Iron indices mediate but not modify association of parathyroid hormone with erythropoietin resistance in hemodialysis patients.

INTRODUCTION: Disordered iron balance and abnormal parathyroid hormone (PTH) concentrations, both prevalent in hemodialysis patients, are risk factors of erythropoietin (EPO) resistance. Few studies have evaluated the correlation between iron indices and PTH and the potential role of iron markers on the association of PTH with EPO resistance in hemodialysis population. METHODS: In this cross-sectional study of 71 maintenance hemodialysis patients, iron indices including hepcidin, ferritin, reticulocyte hemoglobin content (CHr) and transferrin saturation (TSAT) were examined. EPO responsiveness was measured as EPO resistance index (ERI). Lowess regression curves were performed to explore the cor-relations of iron indices, PTH and ERI. The association between PTH and ERI was modeled using linear regressions. Potential role of iron indices on this association was examined using stratified analyses and mediation analyses. RESULTS: The average ERI value of 10.3 ± 5.3 IU w-1 kg-1 (g/dL) -1. ERI was linked to PTH, hepcidin, CHr and TSAT (all P<0.05). PTH was associated with ERI levels (ß=0.007, 95%CI: 0.002-0.012, P=0.007). Hepcidin and PTH were closely correlated with each other (r = 0.28, P = 0.020). No clinically significant interaction between iron indexes and PTH was identified. Hepcidin appeared to mediate about one-fourth of the total association between PTH and ERI in hemodialysis population (25.71%, P=0.020). CONCLUSION: Iron indices and PTH levels were related to ERI values. Hepcidin ap-peared to be closely correlated to PTH and partly mediate the association between PTH and ERI in he-modialysis population.

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Low frequency/high frequency ratio is a predictor of hospitalization and death in patients on maintenance hemodialysis: A prospective study.

INTRODUCTION: This study aims to evaluate the predictive value of the low frequency/high frequency (LF/HF) ratio in all causes of death and hospitalizations in maintenance hemodialysis (MHD) patients. METHODS: This is a single-center prospective study with a 48-h electrocardiograph (ECG) recording. A total of 110 patients were enrolled in the study from October 1, 2021, to September 30, 2022. ECG recordings started before initiation of the hemodialysis (HD) session and lasted for 48 h, covering the intra- as well as inter- HD period. We divided our participants into two groups based on the median value of LF/HF, one of the frequency domain parameters of heart rate variability (HRV). Patients with LF/HF < 1.33 were categorized as group A and those with LF/HF≥1.33 were group B. The endpoint of the study was a composite event of death or hospitalization. We followed all patients until the composite endpoint or the end of the study on February 28, 2023. Multivariate Cox regression was used to assess the adjusted effect of LF/HF on the composite endpoint. RESULTS: Patients in group A were older and the number of patients with diabetes was more than that of group B. With regards to the laboratory data, group A had lower serum creatinine and uric acid and higher ferritin and NT-ProBNP. In the index hemodialysis session, systolic blood pressure was higher but diastolic blood pressure was significantly lower in group A. During the median follow-up period of 8.8 (7.6-9.8) months, 27 hospitalizations and 10 deaths were documented. Increased LF/HF ratio was an independent protective factor of composite endpoint events (HR = 0.357, 95% CI 0.162-0.790, P = 0.011). CONCLUSION: Risks of mortality and hospitalizations are higher among hemodialysis patients having decreased LF/HF ratios. LF/HF in the 48-h recording can be considered as a prognostic factor for risk stratification in HD patients.

Tenapanor in Chinese ESRD patients with hyperphosphatemia on haemodialysis: a randomised, phase 3 trial.

Background: The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD). Methods: This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results: Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference -1.17 mg/dl (95% CI -1.694 to -0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor. Conclusions: Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.

The influencing factors of the erythropoietin resistance index and its association with all-cause mortality in maintenance hemodialysis patients.

