Plasmapheresis compared with conventional treatment for hypertriglyceridemia-induced acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: The treatment of acute pancreatitis (AP) induced by hypertriglyceridemia (HTG) remains controversial with regard to plasmapheresis vs conventional treatment. We reviewed relevant articles to explore the efficacy of plasmapheresis in the management of HTG-induced AP. METHODS: We systematically reviewed studies that compared plasmapheresis with conventional treatment for HTG-induced AP using three databases: PubMed, Embase, and Cochrane Library, as well as relevant references. The primary outcomes were 24 h triglyceride reduction rate and in-hospital mortality. RESULTS: A total of 791 articles were retrieved. Finally, 15 observational studies (1080 participants) were included, most of which were historical cohort studies. Compared with conventional treatment, plasmapheresis assisted in the reduction of serum triglyceride (TG) levels in the first 24 h after hospital admission (standardized mean difference [SMD]: 0.58; 95% confidence interval [CI]: 0.17 to 0.99; P = 0.005). However, it resulted in increased hospitalization costs (thousand yuan) (weighted mean difference [WMD]: 24.32; 95% CI: 12.96 to 35.68; P < 0.001). With regard to in-hospital mortality, although the mortality rate in the plasmapheresis group was higher than that in the conventional treatment group (relative risk [RR]: 1.74; 95% CI: 1.03 to 2.94; P = 0.038), the result was disturbed by confounding factors as per the subgroup and sensitivity analysis, as well as trial sequential analysis (TSA). No significant differences were found in other outcomes, including systematic complications, local complications, the requirement for surgery, and hospitalization duration. CONCLUSION: The effect of plasmapheresis in HTG-induced AP is not superior to that of conventional treatment, even resulting in a greater economic burden to patients and health care system. High quality randomized control trials are required to obtain a more a definitive understanding of this issue.

Weekly pattern of dialysis unit blood pressure is a promising marker for prognosis evaluation in hemodialysis population.

BACKGROUND: Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS: We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS: One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS: Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.

Artemisinin attenuates tubulointerstitial inflammation and fibrosis via the NF-κB/NLRP3 pathway in rats with 5/6 subtotal nephrectomy.

Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway.

Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition.

AIM: Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT. METHODS: Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs. RESULTS: In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner. CONCLUSION: These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.

The characteristics and mortality risk factors for acute kidney injury in different age groups in China-a cross sectional study.

AIM: Age is an independent risk factor for acute kidney injury (AKI). The causes and outcomes of AKI in children, middle-aged, and older patients are different. The objective of this country-based study was to identify the characteristics and mortality factors for AKI in different age groups in China. METHODS: Using data from 374,286 adult patients (≥18 years) admitted to 44 study hospitals, we investigated the characteristics and mortality risk factors for AKI in four different age groups: 18-39 years of age, 40-59 years of age, 60-79 years of age, and ≥80 years of age. The identification criteria for AKI included the 2012 KDIGO AKI definition and an expanded criterion. RESULTS: The country-based survey included 7604 AKI patients (7604/374,286, 2.03%). The proportions of AKI in the four age groups were 11.52%, 30.79%, 41.03%, and 16.66%, respectively. In any age group, the patients with AKI stage 1 were the majority (43.4%, 42.4%, 46.4%, and 52.2%, respectively), and the most common classification of AKI was pre-renal AKI (44.3%, 51.3%, 52.3%, and 56.4%, respectively). The higher AKI peak stage occurred for the in-hospital mortality factors for AKI in all age groups; except for the AKI stage 2 patients in the 18-39 age group. CONCLUSION: The characteristics and mortality factors for AKI vary by age in China. Elderly patients were the primary population with AKI, and the most common type of AKI was pre-renal AKI. Special caution should be taken to the old population in hospitalized patients to prevent the pre-renal AKI.

[Effect of Cordyceps sinensis powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats].

