Background: While chronic dialysis treatment has been suggested to increase pulmonary pressure values, right ventricular dysfunction (RVD) is a major cause of death in patients with end-stage renal disease. We investigated the impact of different dialysis treatments on right ventricular function. Methods: We examined 220 subjects grouped as follows: healthy controls (n = 100), peritoneal dialysis (PD; n = 26), hemodialysis (HD) with radial arteriovenous fistula (AVF; n = 62), and HD with brachial AVF (n = 32). Echocardiography including tissue Doppler imaging (TDI) of the right ventricle was performed in all patients. Results: Pulmonary pressure values progressively rose from controls across the 3 dialysis groups (21.7 ± 6.8, 29.7 ± 6.7, 37.9 ± 6.7 and 40.8 ± 6.6 mm Hg, respectively; p < 0.001). TDI indices of right ventricular function were more impaired in HD patients, particularly in those with brachial AVF. RVD, assessed by TDI myocardial performance index, was higher in HD patients compared with PD patients (71.3 vs. 34.6%, p < 0.001). Moreover, the prevalence of RVD further increased in patients with brachial AVF compared with the radial access (90.6 vs. 61.3%, p < 0.001). Conclusions: Compared to DP, HD increases the risk of RVD, particularly in the presence of brachial AVF. TDI may detect early functional failure of the right ventricle in HD patients.

AVF-induced RVD may contribute to LVD in dialysis patients. AVF plays a pivotal role in triggering LVD via right-to-left ventricular interdependence.

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities.

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Background. The value of incremental peritoneal dialysis (PD) as a bridge to renal transplantation (Tx) has not been specifically addressed. Methods. All consecutive Stage 5 CKD patients with at least 1 year predialysis followup, starting incremental PD or HD under our care and subsequently receiving their first renal Tx were included in this observational cohort study. Age, gender, BMI, underlying nephropathy, residual renal function (RRF) loss rate before dialysis and RRF at RRT start, comorbidity, RRT schedules and adequacy measures, dialysis-related morbidity, Tx waiting time, RRF at Tx, incidence of delayed graft function (DGF), in-hospital stay for Tx, serum creatinine at discharge and one year later were collected and compared between patients on incremental PD or HD before Tx. Results. Seventeen patients on incremental PD and 24 on HD received their first renal Tx during the study period. Age, underlying nephropathy, RRF loss rate in predialysis, RRF at the start of RRT and comorbidity did not differ significantly. While on dialysis, patients on PD had significantly lower epoetin requirements, serum phosphate, calciumxphosphate product and better RRF preservation. Delayed graft function (DGF) occurred in 12 patients (29%), 1 on incremental PD and 11 on HD. Serum creatinine at discharge and 1 year later was significantly higher in patients who had been on HD. Conclusions. In patients receiving their first renal Tx, previous incremental PD was associated with low morbidity, excellent preservation of RRF, easier attainment of adequacy targets and significantly better immediate and 1-year graft function than those observed in otherwise well-matched patients previously treated with HD.

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Histone acetylation/deacetylation play an essential role in modifying chromatin structure and in regulating cell plasticity in eukaryotic cells. Therefore, histone deacetylase (HDAC) pharmacological inhibitors are promising tools in the therapy of fibrotic diseases and in cancer. Peritoneal fibrosis is a pathological process characterized by many cellular and molecular alterations, including the acquisition of invasive/pro-fibrotic abilities by mesothelial cells (MCs) through induction of mesothelial to mesenchymal transition (MMT). The aim of this study was to characterize the molecular mechanism of the antifibrotic role of HDAC1 inhibition. Specifically, treatment with MS-275, an HDAC1-3 inhibitor previously known to promote MMT reversal, induced the expression of several TGFBRI mRNA-targeting miRNAs. Among them, miR-769-5p ectopic expression was sufficient to promote MMT reversal and to limit MC migration and invasion, whereas miR-769-5p silencing further enhanced mesenchymal gene expression. These results were confirmed by HDAC1 genetic silencing. Interestingly, miR-769-5p silencing maintained mesenchymal features despite HDAC1 inhibition, thus indicating that it is necessary to drive MMT reversal induced by HDAC1 inhibition. Besides TGFBRI, miR-769-5p was demonstrated to target SMAD2/3 and PAI-1 expression directly. When analyzing molecular mechanisms underlying miR-769-5p expression, we found that the transcription factor Wilms’ tumor 1 (WT1), a master gene controlling MC development, binds to the miR-769-5p promoter favoring its expression. Interestingly, both WT1 expression and binding to miR-769-5p promoter were increased by HDAC1 inhibition and attenuated by TGFβ1 treatment. Finally, we explored the significance of these observations in the cell-to-cell communication: we evaluated the ability of miR-769-5p to be loaded into extracellular vesicles (EVs) and to promote MMT reversal in recipient mesenchymal-like MCs. Treatment of fibrotic MCs with EVs isolated from miR-769-5p over-expressing MCs promoted the down-regulation of specific mesenchymal targets and the reacquisition of an epithelial-like morphology. In conclusion, we highlighted an HDAC1-WT1-miR-769-5p axis potentially relevant for therapies aimed at counteracting organ fibrosis.

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