Anemia is a common complication of chronic kidney disease with major option treatment of erythropoiesis-stimulating agents (ESAs). This study aimed to investigate the influencing factors of erythropoietin resistance index (ERI) and its association with mortality in maintenance hemodialysis (MHD) patients. Patients enrolled from China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 were included. ERI was calculated as follows: ESA (IU/week)/weight (kg, post-dialysis)/hemoglobin level (g/dL). The Cox regression model was used to analyze the influencing factors on survival outcomes. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were performed. A total of 1270 MHD subjects (687 males and 583 females) were included, with an average age of 60 (49.0, 71.0) years. All subjects were divided into two groups by the median ERI of 14.03. Multivariate logistic regression showed that dialysis vintage (OR 0.957, 95% CI: 0.929-0.986), white blood cells (OR 0.900, 95% CI: 0.844-0.960), high flux dialyzer use (OR 0.866, 95% CI: 0.755-0.993), body mass index (OR 0.860, 95% CI: 0.828-0.892), males (OR 0.708, 95% CI: 0.625-0.801), and albumin (OR 0.512, 95% CI: 0.389-0.673) had a negative association with high ERI baseline (all p < 0.05). There were 176 (13.9%) deaths in total including 89 cardiac/vascular deaths during follow-up. Cox regression analysis showed that ERI was positively associated with all-cause mortality, especially in some subgroups. ERI was associated with increased all-cause mortality in MHD patients, indicating the possibility of death prediction by ERI. Patients with high ERI warrant more attention.

Clinical Outcomes in Patients on Hemodialysis with Congestive Heart Failure.

Introduction: Congestive heart failure (CHF) is one of the common complications in patients with end-stage kidney disease. In the general population, CHF increases the risk of the death. However, there is no well-designed relevant study in the Chinese hemodialysis (HD) population addressing the risks associated with CHF. The aim of this study was to explore the impact of CHF on clinical outcomes in HD patients. Methods: Data from a prospective cohort study, the China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5 (2012-2015), were analyzed. Demographic data, comorbidities, lab data, and death records were extracted. CHF was defined by the diagnosis records upon study inclusion. Our primary outcome was all-cause and cardiovascular (CV) mortality; secondary outcomes were all-cause and cause-specific hospitalization risk. Associations between CHF and outcomes were evaluated using Cox regression models. Stepwise multivariate logistic regression was used to identify the related risk factors, and subgroup analyses were carried out. Results: Of 1,411 patients without missing CHF history information, 24.1% (340) had CHF diagnosis at enrollment. The overall mortality rates were 21.8% versus 12.0% (p < 0.001) in patients with and without CHF during follow-up, respectively. CHF was associated with higher all-cause mortality (adjusted HR: 1.72, 95% confidence interval [CI]: 1.17-2.53, p = 0.006), and the association with CV death was of similar magnitude (HR: 1.60, 95% CI: 0.91-2.81, p = 0.105). CHF patients had more episodes of hospitalization due to heart failure (HR: 2.93, 95% CI: 1.49-5.76, p < 0.01). However, compared with patients without CHF, the all-cause hospitalization risk was not much higher in CHF patients (HR: 1.09, 95% CI: 0.90-1.33, p = 0.39). Subgroup analysis found that the effect of CHF on all-cause mortality was stronger for male patients, patients with residual renal function, the elderly (≥60 years of age), patients with arteriovenous fistulae vascular accesses, nondiabetic patients, low-flux dialyzer users, and inadequately dialyzed patients (standardized Kt/V <2). Conclusion: In HD patients, CHF was found to be associated with a higher risk of all-cause mortality and cause-specific hospitalization risk. Further research is needed to identify opportunities to improve care for HD patients combined with CHF.

High facility-level serum potassium variability associated with mortality in hemodialysis patients: results from Chinese Dialysis Outcomes and Practice Patterns Study (DOPPS).