OBJECTIVE: To observe the effect of Cordyceps sinensis (CS) powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats, and to primarily explore its possible mechanisms. METHODS: Totally 30 male Sprague-Dawley rats were divided into the sham-operation group, the model group, and the treatment group by random digit table, 10 in each group. A chronic kidney disease (CKD) rat model was prepared by one step 5/6 nephrectomy. Rats in the treatment group were intragastrically administered with CS powder solution at the daily dose of 2 g/kg, once per day. Equal volume of double distilled water was intragastrically administered to rats in the sham-operation group and the model group. All medication lasted for 12 weeks. The general condition of rats, their body weight, blood pressure, 24 h proteinuria, urinary N-acetyl-ß-D-glucosaminidase (NAG), serum creatinine (SCr) , and blood urea nitrogen (BUN) were assessed before surgery, at week 2, 4, 6, 8, 10, and 10 after surgery. Pathological changes of renal tissues were observed under light microscope. Morphological changes of mitochondria in renal tubular epithelial cells were observed under transmission electron microscope. Activities of antioxidant enzymes including reduced glutathione (GSH), manganese superoxide dismutase (MnSOD), and malondialdehyde (MDA) in fresh renal tissue homogenate were detected. Mitochondria of renal tissues were extracted to detect levels of mitochondrial membrane potential and changes of reactive oxygen species (ROS). And expressions of cytochrome-C (Cyto-C) and prohibitin in both mitochondria and cytoplasm of the renal cortex were also measured by Western blot. RESULTS: (1) Compared with the sham-operation group, body weight was significantly decreased at week 2 (P <0. 01), but blood pressure increased at week 4 (P <0. 05) in the model group. Compared with the model group, body weight was significantly increased at week 12 (P <0. 01), but blood pressure decreased at week 8 (P < 0. 01) in the treatment group. (2) Compared with the sham-operation group, 24 h proteinuria, urinary NAG, blood SCr and BUN significantly increased in the model group (all P <0. 01). Compared with the model group, blood and urinary biochemical indices all significantly decreased in the treatment group (all P <0. 01). (3) Results of pathological renal scoring: Glomerular sclerosis index, scoring for tubulointerstitial fibrosis, degree of tubulointerstitial inflammatory infiltration were all obviously higher in the model group than in the sham-operation group (all P <0. 01). All the aforesaid indices were more obviously improved in the treatment group than in the model group (all P <0. 01). (4) Compared with the sham-operation group, activities of MnSOD and GSH-Px were significantly reduced, but MDA contents obviously increased in the renal cortex of the model group (all P <0. 01). Compared with the model group, activities of MnSOD and GSH-Px obviously increased (P <0. 05, P <0. 01), but MDA contents obviously decreased in the renal cortex of the treatment group (P <0. 01). (5) Compared with the sham-operation group, the mitochondrial membrane potential significantly decreased, but ROS levels significantly increased in the model group (all P <0.01). Compared with the model group, mitochondrial transmembrane potential increased in the treatment group, thereby inhibiting the tendency of increased production of ROS (both P < 0. 01). (6) Results of Western blot showed that, compared with the sham-operation group, expression levels of mitochondrial Cyto-C and Prohibitin were significantly reduced in the renal cortex (P <0. 01), but significantly elevated in the cytoplasm of the model group (P <0. 01). Compared with the model group, each index was obviously improved in the treatment group with statistical difference (P <0. 05, P <0. 01). CONCLUSION: CS powder had renal protection, and its mechanism might partially depend on in- hibition of oxidative stress and protection for mitochondria.

Cinacalcet attenuates the renal endothelial-to-mesenchymal transition in rats with adenine-induced renal failure.

Elevated serum parathyroid hormone (PTH) is an important complicated phenomenon in patients with chronic kidney disease (CKD). Emerging evidence indicates the involvement of PTH in organ fibrosis, and suppression of PTH by cinacalcet (CINA) ameliorates the progression of fibrotic disorders. However, the underlying mechanisms are largely unknown. The endothelial-to-mesenchymal transition (EndMT) has been shown to be an important mechanism involved in renal fibrosis. The present study aimed to investigate whether CINA treatment attenuated renal EndMT in rats with adenine-induced chronic renal failure (CRF). Compared with the control group, serum PTH was significantly higher in the CRF group and was suppressed after CINA treatment. Serum calcium, phosphorus, and calcium × phosphorus product levels were similar in the CRF group and CINA-treated CRF group. Renal collagen accumulation was significantly increased in the CRF group, which was markedly ameliorated by CINA treatment. Expression of the endothelial marker CD31 was significantly downregulated in rats with CRF, whereas expression of the mesenchymal markers fibroblast specific-protein 1 and α-smooth muscle actin was markedly upregulated. These changes were inhibited by CINA treatment. The protein levels of these EndMT-related markers were strongly correlated with serum PTH concentrations. Furthermore, the in vitro study showed that PTH could significantly increase the expression of fibroblast specific-protein 1 and α-smooth muscle actin and decrease CD31 in mRNA and protein levels in a concentration- and time-dependent manner. In conclusion, our study suggests that reducing serum PTH by CINA treatment could attenuate renal fibrosis via suppression of EndMT in the adenine-induced CRF rat model.

