Jianzhou Zou

Acute Kidney Injury in a Chinese Hospitalized Population

Objectives: This study’s objective was to determine the incidence and mortality rate of acute kidney injury (AKI) among hospitalized adult patients in a tertiary metropolitan hospital of China, and to evaluate the impact of AKI on in-hospital mortality, cost and length of stay (LOS). Methods: Patients who were admitted to Zhongshan Hospital, Fudan University, Shanghai, China between September 1st, 2004 and June 30th, 2008 were involved. The presence and severity of AKI were assessed using absolute and relative increases from baseline to peak serum creatinine concentration during hospitalization. AKI was defined as a relative 50% increase or an absolute increment of 0.3 mg/dl (26.5 µmol/l) in serum creatinine within 48 h. After screening the computer-based data on kidney function, patients with AKI were identified and further history reviews were performed to obtain information regarding patients’ demography, prognosis, severity of kidney injury and causes of AKI. Results: There were 176,155 admissions during the study period and 5,619 met the diagnostic criteria of AKI. The overall incidence rate of AKI was 3.19%. Cardiovascular diseases followed by urogenital diseases and malignancy were the most common admission diagnoses. In-hospital mortality rate was 2.84% in all discharges and 19.68% in patients with AKI. Of AKI patients, old age, intensive care unit admission, Acute Kidney Injury Network score, need for renal replacement therapy and organ system failure number were independent predictors of hospital mortality according to forward conditional logistic regression. Conclusions: AKI is prevalent in the Chinese hospitalized patients. Slight elevations of serum creatinine are associated with significantly increased mortality, LOS and hospital cost. Moreover, outcomes are related directly to the severity of AKI characterized by percent changes in serum creatinine.

The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration

BACKGROUND Chronic hypoxia in the kidney has been suggested as a final common pathway in the progression of chronic kidney disease (CKD) leading to eventual kidney failure. Hypoxia-inducible factor (HIF) activation might offer a promising approach to the protection of hypoxic tissues, but the effect of HIF activation on CKD is still controversial. In this study, we investigated whether HIF activation had a beneficial or deleterious effect on CKD in the rat remnant kidney (RK) model. METHODS One week after a subtotal nephrectomy, rats were randomized and each received special administration of prolyl hydroxylases (PHD) inhibitor L-mimosine (L-Mim) as follows: in the early long-time L-Mim treatment group they were administered L-Mim at Weeks 2-12; in the advanced medium-term L-Mim treatment group they were administered L-Mim at Weeks 4-12 and in the end-stage L-Mim treatment group they were administered L-Mim at Weeks 8-12. RESULTS Compared with the control group, renal dysfunction and increased collagen III deposition, α-smooth muscle actin expression and ED-1-positive macrophage infiltration in tubulointerstitium were exacerbated by early long-term L-Mim treatment and improved by advanced medium-term L-Mim treatment. End-stage L-Mim treatment had no effect on RK rats. Furthermore, early long-term L-Mim treatment activated HIF-1α, connective tissue growth factor (CTGF) and phospho-Smad3 prominently throughout the time course and activated HIF-2α, vascular endothelial growth factor (VEGF) and erythropoietin (EPO) slightly at the end stage, while advanced medium-term L-Mim treatment activated HIF-2α, VEGF and EPO significantly and had no effect on HIF-1α, CTGF and phospho-Smad3. CONCLUSION HIF-α activation by PHD inhibitor L-Mim has dual roles in the development of CKD in the rat RK model depending on the timing of the administration and possibly the activated isoform of HIF-α.

Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine

Aim:  Hypoxia‐inducible factor (HIF) activity during the course of chronic kidney disease (CKD) development is poorly defined, and the effect of HIF activation on CKD is still controversial. The purpose of the present study was to characterize HIF expression during the course of CKD development, and to investigate the effect of HIF activation on CKD by using prolyl hydroxylase (PHD) inhibitor L‐mimosine.

