Dual therapy with an angiotensin receptor blocker and a JAK1/2 inhibitor attenuates dialysate-induced angiogenesis and preserves peritoneal membrane structure and function in an experimental CKD rat model.

BACKGROUND: Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D. METHODS: Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks (N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose). RESULTS: 4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy (p < 0.05) but with inconsistent responses by monotherapies. CONCLUSION: Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.

Characteristics of a New X-Ray Imaging System for Interventional Procedures: Improved Image Quality and Reduced Radiation Dose.

PURPOSE: To compare image quality and radiation exposure between a new angiographic imaging system and the preceding generation system during uterine artery embolization (UAE). MATERIALS AND METHODS: In this retrospective, IRB-approved two-arm study, 54 patients with symptomatic uterine fibroids were treated with UAE on two different angiographic imaging systems. The new system includes optimized acquisition parameters and real-time image processing algorithms. Air kerma (AK), dose area product (DAP) and acquisition time for digital fluoroscopy (DF) and digital subtraction angiography (DSA) were recorded. Body mass index was noted as well. DF image quality was assessed objectively by image noise measurements. DSA image quality was rated by two blinded, independent readers on a four-rank scale. Statistical differences were assessed with unpaired t tests and Wilcoxon rank-sum tests. RESULTS: There was no significant difference between the patients treated on the new (n = 36) and the old system (n = 18) regarding age (p = 0.10), BMI (p = 0.18), DF time (p = 0.35) and DSA time (p = 0.17). The new system significantly reduced the cumulative AK and DAP by 64 and 72%, respectively (median 0.58 Gy and 145.9 Gy*cm2 vs. 1.62 Gy and 526.8 Gy*cm2, p < 0.01 for both). Specifically, DAP for DF and DSA decreased by 59% (75.3 vs. 181.9 Gy*cm2, p < 0.01) and 78% (67.6 vs. 312.2 Gy*cm2, p < 0.01), respectively. The new system achieved a significant decrease in DF image noise (p < 0.01) and a significantly better DSA image quality (p < 0.01). CONCLUSIONS: The new angiographic imaging system significantly improved image quality and reduced radiation exposure during UAE procedures.

Radiologic-pathologic analysis of quantitative 3D tumour enhancement on contrast-enhanced MR imaging: a study of ROI placement.

OBJECTIVES: To investigate the influence of region-of-interest (ROI) placement on 3D tumour enhancement [Quantitative European Association for the Study of the Liver (qEASL)] in hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). METHODS: Phase 1: 40 HCC patients had nine ROIs placed by one reader using systematic techniques (3 ipsilateral to the lesion, 3 contralateral to the lesion, and 3 dispersed throughout the liver) and qEASL variance was measured. Intra-class correlations were computed. Phase 2: 15 HCC patients with histosegmentation were selected. Six ROIs were systematically placed by AC (3 ROIs ipsilateral and 3 ROIs contralateral to the lesion). Three ROIs were placed by 2 radiologists. qEASL values were compared to histopathology by Pearson's correlation, linear regression, and median difference. RESULTS: Phase 1: The dispersed method (abandoned in phase 2) had low consistency and high variance. Phase 2: qEASL correlated strongly with pathology in systematic methods [Pearson's correlation coefficient = 0.886 (ipsilateral) and 0.727 (contralateral)] and in clinical methods (0.625 and 0.879). However, ipsilateral placement matched best with pathology (median difference: 5.4 %; correlation: 0.89; regression CI: [0.904, 0.1409]). CONCLUSIONS: qEASL is a robust method with comparable values among tested placements. Ipsilateral placement showed high consistency and better pathological correlation. KEY POINTS: Ipsilateral and contralateral ROI placement produces high consistency and low variance. Both ROI placement methods produce qEASL values that correlate well with histopathology. Ipsilateral ROI placement produces best correlation to pathology along with high consistency.

Ligand and coactivator recruitment preferences of peroxisome proliferator activated receptor alpha.

The mechanism by which ligands of nuclear receptors show differential effects on gene transcription is not fully understood, but is believed to result in part from the preferential recruitment and/or displacement of coactivators and corepressors. We have explored the interaction of several known ligands and the nuclear receptor (peroxisome proliferator activated receptor alpha, PPARalpha) using scintillation proximity assay (SPA) and the interaction of LXXLL containing peptides derived from three coactivators (SRC-1, CBP and PGC-1) with PPARalpha in the presence of PPARalpha agonist ligands using fluorescence resonance energy transfer (FRET). The EC(50)s of the individual ligands for recruitment showed the same rank order regardless of the coactivator peptide used, with GW2331