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats.

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-ß-D-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-ß(1), connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.

FTY720 attenuates tubulointerstitial inflammation and fibrosis in subtotally nephrectomized rats.

Tubulointerstitial fibrosis is a common pathway that leads to kidney failure, and persistent tubulointerstitial inflammation is a key event in the development of tubulointerstitial fibrosis. The new immunosuppressive drug FTY720 modifies lymphocyte migration into injured tissues by sequestering lymphocytes within secondary lymphoid organs. However, its therapeutic effect on tubulointerstitial inflammation and fibrosis had not been well understood. This study was designed to explore the effect of FTY720 on tubulointerstitial inflammation and fibrosis in subtotally nephrectomized (SNX) rats. In total, 24 male Sprague-Dawley rats were used. Seven days after 5/6 nephrectomy, rats were randomized to FTY720 (1 mg/kg/d) and placebo-treated groups. Sham-operated rats served as controls. FTY720 significantly attenuated the rise in proteinuria, serum creatinine, urea nitrogen and N-acetyl-ß-D-glucosaminidase activity in SNX rats, and reduced the count of peripheral white blood cells and lymphocytes in SNX rats. Morphological analysis revealed that there was severe tubulointerstitial inflammation and fibrosis in SNX group and much more tubulointerstitial infiltrating inflammatory cells with high expression of CD3, CD4, CD8, CD20, CD68, CD163 and CCR-7 in SNX group, as compared with the controls, but the lesions were attenuated significantly by treatment with FTY720. Furthermore, the expressions of proinflammatory molecules (IL-6, TNF-α and MCP-1), profibrotic molecule (TGF-ß1) and production of extracellular matrix proteins such as fibronectin and types I and III collagens were upregulated in SNX rats. FTY720 administration significantly reduced these abnormalities. In summary, FTY720 exerts therapeutic effects on tubulointerstitial fibrosis in SNX rats by inhibiting the tubulointerstitial inflammatory response.

[Pulmonary mucormycosis: report of 5 cases and review of 46 cases reported in China].

OBJECTIVE: To describe the clinical manifestations and diagnosis of pulmonary mucormycosis. METHODS: We presented 5 proven diagnosed cases of pulmonary mucormycosis in our hospital and reviewed all proven cases of pulmonary mucormycosis previously reported in mainland China. Publications in the form of case reports and articles between January 1982 and December 2011 were searched from Wan Fang Data and China Hospital Knowledge Database. RESULTS: Of the 5 patients in our hospital, the main symptoms included cough, fever, and hemoptysis. Two cases were diagnosed by transbronchial lung biopsy (TBLB), 1 by surgery, 1 by CT-guided percutaneous lung biopsy, and 1 by blood culture. Three patients were cured by antifungal chemotherapy alone, 1 was cured by surgery, and 1 died. Forty-six proven diagnosed cases of pulmonary mucormycosis were retrieved from Wan Fang Data and China Hospital Knowledge Database using key word (pulmonary mucormycosis). Of the 51 patients in total, there were 31 males and 20 females, with a mean age of (47 ± 13)years. The most common risk factors for pulmonary mucormycosis were poorly controlled diabetes mellitus (18 cases), administration of immunosuppressants (7 cases), malignancy (5 cases) and kidney diseases (5 cases). Chest CT showed nodules (27 cases), infiltrates (21 cases), and cavities (18 cases). White blood cell count and neutrophil percentage were elevated in 26 patients. Eighteen cases were diagnosed by histological study of transbronchial biopsy or TBLB specimen. The diagnosis was proven with surgical specimen in 15 patients, CT-guided percutaneous lung biopsy specimen in 7 patients, autopsy in 4 patients, skin biopsy in 1 patient, and renal biopsy in one patient. Three cases were diagnosed by pleural effusion cultures and 2 were diagnosed by blood cultures. Administration of low-dose liposomal amphotericin B (AMB) alone or combined with posaconazole in 12 patients were effective and safe. Fourteen patients who had received surgical resection were cured. CONCLUSIONS: There were no specific clinical features of pulmonary mucormycosis. Transbronchial biopsy and CT-guided percutaneous lung biopsy are useful diagnostic tools for pulmonary mucormycosis. Surgical resection and administration of low-dose liposomal AMB alone or combined with posaconazole were all effective and safe.

