Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.

Relationships of social support and attitudes towards death: A mediator role of depression in older patients on haemodialysis.

AIM: To explore the mediating role of depression in older people receiving haemodialysis on social support and the attitude of participants towards death. DESIGN: A cross-sectional questionnaire survey. METHODS: Data were collected from older people undergoing dialysis (N = 209) at two regional hospitals in the north of Taiwan. Confirmatory factor analysis with structural equation model was used to clarify the strength of relationships and intermediary effects of three scales in which with 5,000 bootstrap samples using LISREL 9.31. RESULTS: The final model provided a good fit for the data. Social support and depression have statistically significant effects on dialysis older person' negative death attitudes. The direct effect of social support on depression was the strongest (p<.001). Overall, depression completely mediates social support and positive death attitudes. Depression partially mediates social support and negative death attitude.

Correlation between breath ammonia and blood urea nitrogen levels in chronic kidney disease and dialysis patients.

Previous studies have shown that breath ammonia (breath-NH3) concentration is associated with blood urea nitrogen (BUN) levels. However, interindividual variations in breath-NH3 concentrations were observed. Thus, the present study aimed to assess the effect of oral cavity conditions on breath-NH3 concentration and to validate whether the measurement of breath-NH3 concentration is feasible in clinical settings. A total of 125 individuals, including patients with stage 3 to 5 chronic kidney disease (CKD3-5), those on dialysis, and healthy participants, were recruited. A nanostructured sensor was used to detect breath-NH3 concentrations. Pre- and post-gargling as well as pre- and post-hemodialysis (HD) breath-NH3, salivary pH, and salivary urea levels were measured. Breath-NH3, salivary urea, salivary pH, and BUN levels were positively correlated to each other. Breath-NH3 concentrations were associated with BUN levels (r = 0.43, p < 0.001) and were significantly higher in CKD3-5 (p < 0.005) and dialysis patients (p < 0.001) than in healthy participants. Higher correlation coefficients were noted between breath-NH3 concentrations and BUN levels during follow-up (r = 0.59-0.94, p < 0.05). When the cutoff value of breath-NH3 was set at 523.65 ppb, its sensitivity and specificity in predicting CKD (BUN level >24 mg dl-1) were 87.6% and 80.9%, respectively. Breath-NH3 concentrations decreased after HD (p < 0.001) and immediately after gargling (p < 0.01). Breath-NH3 concentration, which was affected by gargling, was correlated to BUN level. The measurement of breath-NH3 concentration using the nanostructured device may be used as a tool for CKD detection and personalized point-of-care for CKD and dialysis patients. The current study had a small sample size. Thus, further studies with a larger cohort must be conducted to validate the effect of oral factors on breath-NH3 concentration and to validate the benefit of breath-NH3 measurement.

Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability.

Cadmium is a known environmental carcinogen. Exposure of Cd leads to the activation of several proto-oncogenes in cells. We investigated here the mechanism of c-Myc expression in hepatic cells under Cd treatment. The c-Myc protein and mRNA levels increased in dose- and time-dependent manners in HepG2 cells with Cd treatment. This increase was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated by Cd. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. We conclude that Cd-induced accumulation of c-Myc requires the activation of several signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins.

Determination of urine cofilin-1 level in acute kidney injury using a high-throughput localized surface plasmon-coupled fluorescence biosensor.

The actin-depolymerizing factor (ADF)/cofilin protein family has been reported to be associated with ischemia-induced renal disorders. We examine whether cofilin-1 is associated with acute kidney injury (AKI) using human urine samples. We exploited a 96-well based high-throughput biosensor that uses gold nanoparticles and a sandwich immunoassay to detect the urine cofilin-1 level of AKI patients. The mean urine cofilin-1 level of the AKI patients (n=37 from 47 cases analyzed) was twofold higher than that of healthy adults (n=21 from 29 cases analyzed). The receiver operating characteristic (ROC) curve showed that cofilin-1 was acceptable for discriminating AKI patients from healthy adults. However, an increase of the sample size is required to conclude the importance of urine cofilin-1 on AKI diagnosis, and the high-throughput ultrasensitive biosensor used in this study would greatly accelerate the measurement of urine cofilin-1 in an increased sample size.

Association of Asef and Cdc42 expression to tubular injury in diseased human kidney.

