Jiachang Hu

Global Incidence and Outcomes of Adult Patients With Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES To estimate the global incidence and outcomes of acute kidney injury (AKI) after cardiac surgery in adult patients. DESIGN A systematic review and meta-analysis. SETTING Cardiac surgery wards. PARTICIPANTS Adult patients after cardiac surgery INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The authors searched PubMed, Web of Science, Cochrane Library, OVID, and EMBASE databases for all articles on cardiac surgery patients published during 2004 to 2014. Meta-analyses were conducted to generate pooled incidence, mortality, ICU length of stay, and length of hospital stay. The authors also described the variations according to study design, criteria of AKI, surgical methods, countries, continents, and their economies. After a primary and secondary screen, 91 observational studies with 320,086 patients were identified. The pooled incidence rates of AKI were 22.3% (95% confidence interval [CI], 19.8 to 25.1) in total and 13.6%, 3.8%, and 2.7% at stages 1, 2, and 3, respectively, whereas 2.3% of patients received renal replacement therapy. The pooled short-term and long-term mortality were 10.7% and 30%, respectively, and increased along with the severity of stages. The pooled unadjusted odds ratio for short-term and long-term mortality in patients with AKI relative to patients without AKI was 0.144 (95% CI, 0.108 to 0.192, p<0.001) and 0.342 (95% CI 0.287-0.407, p<0.001), respectively. The pooled average ICU length of stay and length of hospital stay in the AKI group were 5.4 and 15 days, respectively, while they were 2.2 and 10.5 days in the no-AKI group. CONCLUSIONS AKI is a great burden for patients undergoing cardiac surgery and can affect short-term and long-term prognoses of these patients.

MicroRNA-21 Is Required for Local and Remote Ischemic Preconditioning in Multiple Organ Protection Against Sepsis.

Objective: Sepsis, triggered by microbial infection, is a common and life-threatening systemic illness, often leads to impaired function of vital organs. Ischemic preconditioning induced by transient brief episodes of ischemia is a powerful innate mechanism of organ protection. We have reported that a 15-minute renal ischemic preconditioning substantially attenuated subsequent renal ischemia-reperfusion injury. Here, we investigate whether a brief ischemia and reperfusion in kidney can provide protection at local and remote sites against sepsis-induced organ injury, and whether this protection is microRNA-21 dependent. Design: Laboratory study. Setting: University laboratory. Subjects: Mouse renal tubular epithelial cells, C57BL/6 J wildtype (Animal Center of Fudan University, Shanghai, China) and microRNA-21–/– mice (B6.129-Mir21atm1Smoc, Shanghai Biomodel Organism Science & Technology Development Co. Shanghai, China). Interventions: Mouse renal tubular epithelial cells were treated with hypoxia (2% oxygen). Renal ischemic preconditioning was induced by bilateral renal pedicle clamping for 15 minutes, and sepsis was induced by a single intraperitoneal injection of lipopolysaccharide at a dose of 20 mg/kg or cecal ligation and puncture in mice. Measurements and Main Results: Mice treated with renal ischemic preconditioning were protected from endotoxemia or polymicrobial sepsis-induced multiple organ injury, including kidneys, heart, liver, and lungs. Renal ischemic preconditioning induced activation of hypoxia-inducible factor-1&agr; in kidneys, which up-regulated microRNA-21 at transcriptional level, subsequently, leading to increased expression of microRNA-21 in serum exosomes and remote organs, resulting in decreased apoptosis and reduced proinflammatory cytokines production in these organs. In vivo knockdown of microRNA-21 or genetic deletion of microRNA-21 abrogated the organoprotective effects conferred by renal ischemic preconditioning. Mechanistically, we discovered that knockdown of microRNA-21 increased programmed cell death protein 4 expression and nuclear factor-kappa B activity, decreased expression of anti-apoptotic B-cell lymphoma-2. Conclusion: MicroRNA-21 is required for local and remote ischemic preconditioning in multiple organ protection against sepsis, and up-regulation of miR-21 may be a potential therapy for sepsis.