A point mutation in the DNA-binding domain of HPV-2 E2 protein increases its DNA-binding capacity and reverses its transcriptional regulatory activity on the viral early promoter.

BACKGROUND: The human papillomavirus (HPV) E2 protein is a multifunctional DNA-binding protein. The transcriptional activity of HPV E2 is mediated by binding to its specific binding sites in the upstream regulatory region of the HPV genomes. Previously we reported a HPV-2 variant from a verrucae vulgaris patient with huge extensive clustered cutaneous, which have five point mutations in its E2 ORF, L118S, S235P, Y287H, S293R and A338V. Under the control of HPV-2 LCR, co-expression of the mutated HPV E2 induced an increased activity on the viral early promoter. In the present study, a series of mammalian expression plasmids encoding E2 proteins with one to five amino acid (aa) substitutions for these mutations were constructed and transfected into HeLa, C33A and SiHa cells. RESULTS: CAT expression assays indicated that the enhanced promoter activity was due to the co-expressions of the E2 constructs containing A338V mutation within the DNA-binding domain. Western blots analysis demonstrated that the transiently transfected E2 expressing plasmids, regardless of prototype or the A338V mutant, were continuously expressed in the cells. To study the effect of E2 mutations on its DNA-binding activity, a serial of recombinant E2 proteins with various lengths were expressed and purified. Electrophoresis mobility shift assays (EMSA) showed that the binding affinity of E2 protein with A338V mutation to both an artificial probe with two E2 binding sites or HPV-2 and HPV-16 promoter-proximal LCR sequences were significantly stronger than that of the HPV-2 prototype E2. Furthermore, co-expression of the construct containing A338V mutant exhibited increased activities on heterologous HPV-16 early promoter P97 than that of prototype E2. CONCLUSIONS: These results suggest that the mutation from Ala to Val at aa 338 is critical for E2 DNA-binding and its transcriptional regulation.

Nerve growth factor of red nucleus involvement in pain induced by spared nerve injury of the rat sciatic nerve.

Nerve growth factor (NGF), a member of the neurotrophin family, is essential for the development and maintenance of sensory neurons and for the formation of central pain circuitry. The current study was designed to evaluate the expression of NGF in the brain of rats with spared nerve injury (SNI), using immunohistochemical technique. The results showed that the level of NGF in the Red nucleus (RN) of SNI rats was apparently higher than that of sham-operated rats. To further study the effect of NGF in the development of neuropathic pain, different doses of anti-NGF antibody (20, 2.0 and 0.2 microg/ml) were microinjected into the RN contralateral to the nerve injury side of SNI rats. The data suggested that the higher doses of anti-NGF antibody (20 and 2.0 microg/ml) significantly attenuated the mechanical allodynia of neuropathic rats, while the 0.2 microg/ml antibody showed no analgesic effect. These results suggest that the NGF of RN is involved in the development of neuropathic allodynia in SNI rats.

Association of lipoprotein(a) and coronary artery disease in 1003 patients with stage 3-5 chronic kidney disease undergoing coronary angiography.

