Nintedanib (BIBF1120) is a triple kinase inhibitor of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptor (VEGFR), and Src family kinase, which has recently been approved by FDA to treat idiopathic pulmonary fibrosis. Whether it affects renal fibrosis remains unknown. Here, we demonstrated that administration of nintedanib immediately or 3 days after unilateral ureteral obstruction (UUO) injury and with folic acid (FA) injection attenuated renal fibrosis and inhibited activation of renal interstitial fibroblasts. Delayed administration of nintedanib also partially reversed established renal fibrosis. Treatment with nintedanib blocked UUO-induced phosphorylation of PDGFRβ, FGFR1, FGFR2, VEGFR2, and several Src family kinases including Src, Lck, Lyn as well as activation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB (NF-κB), and Smad-3 in the kidney. Furthermore, nintedanib inhibited UUO-elicited renal proinflammatory cytokine expression and macrophage infiltration. These data indicate that nintedanib is a potent anti-fibrotic agent in the kidney and may hold therapeutic potential as a treatment of chronic fibrotic kidney disease.

Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment.

Triptolide is a major active component of Tripterygium wilfordii Hook F, which exerts marked immunosuppressive, anti-inflammatory and podocyte-protective effects. In this study, the ability of triptolide to inhibit inflammation and attenuate podocyte injury was examined in a rat model of diabetic nephropathy (DN). Type II diabetic rats with DN were treated with triptolide at a dose of 100 μg.kg−1.day−1. Following 8 weeks of triptolide treatment, the urine albumin level, kidney weight/body weight and the number of cells positive for ED-1 (a marker for rat mononuclear macrophages) in the kidney were assessed. The effects of triptolide on podocyte injury and chronic inflammation were analyzed using quantitative polymerase chain reaction (qPCR), western blotting and immunohistochemistry. Following triptolide treatment, the albuminuria in the type II diabetic rats was significantly reduced. Furthermore, the glomerular hypertrophy and foot process effacement were improved, and there was a recovery of the slit diaphragm associated with nephrin and podocin expression. The inflammation in the kidneys was also attenuated. Furthermore, triptolide significantly reduced the expression of transforming growth factor-β1 and osteopontin, and the infiltration of ED-1-positive cells into the kidney. The results demonstrated that triptolide markedly attenuated albuminuria and podocyte injury in the rat model of DN, which may have been correlated with the inhibition of inflammation and macrophage infiltration in the kidneys.

ObjectivesTo investigate the risk factors associated with early-onset peritonitis (EOP) and their influence on patients’ technique survival and mortality.Study designRetrospective, cohort study.SettingThree peritoneal dialysis (PD) units in Shanghai.ParticipantsPD patients from 1 June 2006 to 1 May 2018 were recruited and followed up until 31 December 2018. According to time-to-first episode of peritonitis, patients were divided into non-peritonitis (n=144), EOP (≤6 months, n=74) and late-onset peritonitis (LOP) (>6 months, n=139).Primary and secondary outcome measuresEOP was defined as the first episode of peritonitis occurring within 6 months after the initiation of PD. The outcomes were all-cause mortality and technique failure.ResultsOf the 357 patients, 74 (20.7%) patients developed their first episode of peritonitis within the first 6 months. Compared with the LOP group, the EOP group had older ages, more female patients, higher Charlson Comorbidity Index (CCI) score, lower serum albumin levels and renal function at the time of initiation of PD, and higher diabetes mellitus and peritonitis rates (p<0.05).Staphylococcuswas the most common Gram-positive organism in both EOP and LOP groups. The multivariate logistic regression analysis showed that factors associated with EOP included a higher CCI score (OR 1.285, p=0.011), lower serum albumin level (OR 0.924, p=0.016) and lower Kt/V (OR 0.600, p=0.018) at start of PD. In the Cox proportional-hazards model, EOP was more likely a predictor of technique failure (HR 1.801, p=0.051). There was no difference between EOP and LOP for all-cause mortality.ConclusionA higher CCI score and lower serum albumin level and Kt/V at PD initiation were significantly associated with EOP. EOP also predicted a high peritonitis rate and poor clinical outcome.