Social functioning and socioeconomic changes after introduction of regular dialysis treatment and impact of dialysis modality: a multi-centre survey of Japanese patients.

AIM: Patient socialization and preservation of socioeconomic status are important patient-centred outcomes for those who start dialysis, and retention of employment is a key enabler. This study examined the influence of dialysis inception and modality upon these outcomes in a contemporary Japanese cohort. METHODS: We conducted a survey of prevalent chronic dialysis patients from 5 dialysis centres in Japan. All patients who had been on peritoneal dialysis (PD) since dialysis inception were recruited, and matched with a sample of those on in-centre haemodialysis (ICHD). We assessed patients' current social functioning (Short Form 36 Health Survey), and evaluated changes to patient employment status, annual income, and general health condition from the pre-dialysis period to the current time. RESULTS: A total of 179 patients were studied (102 PD and 77 ICHD). There were no differences in social functioning by modality. Among them, 113 were employed in the pre-dialysis period with no difference by modality. Of these, 22% became unemployed after dialysis inception, with a corresponding decline in average working hours and annual income. The odds of unemployment after dialysis inception were 5.02 fold higher in those on ICHD compared to those on PD, after adjustment for covariates. There were no changes for those who were already unemployed in the pre-dialysis period. CONCLUSIONS: Employment status is significantly hampered by dialysis inception, although PD was associated with superior retention of employment and greater income compared to ICHD. This supports a positive role for PD in preservation of socioeconomic status and potentially other patient-centred outcomes.

The combination of brentuximab vedotin and chidamide synergistically suppresses the proliferation of T-cell lymphoma cells through the enhancement of apoptosis.

PURPOSE: Peripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL. METHODS: A high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice. RESULTS: Chidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group. CONCLUSION: The use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other.

When should icodextrin be started to improve atherosclerosis in peritoneal dialysis patients?

Icodextrin-based peritoneal dialysis (PD) has many advantages over glucose-based PD. The present study aimed to investigate when icodextrin should be started for better management of cardiovascular status (as defined by echocardiography findings) and residual renal function (RRF). We retrospectively analyzed 40 patients treated with continuous ambulatory PD or automated PD. The patients were divided into these groups: Group A: started icodextrin within 2 weeks after PD onset. Group B: started icodextrin 1 year after PD onset. Group C: started icodextrin 2 years after PD onset. Group D: never used icodextrin during the study period. At the start of PD, we observed no significant difference in left ventricular mass index (LVMI) or urine volume (UV) between the groups. At 4 years, LVMI and UV were both significantly improved in group A compared with group D. The amelioration in LVMI was negatively associated with phosphate elimination. Our study showed that icodextrin preserved RRF and ameliorated left ventricular hypertrophy. Moreover, the timing of icodextrin introduction in PD patients influenced the clinical effects, including progression of cardiac hypertrophy and RRF.

Icodextrin eliminates phosphate and ameliorates cardiac hypertrophy and valvular calcification in patients with end-stage renal disease and diabetes mellitus undergoing peritoneal dialysis.

Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico)-based peritoneal dialysis (PD) has many advantages over glucose (Glu)-based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Ico-based PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD andDM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination might potentially be a means of controlling cardiovascular disease in PD patients with DM.

Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors.

STAT transcription factors are tyrosine phosphorylated upon cytokine stimulation and enter the nucleus to activate target genes. We show that Rac1 and a GTPase-activating protein, MgcRacGAP, bind directly to p-STAT5A and are required to promote its nuclear translocation. Using permeabilized cells, we find that nuclear translocation of purified p-STAT5A is dependent on the addition of GTP-bound Rac1, MgcRacGAP, importin alpha, and importin beta. p-STAT3 also enters the nucleus via this transport machinery, and mutant STATs lacking the MgcRacGAP binding site do not enter the nucleus even after phosphorylation. We conclude that GTP-bound Rac1 and MgcRacGAP function as a nuclear transport chaperone for activated STATs.

Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis.

BACKGROUND: Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations. METHODS: PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632. RESULTS: Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-ß, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-ß expression and VEGF secretion, which were blocked by Y-27632. CONCLUSIONS: The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

The expression of CD30 and its clinico-pathologic significance in peripheral T-cell lymphomas.

