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Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.

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Background Transfused patients with low- to intermediate-risk myelodysplastic syndromes (MDS) are known to suffer from iron overload. Iron chelation therapy (ICT) may improve outcomes, however, it remains to be thoroughly investigated. Methods We conducted a systematic review and meta-analysis to assess the benefit of ICT in patients with MDS. MEDLINE, EMBASE, and Cochrane CENTRAL were searched for studies on ICT for low- to intermediate-risk MDS that reported adjusted hazard ratios (aHR) or overall survival (OS). Two reviewers independently screened titles and abstracts and subsequent full texts for eligibility. Studies were extracted for general demographics, AML progression rate, incidence of cardiac injury, and median OS or aHR. aHR risk ratios were calculated using a random-effects model meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and Newcastle-Ottawa scale for non-randomized studies. Results The initial search yielded 1177 citations, of which we included 11 observational studies (n = total patient number) and one RCT (n = total patient number) for analysis. The heterogeneity was moderate (I 2=57%; P=0.02). There was a significant reduction in risk of mortality in patients with iron overload and low- or intermediate-risk MDS treated with ICT (aHR 0.43; 95% CI 0.32-0.57; P < 0.00001) (figure 1). The median OS among patients receiving ICT and patients receiving no ICT was reported for nine studies. The median OS for patients receiving ICT was consistently longer than the median OS in the non-ICT group across all studies (figure 2). Conclusion Iron chelation therapy (ICT) is associated with a lower risk of mortality in low- to intermediate- risk myelodysplastic syndrome patients. Given the limited number of RCTs, more high-quality studies are required before ICT becomes a standard of care for this group of patients Figure 1 Figure 1. Disclosures Crowther: Syneos Health: Honoraria; Precision Biologicals: Honoraria; Pfizer: Speakers Bureau; CSL Behring: Speakers Bureau; Bayer: Speakers Bureau; Hemostasis reference laboratories: Honoraria.