The role of facility-level serum potassium (sK+) variability (FL-SPV) in dialysis patients has not been extensively studied. This study aimed to evaluate the association between FL-SPV and clinical outcomes in hemodialysis patients using data from the China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5. FL-SPV was defined as the standard deviation (SD) of baseline sK+ of all patients in each dialysis center. The mean and SD values of FL-SPV of all participants were calculated, and patients were divided into the high FL-SPV (>the mean value) and low FL-SPV (≤the mean value) groups. Totally, 1339 patients were included, with a mean FL-SPV of 0.800 mmol/L. Twenty-three centers with 656 patients were in the low FL-SPV group, and 22 centers with 683 patients were in the high FL-SPV group. Multivariate logistic regression analysis showed that liver cirrhosis (OR = 4.682, 95% CI: 1.246-17.593), baseline sK+ (<3.5 vs. 3.5 ≤ sK+ < 5.5 mmol/L, OR = 2.394, 95% CI: 1.095-5.234; ≥5.5 vs. 3.5 ≤ sK+ < 5.5 mmol/L, OR = 1.451, 95% CI: 1.087-1.939), dialysis <3 times/week (OR = 1.472, 95% CI: 1.073-2.020), facility patients' number (OR = 1.088, 95% CI: 1.058-1.119), serum HCO3- level (OR = 0.952, 95% CI: 0.921-0.984), dialysis vintage (OR = 0.919, 95% CI: 0.888-0.950), other cardiovascular disease (OR = 0.508, 95% CI: 0.369-0.700), and using high-flux dialyzer (OR = 0.425, 95% CI: 0.250-0.724) were independently associated with high FL-SPV (all p < .05). After adjusting potential confounders, high FL-SPV was an independent risk factor for all-cause death (HR = 1.420, 95% CI: 1.044-1.933) and cardiovascular death (HR = 1.827, 95% CI: 1.188-2.810). Enhancing the management of sK+ of hemodialysis patients and reducing FL-SPV may improve patient survival.

High-flux Hemodialysis Does Not Increase Vitamin B Loss Compared With Low-flux Hemodialysis.

OBJECTIVES: A consistent effect of hemodialysis (HD) on vitamin B loss has not been fully demonstrated and the effect of high-flux hemodialysis (HFHD) is also inconclusive. The aim of this study was to identify the loss of vitamin B1, B3, B5, and B6 in a single HD session and to evaluate the effect of HFHD on vitamin B removal. METHODS: Patients on maintenance HD were enrolled in this study. They were divided into low-flux hemodialysis (LFHD) group and HFHD group. Vitamin B1, B3, B5, and B6 (pyridoxal 5'-phosphate [PLP]) concentrations in blood pre- and post-HD sessions, as well as in the spent dialysate were measured. Loss of vitamin B was calculated and the difference in vitamin B loss between the 2 groups was compared. The association between HFHD and vitamin B loss was estimated using multivariable linear regression analysis. RESULTS: Seventy-six patients were included, of whom 29 were on LFHD and 47 were on HFHD. The median reduction ratio of serum vitamins B1, B3, B5, and B6 after a single HD session was 38.1%, 24.9%, 48.4%, and 44.7%, respectively. The median concentration of vitamins B1, B3, B5, and B6 in the dialysate was 0.3 µg/L, 2.9 µg/mL, 2.0 µg/L, and 0.4 ng/mL. There was no difference in either the reduction ratio of vitamin B in blood, or the concentration in dialysate between LFHD and HFHD groups. After adjusting for covariates by multivariable regression, HFHD had no effect on vitamin B1, B3, B5, or B6 removal. CONCLUSIONS: Vitamins B1, B3, B5, and B6 can be removed by HD and HFHD does not increase the loss.

Incidence and risk factors of falls in patients undergoing hemodialysis: A multicenter survey in northern China.

INTRODUCTION: Patients undergoing hemodialysis (HD) are at a higher risk of falls than healthy individuals. Further knowledge regarding the risk of falls could lead to better risk prevention strategies. We designed a multicenter, prospective cohort study according to the strengthening of the reporting of observational studies in epidemiology (STROBE) guidelines to investigate the incidence and risk factors of falls in patients undergoing hemodialysis in Northern China. METHODS: Patients undergoing hemodialysis in six hemodialysis units were recruited from January 2019 to January 2020. Data on demographics and disease conditions were collected at baseline. Data on other variables, the incidence of falls, and related conditions were collected every 3 months during a 1-year follow-up. The Generalized Estimating Equation model was used to evaluate factors associated with falls. FINDINGS: This study included 472 patients. The incidence of falls was 0.31 per patient year. In patients aged 45-64 years (p = 0.01; odds ratio [OR]: 14.801; 95% confidence interval [CI]: 1.897-115.453) and ≥ 65 years (p = 0.007; OR: 16.562; 95% CI: 2.118-129.521), anemia (p = 0.015; OR: 2.122; 95% CI: 1.154-3.902) and moderately (p = 0.003; OR: 5.439; 95% CI: 1.791-16.516) and severely abnormal timed up and go test (TUGT) levels (p = 0.001; OR: 7.032; 95% CI: 2.226-22.216) were identified as independent risk factors of falls. DISCUSSION: Falls are prevalent among patients undergoing in-center hemodialysis. Advanced age, anemia, and moderately and severely abnormal TUGT levels may be risk factors of falls.

