Cpd-0225 attenuates renal fibrosis via inhibiting ALK5.

Chronic kidney disease (CKD) is an increasing public health concern, characterized by a reduced glomerular filtration rate and increased urinary albumin excretion. Renal fibrosis is an important pathological condition in patients with CKD. In this study, we evaluated the anti-fibrotic effect of Cpd-0225, a novel transforming growth factor-ß (TGF-ß) type I receptor (also known as ALK5) inhibitor, in vitro and in vivo, by comparing its effect with that of SB431542, a classic ALK5 inhibitor, which has not entered the clinical trial stage owing to multiple side effects. Our data showed that Cpd-0225 attenuated fibrotic response in TGF-ß1-stimulated human kidney tubular epithelial cells and repeated hypoxia/reoxygenation-treated mouse tubular epithelial cells. We further confirmed that Cpd-0225 improved renal tubular injury and ameliorated collagen deposition in unilateral ureteral obstruction-, ischemia/reperfusion-, and aristolochic acid-induced mouse models of renal fibrosis. In addition, molecular docking and site-directed mutagenesis showed that Cpd-0225 exerted a higher reno-protective effect than SB431542, by physically binding to the key amino acid residues, Lys232 and Lys335 of ALK5, thereby suppressing the phosphorylation of Smad3 and ERK1/2. Taken together, these findings suggest that Cpd-0225 administration attenuates renal fibrosis via ALK5-dependent mechanisms and displays a more effective therapeutic effect than SB431542. Thus, Cpd-0225 may serve as a potential therapeutic agent for the treatment of CKD.

Vena cava 3D contrast-enhanced MR venography: a pictorial review.

Three-dimensional contrast-enhanced magnetic resonance venography (CE MRV) is a sensitive and accurate method for diagnosing vena cava pathologies. The commonly used indirect approach involves a nondiluted gadolinium contrast agent injected into an upper limb vein or, occasionally, a pedal vein for assessment of the superior or inferior vena cava. In our studies, a coronal 3D fast multi-planar spoiled gradient-echo acquisition was used. A pre-contrast scan was obtained to ensure correct coverage of the region of interest. We initiated contrast-enhanced acquisition 15 sec after the start of contrast agent injection and performed the procedure twice. The image sets were obtained during two 20-30-sec breath hold, with a breathing rest of 5-6 sec, to obtain the first-pass and delayed arteriovenous phases. For patients with Budd-Chiari syndrome, a third acquisition coinciding with late venous phase was collected to visualize the hepatic veins, which was carried out by one additional acquisition after a 5-6-sec breathing time. This review describes the clinical application of 3D CE MRV in vena cava congenital anomalies, superior and inferior vena cava syndrome, Budd-Chiari syndrome, peripheral vein thrombosis extending to the vena cava, pre-operational evaluation in portosystemic shunting and post-surgical follow-up, and road-mapping for the placement and evaluation of complications of central venous devices.

Budd-Chiari syndrome: diagnosis with three-dimensional contrast-enhanced magnetic resonance angiography.

AIM: To evaluate the role of three-dimensional contrast-enhanced magnetic resonance angiography (3D CE MRA) in the diagnosis of Budd-Chiari syndrome (BCS). METHODS: Twenty-three patients with BCS underwent 3D CE MRA examination, in which 13 cases were secondary to either hepatocellular carcinoma (11 cases), right adrenal carcinoma (1 case) or thrombophlebitis (1 case) and 10 suffered from primary BCS. The patency of the inferior vena cava (IVC), hepatic and portal veins as well as the presence of intra- and extrahepatic collaterals, liver parenchymal abnormalities and porto-systemic varices were evaluated. Inferior vena cavography was performed in 10 cases. The diagnosis of IVC obstruction by 3D CE MRA was compared with that demonstrated by inferior vena cavography. RESULTS: The major features of BCS could be clearly displayed on 3D CE MRA. Positive hepatic venous signs included tumor thrombosis (9 cases), tumor compression (2 cases), nonvisualization (4 cases) and focal stenosis (2 cases). Positive IVC findings were noted as severe stenosis or occlusion (10 cases), tumor invasion (2 cases), thrombosis (3 cases), thrombophlebitis (1 case) and septum formation (3 cases). Intrahepatic collaterals were shown in 9 patients, 2 of them with "spider web" sign. The displayed extrahepatic collaterals included dilated azygos and hemi-azygos veins (13 cases) and left renal-inferior phrenic-pericardiophrenic veins (2 cases). The occlusion of the left intrahepatic portal veins was found in 2 cases. Porto-systemic varices were detected in 10 patients. Liver parenchymal abnormalities displayed by 3D CE MRA were enlargement of the caudate lobe (7 cases), heterogenous enhancement (18 cases) and complicated tumors (13 cases). Compared with the inferior vena cavography performed in 10 cases, the accuracy of 3D CE MRA was 100 % in the diagnosis of IVC obstruction. CONCLUSION: 3D CE MRA can display the major features of BCS and provide an accurate diagnosis.

