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The therapeutic effects of low intensity pulsed ultrasound (LIPUS) on renal ischemia/reperfusion injury (IRI) with acute kidney injury (AKI) are still unclear. A renal tubule cell model under H 2 O 2 or hypoxia/reoxygenation (H/R) conditions with or without LIPUS pre-treatment (1 MHz, 30 and 100 mW/cm 2 , 15 min) was used to test the in vitro effects of LIPUS. An AKI mouse model of unilateral IRI with nephrectomy of the contralateral kidney for 48 h with or without LIPUS treatment (3 MHz, 100 mW/cm 2 , 20 min/day) 5 day before IRI were used to investigate the in vivo effects of LIPUS. LIPUS significantly protected the renal tubule cell viability and prevented inflammatory signals against H 2 O 2 challenge. LIPUS could inhibit the apoptosis-related molecular signals and increase the protein levels of endogenous antioxidant enzymes, α-Klotho, and Sirt1 in renal tubule cells after H/R challenge. LIPUS alleviated the increases in the serum levels of blood urea nitrogen, creatinine, and cystatin C, renal pathological changes and apoptosis-related molecular signals, and impaired antioxidant enzymes in AKI mice. The IRI-induced inflammatory responses in the kidneys and spleens could be reversed by LIPUS. These findings suggest that LIPUS treatment displays the benefits for renal protection in IRI-induced AKI mice.

Although chronic kidney disease (CKD) is associated with functional decline, whether proteinuria alone is associated with functional statuses over the course of acute illnesses independent of CKD is unclear. During 2014, we prospectively enrolled non-dialysis patients aged ≥65 years, and all participants underwent spot dipstick urinalysis on admission, divided into 3 groups according to the results (none, trace to 1 + , and 2 + or higher); functional status was evaluated using the pre-morbid and in-hospital Barthel index (BI) scores. Of 136 community-dwelling elderly patients enrolled (age 80.7 ± 8.2 years, with 19% having CKD), 17%, 57%, and 26% had no, trace to 1 + , or 2 + or higher proteinuria. Overall pre-morbid, on-admission, and on-discharge BI scores were 50.4 ± 41.9, 38.6 ± 31.8, and 38.7 ± 35.3, respectively with significant negative correlations with proteinuric severity on admission. Finally, multivariate linear stepwise regression analysis with backward variable selection found that dipstick proteinuric severity was significantly associated with pre-morbid, on-admission, and on-dischrage BI scores (p = 0.048, <0.01, and <0.01, respectively), independent of diabetes and CKD. This relationship between dipstick proteinuric levels and functional status of hospitalized elderly suggests an under-recognized association. Prospective evaluation of long-term outcome is needed., Competing Interests: The authors declare no competing financial interests.

Urinary sediment is used to evaluate patients with possible urinary tract diseases. Currently, numerous protocols are applied to detect dysmorphic red blood cells (RBCs) and renal tubular epithelial cells (RTECs) in urinary sediment. However, distinct protocols are used by nephrologists and medical technologists for specimen concentration and observation, which leads to major discrepancies in the differential counts of formed elements such as dysmorphic RBCs and RTECs and might interfere with an accurate clinical diagnosis. To resolve these problems, we first tested a modified urinalysis protocol with an increased relative centrifuge force and concentration factor in 20 biopsy-confirmed glomerulonephritis patients with haematuria. We successfully improved the recovery ratio of dysmorphic RBCs in clinical specimens from 34.7% to 42.0% (P < 0.001). Furthermore, we confirmed the correlation between counts by the modified urinary protocol and Sysmex UF-1000i urinary flow cytometer (r ≥ 0.898, P < 0.001). A total of 28 types of isomorphic and dysmorphic RBCs were detected using a bright field microscope, with results comparable to those using a standard phase contrast microscope. Finally, we applied Sternheimer stain to enhance the contrast of RTECs in the urinary sediments. We concluded that this modified urinalysis protocol significantly enhanced the quality of urinalysis.