Association of Indoxyl Sulfate with Heart Failure among Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Indoxyl sulfate, a protein-bound uremic toxin, may be associated with cardiovascular events and mortality in patients with CKD. This study aimed to investigate the relationship between indoxyl sulfate and heart failure in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients on hemodialysis for >6 months were enrolled within 6 months. Patients with congestive heart failure, angina pectoris, acute myocardial infarction, cerebral infarction, or cerebral hemorrhage within 3 months before the study or those <18 years old were excluded. The primary end point was first heart failure event during follow-up. RESULTS In total, 258 patients (145 men) with a mean age of 57.0 ± 14.6 years old were enrolled. Median plasma indoxyl sulfate level was used to categorize patients into two groups: the low-indoxyl sulfate group (indoxyl sulfate ≤ 2.35 μg/ml) and the high-indoxyl sulfate group (indoxyl sulfate >32.35 μg/ml). Then, patients were prospectively followed up for a median of 48.0 (interquartile range: 33.5-48.0) months. During follow-up, 68 patients experienced episodes of first heart failure. Kaplan-Meier analysis revealed the incidence of first heart failure event in the high-indoxyl sulfate group was significantly higher than in the low-indoxyl sulfate group (log rank P<0.001). Cox regression analysis showed indoxyl sulfate was significantly associated with first heart failure event (indoxyl sulfate as the continuous variable: hazard ratio, 1.02; 95% confidence interval [95% CI], 1.01 to 1.03; P=0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 3.49; 95% CI, 1.97 to 6.20; P<0.001). After adjustment for other confounding factors, the results remained significant (indoxyl sulfate as the continuous variable: hazard ratio, 1.04; 95% CI, 1.02 to 1.06; P<0.001; indoxyl sulfate as the dichotomous variable: hazard ratio, 5.31; 95% CI, 2.43 to 11.58; P<0.001). CONCLUSIONS Plasma indoxyl sulfate was associated with first heart failure event in patients on hemodialysis. Whether indoxyl sulfate is only a biomarker or involved in the pathogenesis of heart failure in hemodialysis warrants additional study.

miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia–Reperfusion Injury in Mice

Background:MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods:Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Results:Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1&agr; and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1&agr;. Conclusions:These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.

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.

Intermittent Exposure to Xenon Protects against Gentamicin-Induced Nephrotoxicity

Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram-negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe) provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N2) balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia-inducible factor 2α (HIF-2α) and its downstream effector vascular endothelial growth factor, but not HIF-1α. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain-containing protein-2 (PHD2), suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity.

Postoperative Fluid Overload is a Useful Predictor of the Short-Term Outcome of Renal Replacement Therapy for Acute Kidney Injury After Cardiac Surgery.

AbstractTo analyze the predictive value of postoperative percent fluid overload (PFO) of renal replacement therapy (RRT) for acute kidney injury (AKI) patients after cardiac surgery.Data from 280 cardiac surgery patients between 2005 January and 2012 April were collected for retrospective analyses. A receiver operating characteristic (ROC) curve was used to compare the predictive values of cumulative PFO at different times after surgery for 90-day mortality.The cumulative PFO before RRT initiation was 7.9% ± 7.1% and the median PFO 6.1%. The cumulative PFO before and after RRT initiation in intensive care unit (ICU) was higher in the death group than in the survival group (8.8% ± 7.6% vs 6.1% ± 5.6%, P = 0.001; −0.5[−5.6, 5.1]% vs 6.9[2.2, 14.6]%, P < 0.001). The cumulative PFO during the whole ICU stay was 14.3% ± 15.8% and the median PFO was 10.7%. The areas under the ROC curves to predict the 90-day mortality by PFO at 24 hours, cumulative PFO before and after RRT initiation, and PFO during the whole ICU stay postoperatively were 0.625, 0.627, 0.731, and 0.752. PFO during the whole ICU stay ≥7.2% was determined as the cut-off point for 90-day mortality prediction with a sensitivity of 77% and a specificity of 64%. Kaplan–Meier survival estimates showed a significant difference in survival among patients with cumulative PFO ≥ 7.2% and PFO < 7.2% after cardiac surgery (log-rank P < 0.001).Postoperative cumulative PFO during the whole ICU stay ≥7.2% would have an adverse effect on 90-day short-term outcome, which may provide a strategy for the volume control of AKI-RRT patients after cardiac surgery.