3D contrast-enhanced MR portography and direct X-ray portography: a correlation study.

Our objective was to compare 3D contrast-enhanced MR portography (3D CE MRP) on a 1.5-T MR imager with direct X-ray portography. Twenty-six consecutive patients underwent 3D CE MRP with in-plane resolution of 1.4 or 1.8 mm, and direct X-ray portography. The findings of these two methods were evaluated and compared. The main portal vein (PV), right PV with its anterior and posterior segmental branches, and left PV including its sagittal segment were shown clearly without diagnostic problem in all cases on MRP. The main PV appearance was accordant with MRP and X-ray. For intrahepatic PVs, the results agreed in 21 patients but disagreed in 5 patients. In 1 patient with a huge tumor in right liver, the right posterior PV was classified as occluded at MRP, but diffusely narrowed at X-ray. The findings of left intrahepatic PV were discordant in 3 patients with hepatocelluar carcinoma in the left lobe. The MRP demonstrated complete occlusion of the left PVs, whereas X-ray showed proximal narrowing and distal occlusion. In another patient with hepatocelluar carcinoma, a small non-occlusive thrombus involving the sagittal segment of the left PV was seen on MRP but not on X-ray. With demonstration of varices and portosystemic shunts, MRP showed results similar to those of X-ray, except one recanalized para-umbilical vein was excluded from the field of view at MRP due to the patient's limited ability of breathholding. The 3D CE MRP correlated well with direct X-ray portography in most cases, it was limited in distinguishing narrowing of an intrahepatic PV from occlusion, but it showed advantage in demonstrating small thrombus within PV.

Three-dimensional contrast-enhanced MR angiography in diagnosis of portal vein involvement by hepatic tumors.

AIM: To assess the accuracy of three-dimensional contrast-enhanced magnetic resonance angiography (3D CE MRA) in evaluation of the portal vein involvement in patients with hepatic tumors. METHODS: 3D CE MRA was performed in 62 patients with hepatic tumors to assess the patency of the main, right and left portal veins before hepatic surgery. A total of 186 veins were examined for encasement, occlusion and tumor thrombosis. The results of 3D CE MRA diagnosis were then correlated with the surgical-pathological and intra-operative sonographic findings. RESULTS: 3D CE MRA correctly detected 48 of 49 involved and 135 of 137 noninvolved portal veins with the sensitivity of 98 %, specificity of 99 %, positive predictive value of 96 % and negative predictive value of 99 %. CONCLUSION: 3D CE MRA is accurate in evaluation of the portal vein involvement in patients with hepatic tumors.

Characterization of focal hepatic lesions with SPIO-enhanced MRI.

AIM: To evaluate the value of superparamagnetic iron oxide (SPIO) enhanced MRI in characterizing focal hepatic lesions. METHODS: Forty-three patients (32 men,11 women, mean age 51 years, age range 25-74 years) with previously identified focal hepatic lesions were enrolled into this study. All the patients underwent plain, Gd-DTPA enhanced MRI and the SPIO enhanced MRI 1-7 d later. The surgico-pathologic diagnosis was aestablished in 31 cases and the diagnosis in other 12 cases was made on the basis of clinical findings and biochemical tests. The signal changes of lesions were analyzed and the CNRs of lesion-to-liver were measured before and after SPIO enhancement. The data were analyzed by paired t test. RESULTS: Focal hepatic lesions included primary hepatocellular carcinoma (HCC,n=22), hemangioma (n=5), cyst (n=4), metastases (n=5), cirrhotic nodule (n=4), focal nodular hyperplasia (FNH, n=5) and other miscellaneous lesions (n=6). After SPIO enhancement HCC demonstrated iso- or slight hyperintensity on T1WI and moderate hyperintersity on T2WI, hemangioma showed moderate hyperintensity on T1WI and obvious hyperintensity on T2WI, the SI of cyst had no change either on T1WI or on T2WI, cirrhotic nodules revealed iso-intensity on T2WI, and the SI of FNH decreased significantly on T2WI. No specific manifestations were found in the other 6 miscellaneous lesions after SPIO enhancement. CONCLUSION: SPIO enhanced-MRI can improve the characterization confidence for diagnosis of focal hepatic lesions.