AIM: Lipoprotein(a) [Lp(a)] is considered a risk factor for cardiovascular disease. However, the role of Lp(a) in chronic kidney disease (CKD) patients is not well understood. The aim of this study was to evaluate the association between Lp(a) levels and the presence of coronary artery disease (CAD) and the severity of coronary artery stenosis (CAS) in patients with stage 3-5 CKD. PATIENTS AND METHODS: We retrospectively studied patients who were diagnosed with stage 3-5 CKD and underwent coronary artery angiography in Zhongda Hospital. The Gensini scoring system was used to assess the severity of coronary stenosis. RESULTS: A total of 1003 patients were enrolled in this cross-sectional study, and 776 of these patients were diagnosed with CAD. The Lp(a) levels were significantly higher in the CAD group than the non-CAD group [271.50 (168.00-459.25) vs. 195.00 (131.00-347.00) mg/l, P<0.001]. Multivariate logistic regression analysis showed that the Lp(a) tertiles were associated independently with the presence of CAD [tertile 2 vs. tertile 1 [adjusted odds ratio (OR)=2.063, 95% confidence interval (CI): 1.394-3.053, P<0.001] and tertile 3 vs. tertile 1 (adjusted OR=2.022, 95% CI: 1.345-3.040, P=0.001)]. After adjusting for potential confounders, the Lp(a) levels were associated independently with severe CAS [tertile 2 vs. tertile 1 (adjusted OR=1.603, 95% CI: 1.040-2.472, P=0.033); tertile 3 vs. tertile 1 (adjusted OR=1.743, 95% CI: 1.128-2.693, P=0.012)]. CONCLUSION: Higher Lp(a) levels were associated the presence of CAD and the severe CAS among patients with stage 3-5 CKD independently.

Peridialysis BP levels and risk of all-cause mortality: a dose-response meta-analysis.

Blood pressure (BP) management posed great challenge in hemodialysis (HD) population. We conducted a dose-response meta-analysis to investigate the quantitative features and the potential threshold effect of the associations between peridialysis BP levels and all-cause mortality risk in HD population. We searched all of the prospective cohort studies (published before 18 March 2017) on the associations between peridialysis BP levels and all-cause mortality risk. A total of 229,688 prevalent HD patients from 8 studies were included. Significant non-linear associations were noted between peridialytic BP levels and all-cause mortality risk. Significant increased risk of death was found in four peridialysis BP ranges, that is, low levels of predialysis SBP (<135 mmHg, 140 mmHg as the reference), two extremes of predialysis DBP (<55 and >95 mmHg, 90 mmHg as the reference), high levels of postdialysis SBP (>180 mmHg, 130 mmHg as the reference), and low levels of postdialysis DBP (<75 mmHg, 80 mmHg as the reference). Threshold effect was determined in the associations between peridialysis BP and all-cause mortality risk, and potential BP thresholds were identified (149 mmHg for predialysis SBP, 79 mmHg for predialysis DBP, 147 mmHg for postdialysis SBP and 76 mmHg for postdialysis DBP). In conclusion, the proposed peridialysis BP ranges and the threshold values could help clinicians identify high risk HD patients. The interpretation of the peridialysis BP mortality associations should be based on the features of HD population (especially the cardiovascular conditions, volume status and the dialysis vintage).

[Expression of toll-like receptors on CD14+ monocytes from patients with chronic obstructive pulmonary disease and smokers].

