A multicentre, multi-national, double-blind, randomised, active-controlled, parallel-group clinical study to assess the safety and efficacy of PDA10 (Epoetin-alpha) vs. Eprex® in patients with anaemia of chronic renal failure

Background Erythropoietin stimulating agent (ESA) has been standard of care in treating renal anaemia for the past 20 years. Many patients have limited access to ESA in view of long-term costs leading to suboptimal ESA dosage. Biosimilar epoetin is a potential cost-effective alternative to originator for optimal renal anaemia management. Objective To determine efficacy and safety of PDA10 in treating renal anaemia in haemodialysis patients, in comparison to the originator epoetin-α, Eprex®. Methods A phase 3, multicentre, multi-national, double-blind, randomised, active-controlled and parallel group study conducted over 40 weeks in Malaysia and Korea. End stage kidney disease patients undergoing regular haemodialysis who were on erythropoietin treatment were recruited. The study has 3 phases, which included a 12-week titration phase, followed by 28-week double-blind treatment phase and 24-week open-label extension phase. Results The PDA10 and Eprex® were shown to be therapeutically equivalent (p < 0.0001) with mean absolute change in haemoglobin from baseline of − 0.176 (± 0.91) g/dl and − 0.118 (± 1.114) g/dl, respectively. Weekly dose change was 10.01 IU/kg/week in PDA10 group and 10.30 IU/kg/week in Eprex® group, which has no significant difference. There were no significant differences in the safety profile between PDA10 and Eprex® groups. Conclusion This study has confirmed the therapeutic equivalence between PDA10 and Eprex® in terms of efficacy, dosage requirement and safety profile in haemodialysis patients with renal anaemia. Trial registration The study was registered with the National Medical Research Register ( NMRR-13-400-16313 ). This study has been registered retrospectively with Clinical Research Information Service ( CRiS ), Republic of Korea on 25 March 2021.This study was supported by a grant from Duopharma Biotech Bhd. (Malaysia) and Pangen Biotech Inc. (Korea)

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD

The state of nutrition care in outpatient hemodialysis settings in Malaysia: a nationwide survey

Abstract Background This study aimed to assess the situational capacity for nutrition care delivery in the outpatient hemodialysis (HD) setting in Malaysia by evaluating dietitian accessibility, nutrition practices and patients’ outcomes. Methods A 17-item questionnaire was developed to assess nutrition practices and administered to dialysis managers of 150 HD centers, identified through the National Renal Registry. Nutritional outcomes of 4362 patients enabled crosscutting comparisons as per dietitian accessibility and center sector. Results Dedicated dietitian (18%) and visiting/shared dietitian (14.7%) service availability was limited, with greatest accessibility at government centers (82.4%) > non-governmental organization (NGO) centers (26.7%) > private centers (15.1%). Nutritional monitoring varied across HD centers as per albumin (100%) > normalized protein catabolic rate (32.7%) > body mass index (BMI, 30.7%) > dietary intake (6.0%). Both sector and dietitian accessibility was not associated with achieving albumin ≥40 g/L. However, NGO centers were 36% more likely (p = 0.030) to achieve pre-dialysis serum creatinine ≥884 μmol/L compared to government centers, whilst centers with dedicated dietitian service were 29% less likely (p = 0.017) to achieve pre-dialysis serum creatinine ≥884 μmol/L. In terms of BMI, private centers were 32% more likely (p = 0.022) to achieve BMI ≥ 25.0 kg/m2 compared to government centers. Private centers were 62% less likely (p <  0.001) while NGO centers were 56% less likely (p <  0.001) to achieve serum phosphorus control compared to government centers. Patients from centers with a shared/visiting dietitian had 35% lower probability (p <  0.001) to achieve serum phosphorus levels below 1.78 mmol/L compared to centers without access to a dietitian. Conclusions There were clear discrepancies in nutritional care in Malaysian HD centers. Changes in stakeholder policy are required to ensure that dietitian service is available in Malaysian HD centers

Benchmarking diet quality to assess nutritional risk in hemodialysis patients: applying adequacy and moderation metrics of the hemodialysis-healthy eating index