Renal Protection Mediated by Hypoxia Inducible Factor-1α Depends on Proangiogenesis Function of mir-21 by Targeting Thrombospondin 1

Background Angiogenesis contributes to the repair process after renal ischemia/reperfusion (I/R) injury. In the present study, we tested the role of miR-21 in the angiogenesis induced by hypoxia inducible factor (HIF)-1&agr; through inhibiting a predicted target gene thrombospondin 1 (TSP-1). Methods To stabilize HIF-1&agr;, hypoxia (1% O2 for 24 hours) was performed in human umbilical vein endothelial cells and cobalt chloride (CoCl2) was pretreated intraperitoneally 24 hours before renal I/R in mice. Locked nucleic acid modified anti-miR-21 and scrambled control was transfected with hypoxic cells or delivered into the mice via tail vein 1 hour before CoCl2 injection. The kidneys and blood were collected at 24 hours after reperfusion. Results HIF-1&agr; induced by hypoxia and CoCl2 upregulated vascular endothelial growth factor and miR-21, and increased angiogenesis. It was found that expression of TSP-1 was inversely related with miR-21 in vitro and in vivo. Targeting of TSP-1 by miR-21 was further confirmed in vitro. Furthermore, HIF-1&agr; improved renal function, accompanied with increased angiogenesis after I/R injury in mice. The protective effect of HIF-1&agr; was attenuated by inhibition of miR-21. Conclusions HIF-1&agr; induced angiogenesis by upregulating not only vascular endothelial growth factor but also miR-21 via inhibiting a novel target gene TSP-1. Both of them may contribute to the protective effect of HIF-1&agr; on renal I/R injury.

Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats

ABSTRACT Contrast‐induced acute kidney injury (CI‐AKI) is an iatrogenic renal injury and associated with substantial morbidity and mortality in susceptible individuals. Despite extensive study of a variety of agents for renal protection, limited strategies have been shown to be effective in the reduction of CI‐AKI. O‐linked &bgr;‐N‐acetylglucosamine (O‐GlcNAc) is a post‐translational regulatory modification of intracellular proteins and governs the function of numerous proteins, both cytosolic and nuclear. Increasing evidence suggests that O‐GlcNAc levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective. However, the underlying mechanisms by which augmented OGlcNAc signaling provides renoprotection against contrast media insults is still unknown. Here, we investigated the effect of augmented O‐GlcNAc signaling via glucosamine on CI‐AKI and explored the underlying molecular mechanisms, particularly its relationship with PI3‐kinase (PI3K)/Akt signaling. We used a novel and reliable CI‐AKI model consisting of 5/6 nephrectomized (NE) rats, and a low‐osmolar contrast media (iohexol, 10 mL/kg, 3.5gI) injected via the tail vein after dehydration for 48 h. The results showed that augmented O‐GlcNAc signaling by glucosamine prevented the kidneys against iohexol‐induced injury characterized by the attenuation of renal dysfunction, tubular damage, apoptosis and oxidative stress. Furthermore, this renoprotection was blocked by treatment with alloxan, an O‐GlcNAc transferase inhibitor. Augmented O‐GlcNAc signaling also increased the protein expression levels of phospho‐Akt (Ser473, but not Thr308 and Thr450), phospho‐GSK‐3&bgr;, Nrf2, and Bcl‐2, and decreased the levels of Bax and cleaved caspase‐3. Both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway. We further identified O‐GlcNAcylated Akt through immunoprecipitation and western blot. We confirmed that Akt was modified by O‐GlcNAcylation, and glucosamine pretreatment increased the O‐GlcNAcylation of Akt. Collectively, the results demonstrate that glucosamine induces renoprotection against CI‐AKI through augmented O‐GlcNAc and activation of PI3K/Akt signaling, making it a promising strategy for preventing CI‐AKI. HighlightsIncreasing evidence suggests that O‐linked &bgr;‐N‐acetylglucosamine (O‐GlcNAc) levels are increased in response to stress and that acute augmentation of this reaction is cytoprotective.We used a novel and reliable contrast‐induced acute kidney injury (CI‐AKI) model and the results showed that augmented O‐GlcNAc signaling by glucosamine prevented the kidneys against iohexol‐induced injury by the attenuation of apoptosis and oxidative stress.Furthermore, both alloxan and specific inhibitors of PI3K (Wortmannin and LY294002) blocked the protection of glucosamine via inhibiting Akt signaling pathway.