Diagnostic discrepancy, defined as different admission and discharge diagnoses, could be a potential source of diagnostic error. We evaluated whether acute kidney injury (AKI) in the elderly affected their risk for diagnostic discrepancy. Patients aged ≥60 years from the general medical wards were prospectively enrolled and divided according to AKI status upon admission, using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. We compared their discharge and admission diagnoses and identified patients with a diagnostic discrepancy, using multiple logistic regression analysis to evaluate the relationship between initial AKI and the presence of a diagnostic discrepancy. A total of 188 participants (mean age, 77.9 years) were recruited. Regression analysis showed that initial AKI on admission was associated with a higher risk of diagnostic discrepancy upon discharge (odds ratio [OR] 3.3; p < 0.01). In contrast, higher AKI severity was also associated with an increased risk of diagnostic discrepancy (for KDIGO grade 1, 2, and 3; OR 2.92, 3.91, and 4.32; p = 0.04, 0.03, and 0.02, respectively), suggesting that initial AKI upon admission could be an important risk factor for diagnostic discrepancy. Consequently, reducing geriatric AKI might have the potential to reduce diagnostic discrepancy among these patients.

Advanced glycation end-products (AGEs)-induced mesangial cell death is one of major causes of glomerulus dysfunction in diabetic nephropathy. Both endoplasmic reticulum (ER) stress and autophagy are adaptive responses in cells under environmental stress and participate in the renal diseases. The role of ER stress and autophagy in AGEs-induced mesangial cell death is still unclear. Here, we investigated the effect and mechanism of AGEs on glomerular mesangial cells. AGEs dose-dependently decreased mesangial cell viability and induced cell apoptosis. AGEs also induced ER stress signals in a time- and dose-dependent manner. Inhibition of ER stress with 4-phenylbutyric acid effectively inhibited the activation of eIF2α and CHOP signals and reversed AGEs-induced cell apoptosis. AGEs also activated LC-3 cleavage, increased Atg5 expression, and decreased p62 expression, which indicated the autophagy induction in mesangial cells. Inhibition of autophagy by Atg5 siRNAs transfection aggravated AGEs-induced mesangial cell apoptosis. Moreover, ER stress inhibition by 4-phenylbutyric acid significantly reversed AGEs-induced autophagy, but autophagy inhibition did not influence the AGEs-induced ER stress-related signals activation. These results suggest that AGEs induce mesangial cell apoptosis via an ER stress-triggered signaling pathway. Atg5-dependent autophagy plays a protective role. These findings may offer a new strategy against AGEs toxicity in the kidney.

Current evidence of proteinuria reduction as a surrogate target in advanced chronic kidney disease (CKD) is incomplete due to lack of patient-pooled database. We retrospectively studied a multicenter cohort of 1891 patients who were enrolled in the nationwide multidisciplinary pre-end stage renal disease care program with a baseline glomerular filtration rate (GFR) <45 mL/min/1.73 m(2) and followed longitudinally to investigate the effect of the change in proteinuria on renal death (defined as composite of dialysis and death occurring before initiation of dialysis). The group with a change in proteinuria ≤0.30 g/g (n = 1261) had lower cumulative probabilities of renal death (p < 0.001). In a linear regression model, a higher baseline proteinuria and a greater increase in proteinuria were associated with faster annual GFR decline. Cox's analysis showed that every 1 unit increase in natural log(baseline proteinuria, 10 g/g) and every 0.1 g/g increase in the change in proteinuria resulted in 67% (HR = 1.67, 95% CI: 1.46-1.91) and 1% (HR = 1.01, 95% CI: 1.01-1.01) greater risk of renal death respectively after adjusting for the effects of the other covariates. Our study provided a patient-based evidence to support proteinuria as a therapeutic target in advanced CKD.

Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma. However, the response rate is only 40-65%. This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma. The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1). MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP. c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment. Inhibition of JNK activation partially restored cell viability and Bcl-xL expression. Bcl-xL overexpression also rescued cell viability. MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. In summary, MLN4924 synergistically enhanced the anti-tumor effect of cisplatin via an increase in DNA damage, JNK activation and down-regulation of Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutic strategy for the treatment of bladder cancer.

