The percentage of circulating fibrocytes is associated with increased morbidity of pulmonary hypertension in patients on hemodialysis.

INTRODUCTION: Pulmonary hypertension (PH) is highly prevalent in patients receiving dialysis. The precise mechanisms underlying PH in hemodialysis (HD) patients have not been adequately addressed. Emerging experimental evidence indicates that circulating fibrocytes may contribute significantly to this process. METHODS: We measured the proportion of circulating fibrocytes using flow cytometry analysis and prospectively analyzed patients during HD from February 1, 2017, to February 1, 2022. Then we investigated correlations between circulating fibrocytes, inflammation cytokines, PH, and their affective factors that predict the prognosis of HD patients. RESULTS: The cohort included 192 patients. During a follow-up of 5 years, we registered 66 all-cause deaths, and 11 patients received kidney transplantation. The incidence of PH among HD patients was 30.9%. We found that the circulating fibrocyte level significantly correlated with pulmonary arterial systolic pressure (r = 0.412, p < 0.05). In the multiple logistic regression analysis, the percentage of circulating fibrocytes was an independent predictor of PH (odds ratio [OR]: 2.080, 95% confidence interval [CI]: 1.539-2.812, p < 0.001). Controlling for confounding covariates in the multivariate Cox regression models, the presence of PH conferred an increased risk of all-cause mortality in HD patients [hazard ratio (HR): 2.183, 95% CI:1.257-3.788, p = 0.006]. CONCLUSION: The prevalence of PH was high in HD patients and was associated with higher all-cause mortality. Higher circulating fibrocyte level was an independent predictor of the presence of PH; these fibrocytes may serve as early detection markers and novel therapeutic targets.

Fragmented QRS complex on a 12-lead electrocardiogram predicts cardiovascular and all-cause mortality in dialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of mortality in end-stage renal disease (ESRD) patients. Fragmented QRS complex (fQRS) has been reported as a helpful marker in evaluating various cardiovascular pathologies. We aimed to investigate the value of the fQRS complex clinical decision of ESRD patients receiving dialysis. METHODS: This prospective observational study included 411 patients receiving hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) between 2016-01-01 and 2020-12-31. The primary outcomes were all-cause and cardiovascular (CV) mortality. RESULTS: HD patients have elevated values of fQRS complex compared to CAPD patients (39.1% vs. 28.2%, P = 0.027). Significantly, fQRS complex in the anterior/lateral leads is associated with all-cause and CV mortality stronger than fQRS in the inferior leads (P = 0.008). In a multivariate Cox regression analysis, HD patients with fQRS complex had a higher incidence of all-cause mortality (hazard ratio [HR] = 1.860; 95% confidence interval [CI]: [1.032, 3.349]; p = 0.041) and CV mortality (HR = 2.989; 95% CI [1.357, 6.584]; p = 0.007). For CAPD patients, fQRS complex was also associated with increased risk of all-cause mortality (HR = 1.593; 95% CI [1.023, 2.580]; p = 0.049) and increased risk of CV mortality (HR = 2.392; 95% CI [1.348, 4.173]; p = 0.013). CONCLUSIONS: The presence of the fQRS complex was an independent predictor of all-cause and CV mortality in HD and CAPD patients. We suggested a potential role of the fQRS complex in CV risk strata for dialysis patients and the choice of dialysis modality.

Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing.

Lipopolysaccharide (LPS)-stimulated macrophages express an aconitate decarboxylase (IRG1, also called ACOD1), leading to accumulation of the endogenous metabolite itaconate. However, the precise mechanisms by which elevated itaconate levels alter macrophage function are not clear. Our hypothesis is itaconate affects macrophage function through some uncertain mechanism. Based on this, we established a transcriptional and proteomic signature of macrophages stimulated by itaconate and identified the pathways of IL-1ß secretion and altered iron metabolism. Consistently, the effect of IRG1 deficiency on IL-1ß secretion and iron metabolism was confirmed in IRG1 knockout THP-1 cell lines. Several common inhibitors and other compounds were used to examine the molecular mechanisms involved. Only cysteine and antioxidants (catechin hydrate) could inhibit caspase-1 activation and IL-1ß secretion in itaconate-stimulated macrophages. We further found that aconitase activity was decreased by itaconate stimulation. Our results demonstrate the counteracting effects of overexpression of mitochondrial aconitase (ACO2, a tricarboxylic acid cycle enzyme) or cytosolic aconitase (ACO1, an iron regulatory protein) on IL-1ß secretion and altered iron metabolism. Both enzyme activities were inhibited by itaconate because of iron-sulfur (Fe-S) cluster destruction. Our findings indicate that the immunoregulatory functions of IRG1 and itaconate in macrophages are stressful Fe-S cluster of aconitases disrupting and iron metabolism rebalancing.