Diverse Effects of Ischemic Pretreatments on the Long-Term Renal Damage Induced by Ischemia-Reperfusion

Background/Aims: The role of ischemic pretreatment in long-term changes after renal ischemia-reperfusion (I/R) injury remains unknown. In this study, we mainly aimed to investigate the effect of ischemic pretreatments with different durations on the development of tubulointerstitial fibrosis and functional impairment following acute renal I/R. Methods: We established a rat model of renal warm I/R, clamping both pedicles for 40 min followed by reperfusion; the experiment was followed up for 10 weeks. Prior ischemia (10, 20, 30 min) was induced 8 days before the 40-min ischemia. To assess tissue fibrosis, we performed morphometric analysis, Masson’s trichrome and Sirius red staining. We also analyzed the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and phospho-Smad2. Results: Patchy tubulointerstitial fibrosis was found 5 and 10 weeks later in rats subjected to I/R alone or pretreated with 10-min ischemia. Tubulointerstitial fibrosis deteriorated further and renal dysfunction occurred in rats pretreated with 30-min ischemia accompanied by increased expression of α-SMA, TGF-β1, and phospho-Smad2 at 5 weeks. In contrast, the above abnormalities were significantly attenuated in rats pretreated with 20-min ischemia. Conclusion: Severe I/R injury may cause tubulointerstitial fibrosis in the long term, and different ischemic pretreatments have diverse effects on renal fibrosis.

Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway.

Objectives:Septic acute kidney injury is one of the most common and life-threatening complications in critically ill patients, and there is no approved effective treatment. We have shown xenon provides renoprotection against ischemia-reperfusion injury and nephrotoxicity in rodents via inhibiting apoptosis. Here, we studied the effects of xenon preconditioning on septic acute kidney injury and its mechanism. Design:Experimental animal investigation. Setting:University research laboratory. Subjects:Experiments were performed with male C57BL/6 mice, 10 weeks of age, weighing 20–25 g. Interventions:We induced septic acute kidney injury by a single intraperitoneal injection of Escherichia coli lipopolysaccharide at a dose of 20 mg/kg. Mice were exposed for 2 hours to either 70% xenon or 70% nitrogen, 24 hours before the onset of septic acute kidney injury. In vivo knockdown of miR-21 was performed using locked nucleic acid-modified anti-miR, the role of miR-21 in renal protection conferred by the xenon preconditioning was examined, and miR-21 signaling pathways were analyzed. Measurements and Main Results:Xenon preconditioning provided morphologic and functional renoprotection, characterized by attenuation of renal tubular damage, apoptosis, and a reduction in inflammation. Furthermore, xenon treatment significantly upregulated the expression of miR-21 in kidney, suppressed proinflammatory factor programmed cell death protein 4 expression and nuclear factor-&kgr;B activity, and increased interleukin-10 production. Meanwhile, xenon preconditioning also suppressed the expression of proapoptotic protein phosphatase and tensin homolog deleted on chromosome 10, activating protein kinase B signaling pathway, subsequently increasing the expression of antiapoptotic B-cell lymphoma-2, and inhibiting caspase-3 activity. Knockdown of miR-21 upregulated its target effectors programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10 expression, resulted in an increase in apoptosis, and exacerbated lipopolysaccharide-induced acute kidney injury. Conclusion:Our findings demonstrated that xenon preconditioning protected against lipopolysaccharide-induced acute kidney injury via activation of miR-21 target signaling pathways.