INTRODUCTION: Recent studies have shown that CD30 expression can be an important feature of peripheral and cutaneous T-cell lymphomas (PTCLs and CTCLs) and CD30 testing has increased in importance with the emergence of CD30-directed therapy. AREAS COVERED: This article reviews the literature on CD30-related biology, prevalence, and therapy in patients with PTCL or CTCL. We searched the PubMed database from 1 January 2010 to 28 April 2020, using terms 'CD30' ('peripheral T-cell lymphomas' or 'cutaneous T-cell lymphoma') and 'immunohistochemistry' or 'flow cytometry' or 'pathology,' and synonyms including terms for T-cell lymphoma subtypes. EXPERT OPINION: CD30 is expressed at relatively high rates of prevalence across a broad range of PTCLs and CTCLs. CD30 expression may be critical to the development of a subset of PTCLs and also a biomarker for treatment choice in some subtypes. Large-scale randomized, controlled studies have shown that CD30-directed treatment with brentuximab vedotin is significantly more effective against CD30-expressing PTCL and CTCL than current standard-of-care regimens. However, accurate CD30 evaluation is limited by inconsistencies in detection methodology and expression cutoffs defining CD30-expressing disease. Greater understanding of CD30 testing and reporting will enable more patients with CD30-expressing PTCL and CTCL to be identified and treated appropriately.

Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis.

Cell division is finely controlled by various molecules including small G proteins and kinases/phosphatases. Among these, Aurora B, RhoA, and the GAP MgcRacGAP have been implicated in cytokinesis, but their underlying mechanisms of action have remained unclear. Here, we show that MgcRacGAP colocalizes with Aurora B and RhoA, but not Rac1/Cdc42, at the midbody. We also report that Aurora B phosphorylates MgcRacGAP on serine residues and that this modification induces latent GAP activity toward RhoA in vitro. Expression of a kinase-defective mutant of Aurora B disrupts cytokinesis and inhibits phosphorylation of MgcRacGAP at Ser387, but not its localization to the midbody. Overexpression of a phosphorylation-deficient MgcRacGAP-S387A mutant, but not phosphorylation-mimic MgcRacGAP-S387D mutant, arrests cytokinesis at a late stage and induces polyploidy. Together, these findings indicate that during cytokinesis, MgcRacGAP, previously known as a GAP for Rac/Cdc42, is functionally converted to a RhoGAP through phosphorylation by Aurora B.

Application of peritoneal dialysis in elderly patients by classifying the age into young-old, old, and oldest-old.

BACKGROUND: A greater number of end-stage renal disease patients are receiving peritoneal dialysis (PD) or hemodialysis (HD) in Japan. However, medical concerns with advancing age have been raised in PD utilization for elderly patients. The objective of this study was to address the indications for PD in elderly patients in terms of medical concerns such as nutrition state, residual renal function, dialysis efficiency, peritonitis, cardiovascular disease (CVD) complications, and technique survival. METHODS: In a retrospective, two-center study, we evaluated 247 patients who newly started PD from 2002 to 2008. All patients were divided into four groups: young (<64 years, n = 99), young-old (65-74 years, n = 55), old (75-84 years, n = 62) and oldest-old (≥85 years, n = 31). Serum albumin, hemoglobin, ß(2)-microglobulin, cardio-thoracic ratio, 24-hour urine collection and spent dialysate volume was collected at the initiation of PD and after 1, 2, 3, and 4 years. PD withdrawal, occurrence of CVD complications, peritonitis and death were recorded. RESULTS: Nephrosclerosis as a primary disease increased with advancing age (p = 0.001). At baseline, gender, body weight, serum creatinine, hemoglobin and cardio-thoracic ratio were significantly different among the four groups. No significant decrease was shown in urine output with advancing age. The spent dialysate volume was significantly lower (mean 3.8 liters/day) in the oldest-old group compared with the other groups (p = 0.001). However, a smaller volume of PD fluid in the oldest-old group was not accompanied by a significantly higher serum ß(2)-microgloblin level compared with the other groups and there was no reason of PD withdrawal for underdialysis in the old and oldest-old groups. Neither the incidence of CVD complications nor that of peritonitis was increased with advancing age. There was no significant difference in technique survival rate excluding death between each group. These findings suggest that there are no medical concerns to avoid PD therapy in elderly end-stage renal disease patients.

A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line.

We previously identified a guanosine triphosphatase (GTPase)-activating protein (GAP) male germ cell Rac GAP (MgcRacGAP) that enhanced interleukin-6 (IL-6)-induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP was found to play crucial roles in cell division. However, how MgcRacGAP enhanced IL-6-induced differentiation remained elusive. Here we show that MgcRacGAP enhances IL-6-induced differentiation through enhancement of signal transducer and activator of transcription-3 (STAT3) activation. MgcRacGAP, Rac, and STAT3 formed a complex in IL-6-stimulated M1 cells, where MgcRacGAP interacted with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild-type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP-domain deletion mutant (DeltaGAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription. Intriguingly, M1 cells expressing DeltaGAP had no effect on the differentiation signal of IL-6, while forced expression of MgcRacGAP rendered M1 cells hyperresponsive to the IL-6-induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppressed STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. All together, our data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role.