral iron therapy, however, its efficacy is very similar to other parenteral iron formulations. In terms of safety, being used as a single dose it relatively has lesser adverse events but can seldom lead to discontinuation of the drug. This drug can be recommended for iron therapy especially considering single-dose administration but more studies need to be carried out in comparison to other parenteral formulations to further clarify its efficacy in dialysis-dependent CKD patients. [Display omitted] DisclosuresAnwer: BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding.

Polypharmacy, chronic kidney disease, and incident fragility fracture: a prospective cohort study.

Polypharmacy is associated with an increased risk of fracture in aging populations, but no study has accounted for the impact of kidney function on this association. This study aimed to examine the association between polypharmacy and incident fragility fracture based on chronic kidney disease (CKD) status. Participants were 2023 patients (55% men; mean age, 69years) of Sado General Hospital enrolled in the Project in Sado for Total Health (PROST) between June 2008 and December 2016. Among these, 65%, 28%, and 7% had non-CKD, non-dialysis-dependent CKD, and dialysis-dependent CKD, respectively. Multivariable Cox proportional hazards analysis was conducted with adjustments for potential confounders. Prevalences of polypharmacy (≥ 5 medications) and hyperpolypharmacy (≥ 10 medications) among participants were 43% and 9% for non-CKD, 62% and 23% for non-dialysis-dependent CKD, and 85% and 34% for dialysis-dependent CKD, respectively. During a median follow-up of 5.6years, 256 fractures occurred. More medications were associated with a higher risk of fractures. Specifically, compared to participants without polypharmacy, adjusted hazard ratios were 1.32 (95% CI 0.96-1.79) and 1.99 (1.35-2.92) for those with polypharmacy and hyperpolypharmacy, respectively, after adjusting for osteoporosis risk factors, CKD status, and comorbidities. No effect modification by CKD status was observed (interaction P = 0.51). Population-attributable fractions of hyperpolypharmacy for fracture were 9.9% in the total cohort and 42.1% in dialysis-dependent CKD patients. Hyperpolypharmacy is associated with an increased risk of fragility fracture regardless of CKD status, and has a strong impact on incident fragility fractures in dialysis-dependent CKD patients.

An evaluation of roxadustat for the treatment of anemia associated with chronic kidney disease

ABSTRACT Introduction Anemia is one of the major complications of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) have been the mainstay of renal anemia treatment. However, there are several safety drawbacks, and a safer and more effective alternative treatment has been sought. Areas covered Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been developed as a novel orally active therapeutic agent for renal anemia. HIF-PHIs stimulate endogenous EPO and optimize iron utilization. Roxadustat is a first-in-class HIF-PHI for the treatment of anemia in CKD patients approved in China, Japan, South Korea, and Chile. The authors herein evaluate the pharmacology of roxadustat and give their expert perspectives on its use. Expert opinion Phase 3 clinical trials have demonstrated that roxadustat effectively increases and maintains hemoglobin (Hb) levels in both nondialysis-dependent and dialysis-dependent CKD patients. Roxadustat also improved iron metabolism and reduced intravenous (IV) iron requirements. However, pooled analyses of phase 3 studies have revealed frequent thromboembolic events in the roxadustat group, which might be attributed to rapid changes in Hb and inadequate iron supplementation. Roxadustat is an attractive alternative treatment especially for patients with ESA hyporesponsive due to impaired iron utilization, and so appropriate selection of target patients and its proper use are crucially important.

Population pharmacokinetics of roxadustat in Japanese dialysis-dependent chronic kidney disease patients with anaemia.

AimsOur objective was to develop a population pharmacokinetic (PK) model to describe roxadustat plasma concentrations in Japanese dialysis‐dependent chronic kidney disease (DD‐CKD) patients with renal anaemia and to identify the covariate factors that affect exposure of roxadustat.MethodsIn total, 367 patients (male, 256; female, 111) contributing 1285 concentration values from 4 clinical studies were analysed using a nonlinear mixed‐effects modelling approach. Candidate covariates included clinical characteristics hypothesized to affect roxadustat clearance and bioavailability, such as demographics, hepatic parameters and concomitant drugs.ResultsThe roxadustat PK data in Japanese DD‐CKD patients with renal anaemia were well described by a 2‐compartment disposition model with first‐order absorption and interindividual variability on clearance, central volume of distribution and absorption rate constant. Age was identified as a significant covariate on clearance. PK profiles of haemodialysis and peritoneal dialysis patients were comparable. Eighty‐two percent of patients were administered at least 1 phosphate binder (PB). The effect of PBs on roxadustat concentration was modelled as a decrease in bioavailability. Staggered administration of PBs reduced the effect on roxadustat bioavailability. The clinical impact of all covariates on roxadustat PK was mild and manageable as the roxadustat dose was titrated based on haemoglobin level and administered starting from a low dose.ConclusionRoxadustat PK in Japanese DD‐CKD patients were successfully described by a population PK model. The identified key covariates included coadministration of PBs on the roxadustat bioavailability and age on clearance of roxadustat.