The Effect of Metabolic Syndrome and Its Individual Components on Renal Function: A Meta-Analysis.

BACKGROUND: Observational studies have reported inconsistent findings in the relationship between metabolic syndrome (MetS), its components, and loss of renal function, mainly including eGFR decline, new-onset CKD, and ESRD. This meta-analysis was performed to investigate their potential associations. METHODS: PubMed and EMBASE were systematically searched from their inception to 21 July 2022. Observational cohort studies in English assessing the risk of renal dysfunction in individuals with MetS were identified. Risk estimates and their 95% confidence intervals (CIs) were extracted and pooled using the random-effects approach. RESULTS: A total of 32 studies with 413,621 participants were included in the meta-analysis. MetS contributed to higher risks of renal dysfunction (RR = 1.50, 95% CI = 1.39-1.61) and, specifically, rapid decline in eGFR (RR 1.31, 95% CI 1.13-1.51), new-onset CKD (RR 1.47, 95% CI 1.37-1.58), as well as ESRD (RR 1.55, 95% CI 1.08-2.22). Moreover, all individual components of MetS were significantly associated with renal dysfunction, while elevated BP conveyed the highest risk (RR = 1.37, 95% CI = 1.29-1.46), impaired fasting glucose with the lowest and diabetic-dependent risk (RR = 1.20, 95% CI = 1.09-1.33). CONCLUSIONS: Individuals with MetS and its components are at higher risk of renal dysfunction.

There is no association of serum vitamin B levels with all-cause and cardiovascular mortality in hemodialysis patients.

INTRODUCTION: The impact of vitamin B metabolic disorders on hemodialysis (HD) patients' survival is unknown. This study is to investigate the association of serum vitamin B1, B3, B5, and B6 with all-cause and cardiovascular (CV) mortality in HD patients. METHODS: Patients' baseline serum vitamin B1, B3, B5, and B6 levels were collected, and they were followed up for the occurrence of all-cause and CV death. Kaplan-Meier analysis and Cox proportional hazards model were used to examine the association of vitamin B with mortality. RESULTS: Seventy-six HD patients were included. The median follow-up time was 99 months. Kaplan-Meier analysis showed that baseline vitamin B5 < 69.0 nmol/L and vitamin B6 < 8.1 ng/ml were associated with a higher risk of CV mortality, but these associations were nullified after adjustment. CONCLUSIONS: Serum vitamins B1, B3, B5, and B6 were not associated with all-cause or CV mortality in HD patients. CLINICAL TRIAL REGISTRY: ChiCTR2200057078 (Chinese Clinical Trial Registry, https://www.chictr.org.cn/).

Roxadustat improves renal osteodystrophy by dual regulation of bone remodeling.

PURPOSE: Renal osteodystrophy (ROD), a component of chronic kidney disease-mineral and bone disorder (CKD-MBD) can lead to bone loss increasing fracture risks in CKD patients. Therefore, it is important to prevent and treat ROD. Activation of hypoxia-inducible factor-1α (HIF-1α) signaling was reported to prevent osteoporotic bone loss. Roxadustat, which is used to treat renal anemia in the clinic, is a novel HIF stabilizer. In our study, we aimed to investigate the effects of roxadustat on ROD. METHODS: We established an adenine-induced CKD rat model. Roxadustat was administered intragastrically to normal and CKD rats for 4 weeks. Hemoglobin concentrations and serum biochemical parameters were tested, and bone histomorphometric analysis was performed. RESULTS: CKD rats exhibited impaired renal function with anemia, secondary hyperparathyroidism and high-turnover ROD-induced significant bone loss. Roxadustat ameliorated renal anemia and attenuated the extreme increase in intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) in CKD rats. Bone histomorphometric analysis showed that roxadustat significantly alleviated bone loss and bone microarchitecture deterioration in CKD rats by increasing osteoblast activity and inhibiting osteoclast activity. We did not find that roxadustat had significant effects on bone metabolism in normal rats. CONCLUSION: Roxadustat can improve ROD via dual regulation of bone remodeling. The use of roxadustat may be a promising strategy to treat osteoporotic bone disorders, such as ROD.