In this study, we investigated the role of ATP synthase subunit-β (ATP5b) in diabetic nephropathy. Histopathological changes, fibrosis, and protein expressions of α-smooth muscle actin (α-SMA), advanced glycation end-products (AGEs), and ATP5b were obviously observed in the kidneys of db/db diabetic mice as compared with the control db/m(+) mice. The increased ATP5b expression was majorly observed in diabetic renal tubules and was notably observed to locate in cytoplasm of tubule cells, but no significant increase of ATP5b in diabetic glomeruli. AGEs significantly increased protein expression of ATP5b and fibrotic factors and decreased ATP content in cultured renal tubular cells via an AGEs-receptor for AGEs (RAGE) axis pathway. Oxidative stress was also induced in diabetic kidneys and AGEs-treated renal tubular cells. The increase of ATP5b and CTGF protein expression in AGEs-treated renal tubular cells was reversed by antioxidant N-acetylcysteine. ATP5b-siRNA transfection augmented the increased protein expression of α-SMA and CTGF and CTGF promoter activity in AGEs-treated renal tubular cells. The in vivo ATP5b-siRNA delivery significantly enhanced renal fibrosis and serum creatinine in db/db mice with ATP5b down-regulation. These findings suggest that increased ATP5b plays an important adaptive or protective role in decreasing the rate of AGEs-induced renal fibrosis during diabetic condition.

Polycystic kidney disease (PCKD) is the most common hereditary cause of end-stage renal disease, the complications of which may prevent the choice of peritoneal dialysis (PD). The aim of this study was to explore the effects of dialysis modality on outcomes in patients with PCKD. We extracted a cohort of 1417 adult patients with PCKD initiating long-term dialysis therapy in 1999-2010 from the Taiwan National Health Insurance Research Database, among which 125 patients chose PD. The patients on HD were older and had a higher comorbidity index compared to those on PD. We compared the risks for death, hospitalization and medical expenditures between the patients on PD and propensity-score matched patients on hemodialysis (HD). The overall survival did not differ between the patients on PD and HD. The patients on PD tended to have higher hazard ratios (HR) for the first episode of hospitalization (adjusted HR 1.34 [95% CI, 1.04-1.79]). The annual medical expenses were 10% lower for the patients on PD. PD is an equivalent choice of renal replacement therapy to HD for patients with PCKD in terms of survival. Although the patients on PD had a higher risk for hospitalization, the medical expenditure for PD was 10% lower.

Factors associated with increased visceral fat area (VFA) have been well documented in the general population but rarely explored in nondiabetic individuals on peritoneal dialysis (PD). As glycosylated hemoglobin (HbA1c) is positively correlated with VFA in diabetic patients, we hypothesized that the same correlation would exist in nondiabetic PD patients. We enrolled 105 nondiabetic patients who had undergone chronic PD for more than 3 months. Each subject underwent an abdominal computed tomography (CT) scan, and the umbilicus cut was analyzed for VFA. VFA values, corrected for body mass index and subjected to natural logarithm transformations, were examined to determine whether they were correlated with HbA1c and other parameters. PD dialysates prescribed at the time of enrollment were recorded to calculate glucose load. We found that when 105 nondiabetic PD patients were classified according to tertiles of HbA1c, higher HbA1c was associated with larger VFA. Multiple linear regression analysis revealed that HbA1c was an independent determinant of VFA, while glucose load and other PD-specific factors were not. In summary, HbA1c, but not PD-related glucose load, was positively correlated with VFA in nondiabetic PD patients, suggesting clinical utility of HbA1c in the PD population.

Uremia results in a relatively immunocompromised status, and patients under chronic dialysis have an elevated risk of developing herpes zoster (HZ). We sought to investigate the relationship between vitamin D status and immunity to varicella-zoster virus (VZV). A multicenter prevalent hemodialysis cohort was assembled between 2012 and 2013. We assayed the biochemical parameters, 25-hydroxy- (25-OH-D) and 1,25-dihydroxyvitamin D, vitamin D-binding protein levels in the sera. VZV immunity was quantitated using VZV-specific glycoprotein IgG and IgM titers. Eighty-eight patients were enrolled and their sera were analyzed. Chronic hemodialysis patients with 25-OH-D < 30 ng/ml (insufficiency or deficiency) had significantly lower VZV-IgG than those with sufficient 25-OH-D (p = 0.04). This discrepancy became more prominent if active vitamin D users alone were analyzed (p = 0.01). Generalized additive modeling showed that those with 25-OH-D higher than 27.8 ng/ml or bioavailable 25-OH-D higher than 3.88 ng/ml had significantly higher VZV-IgG levels than those with lower values. Linear regression suggested that both total and bioavailable 25-OH-D were significantly associated with higher VZV-IgG levels (p = 0.003 [total] and 0.01 [bioavailable]), whereas patients with cancer had lower VZV-IgG. Vitamin D may therefore be a potentially useful choice for raising VZV immunity in chronic dialysis patients.