Early treatment of Favipiravir in COVID-19 patients without pneumonia: a multicentre, open-labelled, randomized control study.

We investigated Favipiravir (FPV) efficacy in mild cases of COVID-19 without pneumonia and its effects towards viral clearance, clinical condition, and risk of COVID-19 pneumonia development. PCR-confirmed SARS-CoV-2-infected patients without pneumonia were enrolled (2:1) within 10 days of symptomatic onset into FPV and control arms. The former received 1800 mg FPV twice-daily (BID) on Day 1 and 800 mg BID 5-14 days thereafter until negative viral detection, while the latter received only supportive care. The primary endpoint was time to clinical improvement, defined by a National Early Warning Score (NEWS) of ≤1. 62 patients (41 female) comprised the FPV arm (median age: 32 years, median BMI: 22 kg/m²) and 31 patients (19 female) comprised the control arm (median age: 28 years, median BMI: 22 kg/m²). The median time to sustained clinical improvement, by NEWS, was 2 and 14 days for FPV and control arms, respectively (adjusted hazard ratio (aHR) of 2.77, 95% CI 1.57-4.88, P < .001). The FPV arm also had significantly higher likelihoods of clinical improvement within 14 days after enrolment by NEWS (79% vs. 32% respectively, P < .001). 8 (12.9%) and 7 (22.6%) patients in FPV and control arms developed mild pneumonia at a median (range) of 6.5 (1-13) and 7 (1-13) days after treatment, respectively (P = .316). All recovered well without complications. We can conclude that early treatment of FPV in symptomatic COVID-19 patients without pneumonia was associated with faster clinical improvement.Trial registration: Thai Clinical Trials Registry identifier: TCTR20200514001.

Indoxyl sulfate impairs in vitro erythropoiesis by triggering apoptosis and senescence.

Anemia is a major complication in over 50% of chronic kidney disease (CKD) patients. One of the main causes of anemia in CKD is the reduction of erythropoietin (EPO) synthesis from renal tubular cells. Therefore, first-line treatment of CKD is EPO administration; however, EPO unresponsiveness in several patients is frequently found. More undefined causes of anemia in CKD are under interest, especially uremic toxins, which are a group of solutes accumulated in CKD patients. The highly detectable protein-bound uremic toxin, indoxyl sulfate (IS) was investigated for its effects on in vitro erythropoiesis in this study. CD34+ hematopoietic stem cells were isolated from human umbilical cord blood and differentiated toward erythrocyte lineage for 14 days in various concentrations of IS (12.5, 25, 50, and 100 µg/mL). The effects of IS on cell proliferation, differentiation, apoptosis, and senescence were determined. Cell proliferation was investigated by manual cell counting. Cell surface marker expression was analyzed by flow cytometry. Wright's staining was performed to evaluate cell differentiation capacity. Apoptosis and senescence marker expression was measured using reverse transcription polymerase chain reaction (RT-PCR). TUNEL assay was performed to detect apoptotic DNA fragmentation. Our results demonstrated that IS reduced cell proliferation and impaired erythrocyte differentiation capacity. In addition, this study confirmed the effects of IS on cell apoptosis and senescence during erythropoietic differentiation. Therefore, the promotion of apoptosis and senescence might be one of the possible mechanisms caused by uremic toxin accumulation leading to anemia in CKD patients.

P-cresol and Indoxyl Sulfate Impair Osteogenic Differentiation by Triggering Mesenchymal Stem Cell Senescence.

Chronic kidney disease (CKD) patients obtained high levels of uremic toxins progressively develop several complications including bone fractures. Protein-bound uremic toxins especially p-cresol and indoxyl sulfate are hardly eliminated due to their high molecular weight. Thus, the abnormality of bone in CKD patient could be potentially resulted from the accumulation of uremic toxins. To determine whether protein-bound uremic toxins have an impact on osteogenesis, mesenchymal stem cells were treated with either p-cresol or indoxyl sulfate under in vitro osteogenic differentiation. The effects of uremic toxins on MSC-osteoblastic differentiation were investigated by evaluation of bone phenotype. The results demonstrated that p-cresol and indoxyl sulfate down-regulated the transcriptional level of collagen type I, deceased alkaline phosphatase activity, and impaired mineralization of MSC-osteoblastic cells. Furthermore, p-cresol and indoxyl sulfate gradually increased senescence-associated beta-galactosidase positive cells while upregulated the expression of p21 which participate in senescent process. Our findings clearly revealed that the presence of uremic toxins dose-dependently influenced a gradual deterioration of osteogenesis. The effects partially mediate through the activation of senescence-associated gene lead to the impairment of osteogenesis. Therefore, the management of cellular senescence triggered by uremic toxins could be considered as an alternative therapeutic approach to prevent bone abnormality in CKD patients.

Prevalence of and Predictive Factor for Abdominal Aortic Calcification in Thai Chronic Kidney Disease Patients.