Objectives: This study modified Healthy Eating Index (HEI) based on hemodialysis (HD)-specific nutritional guidelines and investigated associations between the diet quality (DQ) and nutritional risk in HD patients. Methods: The HD-HEI tool adapted the Malaysian Dietary Guidelines 2010 framework according to HD-specific nutrition guidelines. This HD-HEI was applied to 3-day dietary records of 382 HD patients. Relationships between HD-HEI scores and nutritional parameters were tested by partial correlations. Binary logistic regression models adjusted with confounders were used to determine adjusted odds ratio (adjOR) with 95% confidence interval (CI) for nutritional risk based on HD-HEI scores categorization. Results: The total HD-HEI score (51.3 ± 10.2) for this HD patient population was affected by ethnicity (Ptrend <.001) and sex (P =.003). No patient achieved “good” DQ (score: 81-100), while DQ of 54.5% patients were classified as “needs improvement” (score: 51-80) and remaining as “poor” (score: 0-51). Total HD-HEI scores were positively associated with dietary energy intake (DEI), dietary protein intake (DPI), dry weight, and handgrip strength, but inversely associated with Dietary Monotony Index (DMI) (all P <.05). Individually, scores for refined grain, total protein, and animal protein were positively associated with DEI (all P <.05), while total, animal, fish, and vegetable proteins indicated positive associations with DPI (all P <.05). Moderating metrics for convenience meals, saturated fats, sodium, and fluid negatively correlated toward DEI with similar trends for DPI excepting convenience meals and fluids. “Poor” DQ was associated with DMI ≥ 29.2 (adjOR 18.83, 95% CI 9.36-37.86, P <.001), Malnutrition Inflammation Score ≥ 5 (adjOR 1.78, 95% CI 1.01-3.15, P =.045), and protein energy wasting (adjOR 1.96, 95% CI 1.14-3.34, P =.031), but became nullified with covariate adjustments. “Poor” DQ was also associated with low lean tissue mass (<32.6 kg) in men (adjOR 2.38, 95% CI 1.01-5.58, P =.046) but not women. Conclusion: “Poor” DQ was associated with poor nutritional status in Malaysian HD patients, who should be targeted for nutritional counseling

Muscle Status Response to Oral Nutritional Supplementation in Hemodialysis Patients with Protein Energy Wasting: A Multi-Center Randomized, Open Label-Controlled Trial

Background: Muscle wasting, observed in patients with end-stage kidney disease and protein energy wasting (PEW), is associated with increased mortality for those on hemodialysis (HD). Oral nutritional supplementation (ONS) and nutrition counseling (NC) are treatment options for PEW but research targeting muscle status, as an outcome metric, is limited. Aim: We compared the effects of combined treatment (ONS + NC) vs. NC alone on muscle status and nutritional parameters in HD patients with PEW. Methods: This multi-center randomized, open label-controlled trial, registered under ClinicalTrials.gov (Identifier no. NCT04789031), recruited 56 HD patients identified with PEW using the International Society of Renal Nutrition and Metabolism criteria. Patients were randomly allocated to intervention (ONS + NC, n = 29) and control (NC, n = 27) groups. The ONS + NC received commercial renal-specific ONS providing 475 kcal and 21.7 g of protein daily for 6 months. Both groups also received standard NC during the study period. Differences in quadriceps muscle status assessed using ultrasound (US) imaging, arm muscle area and circumference, bio-impedance spectroscopy (BIS), and handgrip strength (HGS) methods were analyzed using the generalized linear model for repeated measures. Results: Muscle indices as per US metrics indicated significance (p < 0.001) for group × time interaction only in the ONS + NC group, with increases by 8.3 and 7.7% for quadriceps muscle thickness and 4.5% for cross-sectional area (all p < 0.05). This effect was not observed for arm muscle area and circumference, BIS metrics and HGS in both the groups. ONS + NC compared to NC demonstrated increased dry weight (p = 0.039), mid-thigh girth (p = 0.004), serum prealbumin (p = 0.005), normalized protein catabolic rate (p = 0.025), and dietary intakes (p < 0.001), along with lower malnutrition-inflammation score (MIS) (p = 0.041). At the end of the study, lesser patients in the ONS + NC group were diagnosed with PEW (24.1%, p = 0.008) as they had achieved dietary adequacy with ONS provision. Conclusion: Combination of ONS with NC was effective in treating PEW and contributed to a gain in the muscle status as assessed by the US, suggesting that the treatment for PEW requires nutritional optimization via ONS

Univariate regression analysis of protein analytes versus lung function parameters in COPD subjects with and without metabolic syndrome.

<p>Significance (<i>p</i> values) and effect sizes (spearman correlation) are listed for biomarker associations with lung function parameters. Interaction <i>p</i> values indicate significance of differences in biomarker associations with lung function parameters, between metabolic syndrome and non- metabolic syndrome groups.</p

Overview of data analysis on COPD cohort.

<p>Overview of data analysis on COPD cohort.</p

Multivariate analysis of protein analyte data for COPD subjects.

<p>Spearman correlation and adjusted R squared values were computed using test set samples, in a 5-fold nested cross-validation scheme, averaged over 10 random seeds. R squared values were adjusted for the number of predictor terms in the model.</p

Correlation network illustrating functional co-clustering of analytes associated with FEV₁, FEV₁/FVC and DLCO.

<p>Analytes are plotted in a network using Cytoscape <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038629#pone.0038629-Shannon1" target="_blank">[83]</a> where nodes represent analytes and edges represent significant correlations (<i>r</i> >0.4, <i>p</i><0.05, corrected for multiple testing). Analytes are colored according to whether they were associated with FEV₁ related parameters (green), DLCO (red) or both DLCO and FEV₁ related parameters (orange) in univariate regression. Node size is proportional to the number of lung function parameters that showed significant association with a given analyte. Clusters of co-expressed analytes with similar function are highlighted by dotted regions in the graph as neutrophil function (orange), systemic inflammation (blue) and growth factor pathways (grey).</p