Clinical characteristics and management of hemodialysis patients with pre-dialysis hypertension: a multicenter observational study.

BACKGROUND: Hypertension is a leading preventable risk factor for cardiovascular disease in hemodialysis patients. Pre-dialysis systolic blood pressure (SBP) more than 160 mmHg was thought to be associated with increased risk of cardiovascular events and all-cause mortality. The present study was performed to explore the clinical characteristics and management of hemodialysis patients with pre-dialysis SBP ≥ 160 mmHg. METHODS: A total of 1233 patients undergoing hemodialysis from nine hemodialysis centers were enrolled. Pre-dialysis and home BP were measured and clinical data were collected. The characteristics of patients with pre-dialysis SBP ≥ 160 mmHg were explored. Clinical parameters between hypertensive and non-hypertensive patients were compared. The partial correlation analyses performed to identify the associations between BP and clinical parameters. RESULTS: There were 24.6% of the hemodialysis patients had pre-dialysis SBP ≥ 160 mmHg and the average SBP was 173.8 ± 10.9 mmHg. Only 21.4% of the patients achieved dry weight after dialysis and up to 30.2% of patients were not given combination therapies of antihypertensive drugs. Compared to patients with pre-hemodialysis SBP < 160 mmHg, patients with pre-dialysis SBP ≥ 160 mmHg had lower target-reaching rate of Kt/v and higher incidences of intradialytic hypotension and muscle spasm. Most patients (96%) with pre-dialysis SBP ≥ 160 mmHg had home SBP≥ 135 mmHg. Patients with home SBP ≥ 160 mmHg had higher left ventricular weight index and lower hemoglobin levels when compared to their counterparts with home SBP <160 mmHg. CONCLUSIONS: Pre-dialysis SBP ≥ 160 mmHg is common in clinical practice and most of the patients could diagnosed to be hypertensive according to their home SBP. Patients with pre-dialysis SBP ≥ 160 mmHg are more likely to be subjected to dialysis insufficiency and intradialytic complications. Achieving dry weight and sufficient pharmacologic interventions should be strengthened to improve BP control in the hemodialysis population.

Application of Angiotensin Receptor-Neprilysin Inhibitor in Chronic Kidney Disease Patients: Chinese Expert Consensus.

Chronic kidney disease (CKD) is a global public health problem, and cardiovascular disease is the most common cause of death in patients with CKD. The incidence and prevalence of cardiovascular events during the early stages of CKD increases significantly with a decline in renal function. More than 50% of dialysis patients die from cardiovascular disease, including coronary heart disease, heart failure, arrhythmia, and sudden cardiac death. Therefore, developing effective methods to control risk factors and improve prognosis is the primary focus during the diagnosis and treatment of CKD. For example, the SPRINT study demonstrated that CKD drugs are effective in reducing cardiovascular and cerebrovascular events by controlling blood pressure. Uncontrolled blood pressure not only increases the risk of these events but also accelerates the progression of CKD. A co-crystal complex of sacubitril, which is a neprilysin inhibitor, and valsartan, which is an angiotensin receptor blockade, has the potential to be widely used against CKD. Sacubitril inhibits neprilysin, which further reduces the degradation of natriuretic peptides and enhances the beneficial effects of the natriuretic peptide system. In contrast, valsartan alone can block the angiotensin II-1 (AT1) receptor and therefore inhibit the renin-angiotensin-aldosterone system. These two components can act synergistically to relax blood vessels, prevent and reverse cardiovascular remodeling, and promote natriuresis. Recent studies have repeatedly confirmed that the first and so far the only angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan can reduce blood pressure more effectively than renin-angiotensin system inhibitors and improve the prognosis of heart failure in patients with CKD. Here, we propose clinical recommendations based on an expert consensus to guide ARNI-based therapeutics and reduce the occurrence of cardiovascular events in patients with CKD.

