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Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
Chen, N, Qian, J, Chen, J, Yu, X, Mei, C, Hao, C, Jiang, G, Lin, H, Zhang, X, Zuo, L, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(8):1373-1386
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Abstract
BACKGROUND FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). METHODS In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed. RESULTS In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects. CONCLUSIONS FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.
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Cumulative Fluid Balance and Mortality in Septic Patients With or Without Acute Kidney Injury and Chronic Kidney Disease.
Neyra, JA, Li, X, Canepa-Escaro, F, Adams-Huet, B, Toto, RD, Yee, J, Hedayati, SS, ,
Critical care medicine. 2016;(10):1891-900
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OBJECTIVE Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients. DESIGN Retrospective cohort study. SETTING Urban academic medical center ICU. PATIENTS ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15 mL/min/1.73 m or receiving chronic dialysis were excluded. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04-1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03-1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05-1.13] for acute kidney injury-/chronic kidney disease+; 1.05 [1.03-1.08] for acute kidney injury+/chronic kidney disease-; and 1.07 [1.02-1.11] for acute kidney injury-/chronic kidney disease-). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9 L for acute kidney injury+/chronic kidney disease+; 3.8 L for acute kidney injury-/chronic kidney disease+; 4.3 L for acute kidney injury+/chronic kidney disease-; and 1.5 L for acute kidney injury-/chronic kidney disease-. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury. CONCLUSIONS Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease.
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[Therapeutic effect of Astragalus and Angelica mixture on the renal function and TCM syndrome factors in treating stage 3 and 4 chronic kidney disease patients].
Li, S, Yin, XX, Su, T, Cao, C, Li, X, Rao, XR, Li, X
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2014;(7):780-5
Abstract
OBJECTIVE To compare the therapeutic effect of Astragalus and Angelica Mixture (AAM) on treating CKD patients according to different CKD primary diseases, staging and TCM syndromes. METHODS A multicentre, open-label, and self control clinical design was used, and thirty-two patients in line with inclusive criteria were recruited. Based on maintaining their previous basic CKD treatment, patients additionally took AAM (Astragalus and Angelica each 30 g), once a day, three months consisted of one therapeutic course. Serum creatinine (SCr), estimated glomerular filtration rate (eG- FR), 24 h urinary total protein (UTP), plasma albumin (ALB), hemoglobin (Hb), and changes of TCM syndrome factor integrals were compared before treatment, at the end of month 1, 2, and 3. The differences in the aforesaid indices were compared between CKD patients with different CKD primary diseases (chronic glomerulonephritis, chronic renal tubulointerstitial disease, hypertensive renal damage), different CKD stages (CKD 3 and CKD 4), and patients of qi-blood deficiency syndrome (QBDS) and non-QBDS. RESULTS AAM could improve 78.12% (25/32) patients' renal function. Compared with before treatment, SCr decreased (12.08% +/- 10.11%), eGFR increased (21.14% +/- 18.55%), and ALB increased (2.76% +/- 1.97%) at the end of 3-month treatment (all P < 0.05). As for TCM syndrome factor integrals, compared with before treatment, the integrals for qi deficiency syndrome, blood deficiency syndrome, and yin deficiency syndrome decreased, while the integrals for dampness heat syndrome and turbid-toxin syndrome increased (all P < 0.05). There was no obvious difference in all indices except the integral for hypertensive renal damage patients of yin deficiency syndrome (P > 0.05). The SCr decreasing percent was 19.82% +/- 8.30% for patients of non-QBDS and 5.24% +/- 10.75% for patients of QBDS. The latter was higher with statistical difference (P < 0.05). As for TCM syndrome factor integrals, the integral differences of qi deficiency and blood deficiency were obviously higher in patients of QBDS, when compared with patients of non-QBDS (P < 0.05). CONCLUSION AAM could improve the renal function of CKD patients, elevate their ALB levels, and ameliorate associated qi deficiency syndrome, blood deficiency syndrome, and yin deficiency syndrome, especially for CKD patients of QBDS.
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[The efficacy and safety of high-dose irbesartan in treatment of clinical proteinuria in patients with chronic kidney disease].
Li, X, Chen, XD, Li, ZX
Zhonghua nei ke za zhi. 2011;(12):1034-8
Abstract
OBJECTIVE To evaluate the efficacy and safety of high-dose irbesartan in the treatment of mild and moderate proteinuria in patients with chronic kidney disease (CKD). METHODS A single center, prospective, observational study was performed. A total of 96 subjects were given irbesartan 150 mg/d for 4 weeks. Twenty-six were divided into single-dose (150 mg/d) irbesartan group when their clinical efficacy were eligible for improvement criteria and 70 were divided into high-dose (300 - 600 mg/d) irbesartan group when there were no effect for single-dose treatment. Both groups received treatment for 48 weeks. Then 24-hour quantitative urine protein, systolic pressure, diastolic pressure, TC, LDL-C, plasma albumin, serum creatinine, blood urea nitrogen, blood uric acid, serum potassium and ALT were determined. RESULTS The proteinuria level after treatment in the single-dose irbesartan group was decreased by 68.3% with a statistically significant difference (P < 0.001). In the high-dose group, the dose of irbesartan was increased based on the ineffectiveness when treating with single-dose, and the proteinuria was decreased by 63.4% (P < 0.001). Total effective rate in treating proteinuria in high-dose group was 72.9% (51/70). Among the blood pressure sub-groups, the effective rates for the normal blood pressure group and hypertension group in treating proteinuria were 68.2% and 76.9% respectively (P > 0.05). However, in the normal blood pressure group and hypertension group, the proteinuria was decreased by 61.9% and 67.5% respectively after treatment (P < 0.001, P < 0.01), while without difference between the two groups (P > 0.05). The effective rates of high doses of 300, 450 and 600 mg/d of irbesartan in treating proteinuria were 70.8%, 63.6% and 66.7%, respectively. The difference in effective rates of treating proteinuria among different doses had no statistical significance (P > 0.05). No obvious increase of SCr value before and after treatment in high-dose group (P = 0.583). The increasing level of serum potassium in high-dose group after treatment was higher than that in the single-dose group (P < 0.05), but the highest concentration (4.8 mmol/L) was still within the normal range. The blood pressure of 3 cases who quit observation because of low blood pressure in high-dose group returned to normal after drug withdrawal. CONCLUSION High-dose irbesartan can effectively lower the mild and moderate proteinuria in CKD patients with a good safety and tolerance and the efficacy is independent of lowering blood pressure.