Indoxyl sulfate accelerates vascular smooth muscle cell calcification via microRNA-29b dependent regulation of Wnt/β-catenin signaling

Vascular calcification (VC) is a very common phenomenon in patients with chronic kidney disease(CKD) and it increases the incidence of cardiovascular disease and leads to high mortality in CKD patients. It has been reported that some microRNAs (miRs) play roles in vascular calcification as an epigenetic regulator. Indoxyl sulfate (IS) is a protein-bound uremic toxin which has been proven as one of the major risk factors of cardiovascular disease in CKD. Here we investigated whether microRNA-29b (miR-29b) is involved in IS-induced vascular calcification. We found that vascular miR-29b was down-regulated in radial arteries of patients with end-stage renal disease. Consistently, IS also decreased miR-29b expression in human aortic smooth muscle cells (HASMCs) and potentiated their calcification. MiR-29b mimics significantly suppressed, while miR-29b anti-miR markedly enhanced, IS-induced runt-related transcription factor 2 and osteopontin expression. The expression of Wnt7b/β-catenin in radial arteries was higher in end stage renal disease than in control group, and IS increased Wnt7b/β-catenin expression in HASMCs as early as 3days after stimulation. Furthermore, miR-29b mimics potently repressed Wnt7b/β-catenin protein expression in HASMCs, whereas miR-29b anti-miR increased their expression, indicating miR-29b indeed negatively regulates Wnt7b/β-catenin signaling. Dickkopf-1 protein, the Wnt/β-catenin signaling inhibitor, suppressed anti-miR-29b-enhanced HASMCs calcification. Our data thus indicate that miR-29b downregulation and Wnt/β-catenin signaling activation may be the key mechanism of IS induced vascular calcification in chronic kidney disease.

Factors associated with the elevated percentage of CD4CD69 T cells in maintained hemodialysis patients

Abstract Background: CD4 T-cell abnormality, influencing the outcome of the maintained hemodialysis (MHD), is common in patients on dialysis. We try to find out factors associated with the activated CD4 T cells, CD4CD69 T cells, to improve the dialysis quality. Methods: A cross-sectional study was conducted to evaluate the change of CD4CD69 in MHD patients and healthy controls in our hospital from September 2015 to May 2016. A total of 164 MHD patients and 24 healthy controls were included according to the criteria. Univariate and multivariate logistic regression models after correlation analysis were executed to discover the related factors of CD4CD69 T-cell posterior to the division of the CD4CD69 T cell according to its median. Results: The lymphocytes were lower, but the percentage of CD4CD69 T cells was higher in MHD patients compared with healthy controls, even after the propensity score matching based on age and sex. The percentage of CD4 T cells showed no significant difference between the two groups. Further multivariate logistic regression models revealed that CD4CD69 T cell was independently associated with serum total protein (OR 95%CI: 0.830[0.696, 0.990], p = .038), transferrin (OR 95%CI: 3.072[1.131, 8.342], p = .028) and magnesium (OR 95%CI: 16.960[1.030, 279.275], p = .048). Conclusion: The percentage of CD4CD69 T cells, activated CD4 T cells, elevated in hemodialysis patients despite the decrease in lymphocytes. The elevated CD4CD69 T cells were independently associated with serum total protein negatively, but transferrin and magnesium positively. Strengthening nutrition, reducing the concentration of transferrin and magnesium might be beneficial to reduce the activation of CD4 T cells and improve the outcome of MHD patients.

Dysnatremia is an Independent Indicator of Mortality in Hospitalized Patients

Background Dysnatremia is a risk factor for poor outcomes. We aimed to describe the prevalence and outcomes of various dysnatremia in hospitalized patients. High-risk patients must be identified to improve the prognosis of dysnatremia. Material/Methods This prospective study included all adult patients admitted consecutively to a university hospital between October 1, 2014 and September 30, 2015. Result All 90 889 patients were included in this study. According to the serum sodium levels during hospitalization, the incidence of hyponatremia and hypernatremia was 16.8% and 1.9%, respectively. Mixed dysnatremia, which was defined when both hyponatremia and hypernatremia happened in the same patient during hospitalization, took place in 0.3% of patients. The incidence of dysnatremia was different in various underlying diseases. Multiple logistic regression analyses showed that all kinds of dysnatremia were independently associated with hospital mortality. The following dysnatremias were strong predictors of hospital mortality: mixed dysnatremia (OR 22.344, 95% CI 15.709–31.783, P=0.000), hypernatremia (OR 13.387, 95% CI 10.642–16.840, P=0.000), and especially hospital-acquired (OR 16.216, 95% CI 12.588–20.888, P=0.000) and persistent (OR 22.983, 95% CI 17.554–30.092, P=0.000) hypernatremia. Hyponatremia was also a risk factor for hospital mortality (OR 2.225, 95% CI 1.857–2.667). However, the OR increased to 56.884 (95% CI 35.098–92.193) if hyponatremia was over-corrected to hypernatremia. Conclusions Dysnatremia was independently associated with poor outcomes. Hospital-acquired and persistent hypernatremia were strong risk factors for hospital mortality. Effective prevention and proper correction of dysnatremia in high-risk patients may reduce the hospital mortality.