OBJECTIVE: To investigate the expression of toll-like receptor-2 (TLR2), TLR4 on the CD14+ monocytes of patients with stable chronic obstructive pulmonary disease (COPD) and healthy smokers, and to explore the role of TLR2 and TLR4 in COPD pathogenesis. METHODS: Thirty COPD patients without evidence of acute exacerbation, 21 healthy smokers, and 25 healthy non-smokers underwent measurement of forced expiratory volume in 1 second (FEV(1))% predicted and FEV(1)/forced vital capacity (FVC) by spirometry. The expression of TLR2 and TLR4 surface molecules on human CD14+ monocytes was assessed using fluorescence activated cell sorter analysis by flow cytometry, expressed as relative mean fluorescence intensity (rmfi) and relative positive cell percent (rpcp), and the correlation of TLR expression with lung function parameters was analyzed. RESULTS: The rmfi and rpcp of TLR2 on CD14+ monocytes of the COPD patients were (6.3 +/- 1.4)% and (52.9 +/- 20.5)% respectively, both significantly lower than those of the healthy smokers [(8.2 +/- 2.2)% and (73.5 +/- 19.0)% respectively] and those of the nonsmokers [(11.0 +/- 2.4)% and (82.8 +/- 17.9)% respectively, all P < 0.01)]. The rmfi of TLR4 of the COPD patients was 2.2 +/- 0.9, significantly lower than that of the nonsmokers (3.0 +/- 0.5, P < 0.01), while similar to that of the healthy smokers (2.5 +/- 0.6, P > 0.05). The rpcp of TLR4 of the COPD patients (M = 1.3%, Q(1) - Q(3): 0.7% - 2.4%) was significantly lower than that of the healthy smokers (M = 4.7%, Q(1) - Q(3): 2.7% - 9.4%, P < 0.01) and nonsmokers (M = 5.3%, Q(1) - Q(3): 2.6% - 8.4%, P < 0.01). The rmfi of TLR2 and TLR4 on CD14+ monocytes of the healthy smokers was lower than that of the nonsmokers (P < 0.05), while the rpcp of TLR2 and TLR4 on CD14+ monocytes of the healthy smokers was similar to that of the nonsmoker (P < 0.05). The expression of TLR2 and TLR4 on monocytes was positively correlated with the lung function parameters, including FEV(1)% predicted and FEV(1)/FVC (all P < 0.01). CONCLUSIONS: The expression levels of TLR2 and TLR4 on CD14+ monocytes of the stable COPD patients and healthy smokers decreased significantly. The innate immune response may be depressed in the COPD patients and smokers, and the down-regulation of TLR is associated with reduced lung function parameters.

Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation.

Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-κB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti-inflammatory effect of HCQ in the treatment of AKI.

mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI.

Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC)-associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin-interacting protein (TXNIP). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion. Consistent with this observation, NLRP3 deletion significantly attenuated I/R-induced kidney damage and markers of inflammasome activation. Then, we observed mitochondrial dysfunction, characterized by ultrastructural changes and cytochrome C (Cyt c) redistribution. Mitochondria-targeted antioxidant MitoTEMPO prevented mROS overproduction and the decline in mitochondrial membrane potential (MMP) in vitro. MitoTEMPO treatment also inhibited NLRP3 inflammasome activation and co-localization of NLRP3 and TXNIP after simulated ischemia/reperfusion (SI/R) injury. Finally, we transfected HK-2 cells with TXNIP siRNA to explore the role of TXNIP in mROS-induced NLRP3 inflammasome activation. We found that TXNIP siRNA significantly inhibited NLRP3 inflammasome activation. These results demonstrate that NLRP3 inflammasome is activated through the mROS-TXNIP-NLRP3 pathway and provide a potential therapeutic target in ischemic AKI.

Hospital-acquired acute kidney injury: an analysis of baseline estimated glomerular filtration rate and in-hospital mortality.

AIM: The objective of this study was to determine whether the baseline estimated glomerular filtration rate (eGFR) level was independently associated with in-hospital mortality in generalized patients with hospital-acquired acute kidney injury (HA-AKI) in China. METHODS: All of the patients admitted to a tertiary medical center of Nanjing, China, between January 1, 2013, and December 31, 2013, were involved. Through the use of an electronic database and the Acute Kidney Injury Network (AKIN) classification, the patients with HA-AKI were indentified. We included the hospitalized adult patients with HA-AKI. Epidemiological information and in-hospital outcomes were collected and were analyzed according to different baseline eGFR strata of the included individual patients. RESULTS: Of the 42,664 admissions during the study period, 1327 patients were identified as AKI. The incidence of HA-AKI was 3.1 %. HA-AKI patients with a compromised baseline eGFR tended to be older and had a higher prevalence of various comorbid conditions. With the gradual deterioration of the baseline eGFR, the odds ratio of in-hospital mortality increased incrementally and a graded independent association between the baseline eGFR and in-hospital mortality was observed when the baseline eGFR dropped below 60 ml/min per 1.73 m(2). CONCLUSION: Baseline eGFR was a potential risk factor for in-hospital mortality in HA-AKI. Serum Creatinine (SCr)-based definition of AKI needs to incorporate baseline eGFR to optimize or refine risk stratification.