Hepatitis C Prevalence, Incidence, and Treatment in Chinese Hemodialysis Patients: Results From the Dialysis Outcomes and Practice Patterns Study-China (2019-21).

Background: Prior work from the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed HCV prevalence in China in 2012-2015 being in the upper third and HCV incidence the 2nd highest among 15 different countries/regions investigated. The goal of the present investigation was to: (1) determine if HCV prevalence and incidence has changed, and (2) collect detailed data to understand how HCV is treated, monitored, and managed in Chinese HD facilities and non-dialysis chronic kidney disease (CKD) clinics. Data and Methods: Detailed data for 1,700 randomly selected HD patients were reported by 39 randomly selected HD facilities from Beijing, Shanghai, and Guangzhou participating in the DOPPS 7-China study from 2019 to 2021. The study site medical directors completed a survey regarding numerous aspects of HCV treatment and management in HD and ND-CKD patients. Results: In this 2019 to 2021 cohort, HCV prevalence was 7.4%, which was lower than the 14.8 and 11.5% HCV prevalence for the 2009-2011 and 2012-2015 cohorts, respectively. HCV incidence of 1.2 cases per 100 pt-yrs also was lower compared to the incidence of 2.1 for the 2012-2015 cohort. Although the great majority of study site medical directors indicated that all or nearly HCV+ patients should be treated for their HCV, very few HCV+ patients have been treated presumably due to substantial cost barriers for affording the new direct acting antivirals (DAAs). The randomly selected facilities in our DOPPS 7-China study appear to have excellent programs in place for frequent monitoring of patients and staff for HCV, education of staff, and referral of HCV cases to external infectious disease, gastroenterology, and liver disease specialists. Liver biopsies were not commonly performed in HCV+ HD patients. HCV genotyping also was rarely performed in participating units. Conclusions: Our study indicates a 50% decline in HCV prevalence and a >40% decline in HCV incidence in Chinese HD patients over the past 10-12 yrs. Chinese HD facilities and associated specialists appear to be well-equipped and organized for successfully treating and managing their HCV+ HD and CKD patients in order to achieve the WHO goal of eliminating HCV by 2030.

Ethnicity evaluation of ferric pyrophosphate citrate among Asian and Non-Asian populations: a population pharmacokinetics analysis.

PURPOSE: To evaluate the potential ethnic differences of ferric pyrophosphate citrate (FPC, Triferic) in healthy subjects and patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) and identify covariates that may influence pharmacokinetics (PK) of FPC. METHODS: Data were collected from 2 Asian and 4 non-Asian clinical studies involving healthy subjects and CKD-5HD patients. Three population PK models were developed: M1 for intravenous (IV) administration of FPC in healthy subjects; M2 for dialysate administration of FPC in CKD-5HD patients; M3 for pre-dialyzer administration of FPC in CKD-5HD patients. All the models were fitted to concentration versus time data of FPC using the nonlinear mixed effect approach with the NONMEM® program. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 26 Asians and 65 non-Asians were included in the final model analysis database. Forty healthy subjects were administered FPC via intravenous (IV) route and 51 patients with CKD-5HD via dialysate (N = 50) and pre-dialyzer blood circuit administration (N = 51). The PK parameters of FPC IV were similar. The population PK model showed good parameter precision and reliability as shown by model evaluation, and no relevant influence of ethnicity on PK parameters was observed. In healthy subjects, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) decreased with increase in lean body mass (LBM) and the average serum total iron at 6 h before the baseline period (Feav), whereas, in both patient populations, Cmax and AUC decreased with increase in LBM and decrease in Febaseline. Other factors such as gender, age, Feav, and ethnicity had no influence on PK exposures in patients. The influence of LBM on PK exposures in patients was smaller than that in healthy subjects (ratio of AUC0-24 for the 5th [68 kg] and 95th [45 kg] patient's LBM was almost 1). The influence of Feav and LBM on PK exposures was < 50%. CONCLUSION: The population pharmacokinetics model successfully described the PK parameters of FPC in healthy subjects and CKD-5HD patients and were comparable between Asian and non-Asian populations.