Hydrogen-Rich Saline Alleviates Kidney Fibrosis Following AKI and Retains Klotho Expression

Purpose: Acute kidney injury (AKI) is a prominent risk factor for the development of chronic kidney disease (CKD). To date, the related mechanism and effective therapy have not been rigorously explored. The present study aims to investigate the reno-protection of hydrogen-rich saline (HRS) against ischemia/reperfusion (IR)-induced AKI. Methods: Adult male C57 mice were randomly allocated into three groups: Sham, IR, IR+HRS. Renal IR injury model was generated via 35 min occlusion of bilateral kidney pedicles, and then, mice were administered with different treatments intraperitoneally in various groups. After 14- or 28-day treatment, mice were perfused and the kidneys were collected following reperfusion. Many proteins were detected by western blots, including renal fibrotic proteins [a-smooth muscle actin (a-SMA), collagen I (Col I)], Klotho, the methylation of Klotho, damage-regulated autophagy modulator (Beclin-1), and microtubule-associated protein light 3-II (LC3-II). Finally, the levels of serum blood urea nitrogen (BUN) and creatinine (Cr) were measured to investigate the renal function. Results: Histological data showed that the HRS treatment significantly decreased the fibrosis in renal tissues when compared with the IR group, and both of BUN and Cr were lower in the HRS group than IR group (8.9 ± 0.6 vs. 9.9 ± 0.1 mmol/l, 51 ± 6.5 vs. 60 ± 5.8 μmol/l) (P < 0.05). The expression of fibrotic markers, a-SMA and Col I, showed a robust increase in IR injury models than the Sham group, which was consistent with the result of Trichrome staining. However, the levels of a-SMA and Col I expression were sharply decreased in the IR+HRS group (P < 0.05). IR injury also enhanced LC3-II and Beclin-1 expression, but decreased Klotho level. The Klotho level was alleviated by HRS, but LC3-II and Beclin-1 were starkly enhanced in HRS group (P < 0.05). Conclusion: HRS showed a protective effect in the prevention of renal injury and could inhibit renal fibrosis after IR injury in mice. This role of HRS might be exerted via retaining Klotho expression and activating autophagy in the kidney.

Remote Ischemic Preconditioning Ameliorates Acute Kidney Injury due to Contrast Exposure in Rats through Augmented O-GlcNacylation

Remote ischemic preconditioning (RIPC) is an adaptive response, manifesting when local short-term ischemic preconditioning reduces damage to adjacent or distant tissues or organs. O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of intracellular proteins denotes a type of posttranslational modification that influences multiple cytoplasmic and nuclear protein functions. Growing evidence indicates that stress can induce an acute increase in O-GlcNAc levels, which can be cytoprotective. The current study aimed to determine whether RIPC can provide renoprotection against contrast-induced acute kidney injury (CI-AKI) by augmenting O-GlcNAc signaling. We established a stable model of CI-AKI using 5/6 nephrectomized rats exposed to dehydration followed by iohexol injection via the tail vein. We found that RIPC increased UDP-GlcNAc levels through the hexosamine biosynthetic pathway as well as global renal O-GlcNAcylation. RIPC-induced elevation of O-GlcNAc signaling ameliorated CI-AKI based on the presence of less tubular damage and apoptosis and the amount of reactive oxygen species. In addition, the use of alloxan, an O-GlcNAc transferase inhibitor, and azaserine, a glutamine fructose-6-phosphate amidotransferase inhibitor, neutralized the protective effect of RIPC against oxidative stress and tubular apoptosis. In conclusion, RIPC attenuates local oxidative stress and tubular apoptosis induced by contrast exposure by enhancing O-GlcNAc glycosylation levels; this can be a potentially useful approach for lowering the risk of CI-AKI.

The effect of long noncoding RNA GAS5 on apoptosis in renal ischemia/reperfusion injury: The effect of lncRNA GAS5 on apoptosis in renal I/R injury

Long non‐coding RNA (lncRNAs) have been shown to play a critical role in a variety of pathophysiological processes, such as cell proliferation, apoptosis and migration. However, there were few studies addressing the function of lncRNAs in renal ischaemia/reperfusion (I/R) injury. Apoptosis is an important pathogenesis during I/R injury. Here, we identified the effect of hypoxia‐responsive lncRNA growth arrest‐specific 5 (GAS5) on apoptosis in renal I/R injury.