Presence and severity of cardiovascular calcifications strongly predict cardiovascular morbidity and mortality in patients with CKD. This multicenter, cross-sectional study primarily aimed to determine prevalence of abdominal aortic calcification (AAC) detected by plain lateral abdominal radiograph, and secondarily aimed to assess predictive factors for AAC. Patients (N = 1500), aged 18-70 years, with CKD stages 3-5D for ≥3 months prior to evaluation, were enrolled at 24 study centers in Thailand; 54.3% were non-dialysis patients. The prevalence of AAC was 70.6% and 70.8% in non-dialysis and dialysis patients, respectively. Patient's advanced age and widening pulse pressure were identified as predictive factors for AAC ≥ 5 in non-dialysis patients, while patient's age, history of coronary heart disease or diabetes, longer dialysis vintage, and increasing corrected serum calcium or high-sensitivity C-reactive protein were identified as such in dialysis patients. With additional regression having covariates in binary, corrected serum calcium ≥9.5 mg/dL gave an OR 1.974 (95% CI: 1.324-2.943) for AAC ≥ 5 among the dialysis patients. AAC in diabetes subgroup (N = 692) was additionally evaluated and found that it was prevalent at 84.7% with increased phosphorus as predictive factor (OR, 1.178; 95% CI: 1.032-1.344) and 1,25 (OH)2 vitamin D as protective factor (OR, 0.983; 95% CI, 0.970-0.996). The prevalence of AAC in the Thai CKD population is lower than that reported in the literature, and yet the burden is prominent in patients coexisting with diabetes. Variable relationships identified in this study may guide preventive measures against cardiovascular complications in CKD patients.

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Relative contributions of inflammation and inadequate protein intake to hypoalbuminemia in patients on maintenance hemodialysis.

PURPOSE: Serum albumin is one of the strongest mortality predictors in maintenance hemodialysis (MHD) patients. Yet, the degree to which serum albumin represents dietary protein intake or an inflammatory state, among others, is not clear. We hypothesize that these inadequate protein intake and inflammation contribute somewhat equally to hypoalbuminemia. METHODS: In a cross-sectional analysis, we examined correlates of low serum albumin, <3.8 g/dL, in 812 MHD patients in whom interleukin-6 (IL-6) and normalized protein nitrogen appearance (nPNA), also known as normalized protein catabolic rate (nPCR), were also measured. Logistic regression estimated odds ratios were employed, and spline models were plotted to examine the likelihood of relatively low serum albumin <3.8 g/dL. RESULTS: Mean age (±SD) of patients was 54 ± 15 years; 53 % of patients were men, 50 % Hispanic, 31 % African-American, and 55 % diabetic. The mean dialysis vintage was 31 ± 34 months (median: 19, inter-quartile range: 7-44 months). The baseline serum albumin, averaged over a 3-month period (mean ± SD), was 3.88 ± 0.38 g/mL. The unadjusted correlation coefficients of l IL-6 and nPNA with serum albumin were -0.36 and +0.20, respectively (p < 0.001 for each comparison). The likelihood for an albumin <3.8 gr/dL increased linearly with decreasing nPNA and rising serum IL-6. This trend was steeper with increasing serum IL-6 up to a concentration of 30 ng/mL. CONCLUSIONS: Both low protein intakes and a high state of inflammation are associated with low serum albumin in MHD patients.

Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients.

BACKGROUND: Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis-stimulating agents (ESA) is often the cause of the refractory anemia. We hypothesized that the malnutrition-inflammation complex is an independent predictor of decreased responsiveness to ESAs in hemodialysis patients. METHODS: This cohort study of 754 hemodialysis patients was examined for an association between inflammatory and nutritional markers, including the malnutrition-inflammation score (MIS) and responsiveness to ESA. Cubic spline models were fitted to verify found associations. RESULTS: The mean (±SD) age of patients was 54 ± 15 years, 53% were diabetic and 32% blacks. MIS was worse in the highest quartile of ESAs responsiveness index (ERI, ESA dose divided by hemoglobin) when compared with 1st quartile (6.5 ± 4.5 versus 4.4 ± 3.4; P < 0.001). Both C-reactive protein (log CRP) (ß = 0.19) and interleukin-6 (log IL-6) (ß = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (ß = -0.30) and prealbumin levels (ß = -0.14) were inversely associated with ERI. Each 1 SD higher MIS, higher CRP and lower albumin were associated with 86, 44 and 97% higher likelihood of having highest versus three lowest ERI quartiles in fully adjusted models [odds ratio (and 95% confidence interval) of 1.86 (1.31-2.85), 1.44 (1.08-1.92) and 1.97 (1.41-2.78)], respectively. Cubic splines confirmed the continuous and incremental nature of these associations. CONCLUSIONS: Malnutrition-inflammation complex is an incremental predictor of poor responsiveness to ESAs in hemodialysis patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management.

Cardiorenal syndrome and vitamin D receptor activation in chronic kidney disease.