Roxadustat promotes osteoblast differentiation and prevents estrogen deficiency-induced bone loss by stabilizing HIF-1α and activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Osteoporosis is a very common skeletal disorder that increases the risk of fractures. However, the treatment of osteoporosis is challenging. Hypoxia-inducible factor-1α (HIF-1α) plays an important role in bone metabolism. Roxadustat is a novel HIF stabilizer, and its effects on bone metabolism remain unknown. This study aimed to investigate the effects of roxadustat on osteoblast differentiation and bone remodeling in an ovariectomized (OVX) rat model. METHODS: In vitro, primary mouse calvarial osteoblasts were treated with roxadustat. Alkaline phosphatase (ALP) activity and extracellular matrix mineralization were assessed. The mRNA and protein expression levels of osteogenic markers were detected. The effects of roxadustat on the HIF-1α and Wnt/ß-catenin pathways were evaluated. Furthermore, osteoblast differentiation was assessed again after HIF-1α expression knockdown or inhibition of the Wnt/ß-catenin pathway. In vivo, roxadustat was administered orally to OVX rats for 12 weeks. Then, bone histomorphometric analysis was performed. The protein expression levels of the osteogenic markers HIF-1α and ß-catenin in bone tissue were detected. RESULTS: In vitro, roxadustat significantly increased ALP staining intensity, enhanced matrix mineralization and upregulated the expression of osteogenic markers at the mRNA and protein levels in osteoblasts compared with the control group. Roxadustat activated the HIF-1α and Wnt/ß-catenin pathways. HIF-1α knockdown or Wnt/ß-catenin pathway inhibition significantly attenuated roxadustat-promoted osteoblast differentiation. In vivo, roxadustat administration improved bone microarchitecture deterioration and alleviated bone loss in OVX rats by promoting bone formation and inhibiting bone resorption. Roxadustat upregulated the protein expression levels of the osteogenic markers, HIF-1α and ß-catenin in the bone tissue of OVX rats. CONCLUSION: Roxadustat promoted osteoblast differentiation and prevented bone loss in OVX rats. The use of roxadustat may be a new promising strategy to treat osteoporosis.

Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease.

BACKGROUND AND OBJECTIVE: Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD. METHODS: Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 µg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA). RESULTS: A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 µmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 µmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 µmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively. CONCLUSION: FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based on clinical feasibility and requirement. CLINICAL TRIAL REGISTRATION: CTR20181113 and CTR20181119.

Efficacy and safety of expanded hemodialysis in hemodialysis patients: a meta-analysis and systematic review.

BACKGROUND: Expanded hemodialysis (HDx) is a new dialysis modality, but a systematic review of the clinical effects of using HDx is lacking. This systematic review and meta-analysis aimed to assess the efficacy and safety of HDx for hemodialysis (HD) patients. METHODS: PubMed, the Cochrane library, and EMBASE databases were systematically searched for prospective interventional studies comparing the efficacy and safety of HDx with those of high flux HD or HDF in HD patients. RESULTS: Eighteen trials including a total of 853 HD patients were enrolled. HDx increased the reduction ratio (RR) of ß2-microglobulin (SMD 6.28%, 95% CI 0.83, 1.73, p = .02), κFLC (SMD 15.86%, 95% CI 6.96, 24.76, p = .0005), and λFLC (SMD 22.42%, 95% CI, 17.95, 26.88, p < .0001) compared with high flux HD. The RR of ß2-microglobulin in the HDx group was lower than that in the HDF group (SMD -3.53%, 95% CI -1.16, -1.9, p < .0001). HDx increased the RRs of κFLC (SMD 1.34%, 95% CI 0.52, 2.16, p = .001) and λFLC (SMD 7.28%, 95% CI 1.08, 13.48, p = .02) compared to HDF. There was no significant difference in albumin loss into the dialysate between the HDx and HDF groups (SMD 0.35 g/session, 95% CI -2.38, 3.09, p = .8). CONCLUSIONS: This meta-analysis indicated that compared with high-flux HD and HDF, HDx can increase the clearance of medium and large-molecular-weight uremic toxins. And it does not increase the loss of albumin compared with HDF.