Population pharmacokinetics-pharmacodynamics of fondaparinux in dialysis-dependent chronic kidney disease patients undergoing chronic renal replacement therapy.

Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71years (63-88), weight 73kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18IU/µg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. Model-based simulations showed that standard dosing (2.5mg three times weekly before HD) results in a median anti-Xa activity of 0.55IU/mL and 0.98IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.

MO797JUXTAPOSING THE EFFICACIES BETWEEN IRON-BASED AND NON-CALCIUM PHOSPHATE BINDERS FOR IMPROVING MINERAL AND BONE DISORDER PARAMETERS IN DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE PATIENTS: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background and Aims Hyperphosphatemia is a serious complication in chronic kidney disease (CKD) patients that serves as the main risk factor of CKD–mineral and bone disorder (CKD-MBD) progression. Previous studies suggested that iron-based phosphate binder showed better improvement in CKD-MBD parameters although the results were still inconclusive. This study aims to juxtapose the efficacies between iron-based and non-calcium phosphate binders for improving CKD-MBD parameters in dialysis-dependent (DD)-CKD patients. Method We did comprehensive searching to screen all relevant literature until November 2020 in online databases of Pubmed, EMBASE, ScienceDirect, and The Cochrane Library. We included all randomized controlled trials (RCTs) accessing the efficacies of iron-based phosphate binders (sucroferric oxyhydroxide, ferric citrate) in improving CKD-MBD parameters compared with non-calcium phosphate binders (sevelamer) in DD-CKD patients. The parameters compared in this study are changes in serum phosphate (P), serum calcium ions (Ca), fibroblast growth factors-23 (FGF23), intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (calcidiol), and 1,25-dihydroxyvitamin D (calcitriol). Bias risk was accessed by using the revised Cochrane Risk-of-bias (RoB-2) tool. Analysis was performed to provide standard mean difference (SMD) with 95% confidence interval (CI) using random-effect heterogeneity test. Results Ten RCTs with total of 1,139 participants were included in this analysis. The sucroferric oxyhydroxide decreases FGF23 although not statistically significant (SMD = 0.22. 95% CI = -0.49 to 0.05, p = 0.11, I2 = 52%), but ferric citrate (SMD = -0.92. 95%CI = -1.56 to -0.29, p = 0.004, I2 = 69%) and the overall estimate (SMD = -0.45. 95% CI = -0.82 to -0.09, p = 0.02, I2 = 79%) showed significant FGF23 decline compared with sevelamer. The sucroferric oxyhydroxide showed no significant improvement of calcidiol (SMD = 0.08. 95%CI = -0.02 to 0.17, p = 0.13, I2 = 0%) and calcitriol (SMD = 0.02. 95% CI = -0.08 to 0.12, p = 0.74, I2 = 0%) compared with selevamer. There is also no significant improvement of iPTH in sucroferric oxyhydroxide subgroup (SMD = -0.14. 95%CI = -0.43 to 0.14, p = 0.32, I2 = 85%), ferric citrate subgroup (SMD = -0.02. 95%CI = -0.16 to 0.12, p = 0.80, I2 = 0%), and pooled group analysis (SMD = -0.10. 95%CI = -0.27 to 0.07, p = 0.27, I2 = 75%). Besides, this study also suggests no significant improvement comparison of serum P (SMD = -0.09. 95%CI = -0.19 to 0.02, p = 0.12, I2 = 38%) and Ca (SMD = 0.04. 95%CI = -0.12 to 0.20, p = 0.61, I2 = 57%). Conclusion There is no significant efficacies differences between iron-based and non-calcium phosphate binders for improving serum phosphate, serum calcium ions, iPTH, calcidiol, and calcitriol in dialysis-dependent chronic kidney disease patients, except for the FGF-23 parameter. However, further trials are needed to establish the juxtaposition.

Hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of anemia in chronic kidney disease.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are orally active small molecules and are launched as novel therapeutic agents for anemia in chronic kidney disease (CKD). In contrast to conventional exogenous erythropoietin (EPO) administration, HIF-PHIs stimulate endogenous EPO production and improve iron metabolism via stabilization of hypoxia-inducible factor (HIF). This review summarizes the mechanism of action, the results of clinical trials, and future perspectives of HIF-PHIs. Six HIF-PHIs are currently under phase III studies, some of which have been already completed. According to the results of clinical trials, HIF-PHIs increased and maintained hemoglobin levels in both nondialysis-dependent and dialysis-dependent CKD patients with physiological EPO concentrations. HIF-PHIs also improved iron utilization and were comparably effective regardless of underlying inflammation and iron status. HIF-PHIs have several advantages including oral administration, physiological EPO secretion, and improved iron utilization. Undoubtedly, HIF-PHIs will pave the new way in the field of treatment of anemia in CKD, but it should be noted that HIFs have pleiotropic effects on a plethora of cellular functions, which might lead to either beneficial or undesirable off-target effects. Intensive postmarketing surveillance is crucially important to identify unexpected consequences.