BACKGROUND: Cdc42 is a small guanosine-5'-triphosphatase of the Rho family and plays essential roles in the establishment of cellular polarity and tight junctions in epithelial cells. Adenomatous polyposis coli-associated exchange factor (Asef) is a canonical guanine nucleotide exchange factor of Cdc42 and renders Cdc42 to be guanosine-5'-triphosphate bound and activated. The expression patterns and their significance in human renal diseases are unknown. METHODS: We examined the expression of Cdc42 and Asef in kidney biopsy specimens of 15 patients and in normal kidney tissue using immunofluorescence and correlated the expression patterns with the clinical characteristics. We also analyzed the coexpression pattern of Ki-67, a marker indicating cell division, and Asef in selected patients. RESULTS: Expression of Asef and Cdc42 together was associated with tubular injury with 100% specificity. Expression of Asef, regardless of Cdc42, also showed a significant diagnostic odds ratio for the presence of the injury. Expression of Asef was associated with lower estimated glomerular filtration rate at the time of biopsy and larger area of interstitial fibrosis. All Ki-67-expressing tubular cells expressed Asef. CONCLUSIONS: Induction of Asef and Cdc42 in the renal tubules is a cellular response to injury. Asef induction seems a necessary step for injured tubular cells to enter cell cycle.

Radial artery approach for endovascular salvage of occluded autogenous radial-cephalic fistulae.

BACKGROUND: The endovascular salvage of occluded autogenous radial-cephalic fistulae is a more challenging procedure than that for stenotic fistulae. To obtain an access to the fistula is one of the keys to success. Both retrograde venous approach and brachial artery approach have some disadvantages. The radial artery approach has been used in the endovascular therapy of fistula dysfunction, but few data focused on their feasibility and safety for the totally occluded fistulae. METHODS: We retrospectively reviewed the patients with occluded autogenous radial-cephalic fistulae receiving endovascular salvage via the radial artery approach in our institution. From January 2004 to July 2007, 48 patients fulfilling the above criteria were enrolled. Balloon maceration was used for patients with small clots. Mechanical thrombectomy with an Arrow-Trerotola percutaneous thrombolytic device or an AngioJet rheolytic catheter was used for patients with large clot burden. Outcome variables included anatomic and clinical success, complications and primary and secondary patency. RESULTS: All the transradial punctures were successful. Anatomic and clinical success was achieved in 96% of the cases. The post-interventional primary patency rates were 92%, 77%, 55% and 44% at 1, 3, 6 and 12 months, respectively. The post-interventional secondary patency rates were 96%, 93%, 89% and 89% at 1, 3, 6 and 12 months, respectively. The 12-month primary patency of the short-segment thrombus group was better than that of the long-segment thrombus group (57% versus 19%, P = 0.005). The complication rate was 4%. No puncture-site-related complications were noted, and all the radial arteries were palpable at follow-up. CONCLUSIONS: An endovascular intervention through the radial artery approach is a safe and feasible strategy choice for restoring occluded autogenous radial-cephalic fistulae.

Concurrent hepatic and ruptured renal angiomyolipoma in tuberous sclerosis complex.

Angiomyolipoma of the liver or kidney is one of the clinical manifestations of tuberous sclerosis complex. However, concurrence of angiomyolipoma in both liver and kidney associated with tuberous sclerosis complex is a rare entity. Renal angiomyolipomas with large aneurysms confer a higher probability of rupture as compared to small aneurysms. Herein, we document a case of tuberous sclerosis coexisting with hepatic and renal angiomyolipoma in a 37 year-old woman who presented with an acute abdomen due to ruptured tumor. Computed tomography of the abdomen revealed multiple tumors over the bilateral kidneys and liver. A right nephrectomy was performed. During surgery, a liver biopsy was performed from which a preliminary diagnosis of necrosis was established. However, immunoreactivity staining using monoclonal antibody HMB-45 (Human Melanoma, Black) led to the final diagnosis of angiomyolipoma. We emphasized that pathologists and clinicians should be aware that cases of tuberous sclerosis complex may be associated with renal and hepatic angiomyolipoma. To avoid an inappropriate diagnosis, before diagnosing liver necrosis, immunohistochemical staining for HMB-45 is recommended.