Cardiorenal syndrome (CRS) refers to a constellation of conditions whereby heart and kidney diseases are pathophysiologically connected. For clinical purposes, it would be more appropriate to emphasize the pathophysiological pathways to classify CRS into: (1) hemodynamic, (2) atherosclerotic, (3) uremic, (4) neurohumoral, (5) anemic-hematologic, (6) inflammatory-oxidative, (7) vitamin D receptor (VDR) and/or FGF23-, and (8) multifactorial CRS. In recent years, there have been a preponderance data indicating that vitamin D and VDR play an important role in the combination of renal and cardiac diseases. This review focuses on some important findings about VDR activation and its role in CRS, which exists frequently in chronic kidney disease patients and is a main cause of morbidity and mortality. Pathophysiological pathways related to suboptimal or defective VDR activation may play a role in causing or aggravating CRS. VDR activation using newer agents including vitamin D mimetics (such as paricalcitol and maxacalcitol) are promising agents, which may be related to their selectivity in activating VDR by means of attracting different post-D-complex cofactors. Some, but not all, studies have confirmed the survival advantages of D-mimetics as compared to non-selective VDR activators. Higher doses of D-mimetic per unit of parathyroid hormone (paricalcitol to parathyroid hormone ratio) is associated with greater survival, and the survival advantages of African American dialysis patients could be explained by higher doses of paricalcitol (>10 µg/week). More studies are needed to verify these data and to explore additional avenues for CRS management via modulating VDR pathway.

Charlson comorbidity score is a strong predictor of mortality in hemodialysis patients.

PURPOSE: The Charlson comorbidity index (CCI) is a commonly used scale for assessing morbidity, but its role in assessing mortality in hemodialysis patients is not clear. Age, a component of CCI, is a strong risk factor for morbidity and mortality in chronic diseases and correlates with comorbidities. We hypothesized that the Charlson comorbidity index without age is a strong predictor of mortality in hemodialysis patients. METHODS: A 6-year cohort of 893 hemodialysis patients was examined for an association between a modified CCI (without age and kidney disease) (mCCI) and mortality. RESULTS: Patients were 53±15 years old (mean±SD), had a median mCCI score of 2, and included 47% women, 31% African Americans and 55% diabetics. After adjusting for case-mix and nutritional and inflammatory markers including C-reactive protein and interleukin-6, 2nd (mCCI: 1-2), 3rd (mCCI=3), and 4th (mCCI: 4-9) quartiles compared to 1st (mCCI=0) quartiles showed death hazard ratios (95% confidence intervals) of 1.43 (0.92-2.23), 1.70 (1.06-2.72), and 2.33 (1.43-3.78), respectively. The mCCI-death association was robust in non-African Americans. The CCI-death association linearity was verified in cubic splines. Each 1 unit higher mCCI score was associated with a death hazard ratio of 1.16 (1.07-1.27). CONCLUSIONS: CCI independent of age is a robust and linear predictor of mortality in hemodialysis patients, in particular in non-African Americans.

Evaluation of atherosclerosis, arterial stiffness and related risk factors in chronic hemodialysis patients in Siriraj Hospital.

BACKGROUND: Additional to traditional risk factors for cardiovascular disease (CVD), recent evidence demonstrates that nontraditional risk factors such as high-sensitive C-reactive protein (hsCRP), hyperhomocysteinemia and vascular calcification may cause progressive atherosclerosis in hemodialysis patients. OBJECTIVE: We aim to determine the prevalence of atherosclerosis and assess the arterial stiffness and related risk factors. MATERIAL AND METHOD: Common carotid artery intima-media thicknesses (CIMT), atherosclerotic plaque occurrence were determined by B-mode ultrasonography in 105 hemodialysis patients (mean age, 53 +/- 15.5 years; mean dialysis duration 82 +/- 59.5 months). A history of clinically significant atherosclerotic vascular disease was elicited by patient questionnaire and verified by careful patient chart review and physical examination. Cardiovascular ankle index (CAVI) was use to assess arterial stiffness. Serum biochemical marker for traditional risk factors, hsCRP and homocysteine were measured by standard method. RESULTS: Atherosclerotic vascular disease (defined by a history of CVD or presence of atherosclerotic plaque) was present in 79% of patients. Compared to non-atherosclerotic group, the mean CIMT and serum hsCRP in atherosclerotic group was higher (1.9 +/- 0.8 mm vs. 0.8 +/- 0.6 mm, p < 0.001; 6.5 +/- 8.8 mg/L vs. 3.3 +/- 3.5 mg/L, p = 0.03, respectively), while other biochemical markers were not significantly different, as well as the percentage of abnormal CAVI (69% vs. 54.5%, p = 0.28). CAVI was positively correlated with maximum carotid intima-meida thickness (r = 0.44, p < 0.001). CAVI was also significantly greater in patients with carotid plaque (soft plaque (p < 0.05) and calcified plaque (p < 0.05)) compared with patients without carotid plaque. CONCLUSION: A high prevalence of atherosclerosis and arterial stiffness was observed in hemodialysis patients. Carotid atherosclerosis is associated with an increased inflammatory marker (hsCRP). CAVI may be a useful index to assess arterial stiffness and associated with arterial intima-media thickness.