BACKGROUND: Chronic kidney disease (CKD)-associated anemia (CKD-anemia) is associated with poor survival, and hemoglobin targets are often not achieved with current therapies. Phase 3 trials have demonstrated the treatment efficacy of roxadustat for CKD-anemia. This phase 4 study aims to evaluate the long-term (52-week) safety and effectiveness of roxadustat in a broad real-world patient population with CKD-anemia with and without dialysis in China. METHODS: This Phase 4 multicenter, open-label, prospective study, conducted from 24 November 2020 to 11 November 2022, evaluated the long-term safety and effectiveness of roxadustat for CKD-anemia in China. Patients aged ≥18 years with CKD-anemia with or without dialysis were included. The initial oral dose was 70-120 mg (weight-based followed by dose adjustment) over 52 weeks. The primary endpoint was safety based on adverse events (AEs). The secondary endpoints were hemoglobin changes from baseline and the proportion of patients who achieved mean hemoglobin ≥100 g/L. Effectiveness evaluable populations 1 (EE1) and EE2 included roxadustat-naïve and previously roxadustat-treated patients, respectively. The safety analysis set (SAF) included all patients who received ≥1 occasion. RESULTS: The EE1, EE2, and SAF populations included 1804, 193, and 2021 patients, respectively. In the SAF, the mean age was 50 ± 14 years, and 1087 patients (53.8%) were male. Mean baseline hemoglobin was 96.9 ± 14.0 g/L in EE1 and 100.3 ± 12.9 g/L in EE2. In EE1, the mean (95% confidence interval) hemoglobin changes from baseline over weeks 24-36 and 36-52 were 14.2 (13.5-14.9) g/L and 14.3 (13.5-15.0) g/L, respectively. Over weeks 24-36 and 36-52, 83.3% and 86.1% of patients in EE1 and 82.7% and 84.7% in EE2 achieved mean hemoglobin ≥100 g/L, respectively. In the SAF, 1643 (81.3%) patients experienced treatment-emergent AEs (TEAEs). Overall, 219 (10.8%) patients experienced drug-related TEAEs. Thirty-eight (1.9%) patients died of TEAEs (unrelated to the study drug). Vascular access thrombosis was uncommon. CONCLUSIONS: Roxadustat (52 weeks) increased hemoglobin and maintained the treatment target in Chinese patients with CKD-anemia with acceptable safety, supporting its use in real-world settings. REGISTRATION Chinese Clinical Trial Registry ( www.chictr.org.cn ) ChiCTR2100046322; CDE ( www.chinadrugtrials.org.cn ) CTR20201568.
Humans ; Male ; Female ; Anemia/etiology* ; Middle Aged ; Renal Insufficiency, Chronic/complications* ; Glycine/adverse effects* ; Isoquinolines/adverse effects* ; Aged ; Prospective Studies ; Adult ; Hemoglobins/metabolism* ; Treatment Outcome ; China ; Registries ; East Asian People

Objective To investigate the expression and the effects of tissue inhibitor of metalloproteinases-1 (TIMP-1) on lungs of rats with sepsis.Methods Forty Sprague-Dawley (SD) rats were randomly divided into two groups,namely sham group (n =8) and sepsis model group (n =32).The rats of model group were modeled by cecal ligation and puncture (CLP),and were further divided into four subgroups as per the time after modeling,namely 6 h (n =8),12 h (n =8),24 h (n =8),48 h (n =8)subgroups.Blood and lung samples were taken 6 h,12 h,24 h and 48 h after modeling.The histological changes in lungs of the rats were observed under light microscope.Expressions of TIMP-1 mRNA,Bax mRNA and Bcl-2 mRNA in lungs were measured by RT-PCR.The immunohistochemistry was used to label the CD18 in lungs during different phases of sepsis.The data were processed by t test.Results Compared with sham group,the lung tissues of rats in model group were injured to a certain extent after CLP.The expression of TIMP-1 mRNA and the number of CD18 positive cells increased at the same time (P ＜ 0.01),and peaked 24 hours later (P ＜ 0.01).While the expression of Bax mRNA in model group decreased markedly 12-48 hours after modeling (P ＜ 0.01-0.05),and reached minimum 48 hours later (P ＜ 0.01).The expression of Bcl-2 mRNA in model group changed unnoticeable.The positive correlation between variations in number of CD18 positive cells and expression of TIMP-1 mRNA was found in model group (r =0.426,P ＜ 0.01).Conclusions The increase in expression of TIMP-1 mRNA in lungs is closely associated with the lung injury of sepsis.The mechanism of lung injury is likely attributed to the preservation of inflammatory cells from apoptosis,and the persistent inflammation response causes tissue damage,leading to organ dysfunction.

Objective To investigate the changes in the serum MMP-9 (matrix metalloproteinase-9) and the expressions of MMP-9 in lung, kidney and intestine in rats with multiple organ dysfunction syndrome (MODS) and confirm extracellular matrix injuries being the mechanism in MODS in order to propose a novel theoretical basis for cfinical treatment of MODS. Method Forty wister rats were randomly divided into two groups: control group (n=8) and MODS model group (n=32). The rats of model group were further divided into four subgroups ac-cordingto the time elapsed after modelling: 12 h (n=8), 24 h(n=8) ,48 h(n=8) and 72 h (n=8), and were modelled by celiac injection of mixed liquid of zymosan-paraffin (4 mL/100 g) after blood loss (1mL/100 g) by extirpating their left eyes. Blood,lung, kidney and intestine were sampled 12,24,48 and 72 hours after models were established. The histological changes in the lung, kidney and intestine of the rats were observed by light mi-croscope. The serum MMP-9 were measured by enzyme-linked immunosorbent assay (ELISA). The immunohisto-chemistry was used to observe the expression of MMP-9 in lung,kidney and intestine during different phases of MODS. The data were processed by one-way ANOVA and Bivariate analysis. Results Compared with control group, the organs were injured by congestion, edema and inflammatory cells infiltration to a certain extent in model groups. The serum MMP-9 increased markedly 12 hours after modelling (P<0.01 ) and peaked 48 hours later. The expressions of MMP-9 in lung, kidney and small intestine significantly increased from 12 h to 72 h after mod-elling (P<0.01 or 0.05). Conclusions The MMP-9 increased both in serum and tissue are closely associated with the pathological process of MODS. The mechanism of organ damage probably attributes to the damage of extra-celluar matrix and tissue construction.

Objective To investigate the effect of fresh apple pulp on abdominal distention and constipation in patients with tube feeding.Methods 62 patients with tube feeding were divided into the observation group(n=31) and control group(n=31) randomly.The patients in the observation group were given routine enteral nutrition and fresh apple pulp,while those in the control group were given the routine enteral nutrition and rice soup.Results 3 cases developed abdominal distention in the observation group,but 10 cases in the control group(P<0.05).4 cases developed constipation in the observation group,but 12 cases in the control group(P<0.05).Moreover,the duration of abdominal distention and constipation significantly decreased in the observation group compared with those of the control group(P<0.05).Conclusion Fresh apple pulp can prevent and reduce abdominal distention and constipation in patients with tube feeding.