Huili Dai

Clinical usefulness of novel biomarkers for the detection of acute kidney injury following elective cardiac surgery.

Background/Aims: Acute kidney injury (AKI) is common following cardiac surgery and predicts a poor outcome. However, the early detection of AKI has proved elusive and most cases are diagnosed only following a significant rise in serum creatinine (SCr). We compared a panel of early biomarkers of AKI for the detection of AKI in patients undergoing heart surgery. This study included serum cystatin C (CyC) and urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), retinol-binding protein (RBP) and N-acetyl-β-D-glucosaminidase (NAG). Methods: We retrospectively identified 15 patients undergoing open cardiac surgery who developed AKI within 72 h postoperatively. For these, we identified 15 matched controls also having undergone surgery but without AKI. Serial serum and urine samples had prospectively been postoperatively obtained from all patients at 0, 2, 4, 6, 10, 24, 48 and 72 h after admission to the intensive care unit. AKI was defined as a >50% increase in SCr. CyC was measured by nephelometry, while NGAL, IL-18, and RBP were measured by ELISA and NAG was measured by spectrophotometry. The urinary biomarkers were normalized to urinary creatinine (UCr) concentration. Each marker was assessed at each time point for its predictive value using receiver operating characteristic curves to predict AKI. Results: Following the exclusion of 1 case due to a urinary tract infection, the final cohort consisted of 29 patients aged 62.9 ± 13.7 years with baseline SCr of 73.2 ± 11.9 µmol/l. While there were no differences in the demographics between cases and controls, the aortic clamp time was predictably higher in AKI cases than in controls (60.6 ± 13.9 vs. 43.0 ± 9.2 min, p < 0.05). Each biomarker differed significantly between cases and controls for at least one time point. The optimal area under the curve (AUC) was for CyC at 10 h (sensitivity 0.71, specificity 0.92, cutoff 1.31 mg/l), NGAL at 0 h (sensitivity 0.84, specificity 0.80, cutoff 49.15 µg/g UCr), IL-18 at 2 h (sensitivity 0.85, specificity 0.73, cutoff 285.65 ng/g UCr), RBP at 0 h (sensitivity 0.75, specificity 0.67, cutoff 2,934.65 µg/g UCr) and NAG at 4 h (sensitivity 0.86, specificity 0.67, cutoff 37.05 U/mg UCr). Using a combination of all 5 biomarkers analyzed at the optimal time point as above, we were able to obtain an AUC of 0.98 (0.93–1.02, p < 0.001) in this limited sample. Conclusion: The use of serum and urinary biomarkers for the prediction of AKI in patients undergoing cardiac surgery is highly dependent on the sampling time. Of the evaluated markers urinary NGAL had the best predictive profile. The previously unstudied marker of urinary RBP showed similar predictive power as more established markers. By combining all 5 studied biomarkers we were able to predict significantly more cases, suggesting that the use of more than one marker may be beneficial clinically.

Strong Impact of Acute Kidney Injury on Survival After Liver Transplantation

Acute kidney injury (AKI) is a major complication in orthotopic liver transplantation (OLT). In an evaluation of Acute Kidney Injury Network (AKIN) criteria in liver transplanted patients, we retrospectively analyzed the usefulness of these criteria to predict survival of 193 consecutive patients at a single center who underwent primary OLT for clinical parameters and peak AKI. Postoperative AKI according to AKIN occurred in 60.1% of the patients, namely, stages 1, 2, and 3 in 30%, 13% and 17.1% respectively. Using multivariate logistic regression, AKIN stage 1 and 2 AKI were independently associated with the pre-OLT Model for End-Stage Liver Disease (MELD) score and age, while stage 3 AKI was independently associated with MELD and Acute Physiology and Chronic Health Evaluation (APACHE) II scores. The 28-day and 1-year mortality post-OLT of AKI patients were 15.5% and 25.9% respectively compared with 0% and 3.9% among non-AKI patients (P < .05 for both). The survival rates of non-AKI and stages 1, 2, and 3 AKI subjects were 96%, 85.5%, 84%, and 45.3%, respectively. Cox regression analysis showed independent risk factors for mortality during the first year after transplantation to include post-OLT AKI (12.1; P < .05), post-OLT infection (HR 4.7; P < .01), pre-OLT hypertension (HR 4.4; P < .01) hazard ratio [HR] and post-OLT APACHE II ≥10 (HR 3.6; P < .05). We concluded that AKI as defined by the AKIN criteria is a major complication of OLT linked to a poor outcomes. It remains to be evaluated whether aggressive perioperative therapy to prevent AKI can improve survival among OLT patients.

Clinical Outcome of Twice-Weekly Hemodialysis Patients in Shanghai

Background: Twice-weekly hemodialysis (HD) is prevalent in the developing countries and the clinical outcome of this population remains to be elucidated. Methods: Data were collected from Shanghai Renal Registry. 2,572 patients undergoing regular HD in Shanghai on January 2007 were enrolled into the cohort study with 2 years’ follow-up. Clinical and HD parameters obtained from the network were utilized to compare twice-weekly with thrice-weekly HD. Results: Compared with patients on thrice-weekly HD, the twice-weekly HD patients were significantly younger and had significantly longer HD session time, higher single-pool Kt/V (spKt/V) but shorter HD vintage (p < 0.001). Kaplan-Meier survival analysis indicated that the two groups had similar survival. Multivariate Cox regression analysis showed that age, body mass index, serum albumin and weekly Kt/V were predictors of patient mortality. Conclusions: The similar survival between twice-weekly HD and thrice-weekly HD is likely relating to patient selection; dialysis adequacy of twice-weekly HD remains to be elucidated.

Autophagy Protects Renal Tubular Cells Against Ischemia / Reperfusion Injury in a Time-Dependent Manner

Background/Aims: Autophagy is a dynamic catabolic process that maintains cellular homeostasis. Whether it plays a role in promoting cell survival or cell death in the process of renal ischemia/reperfusion (I/R) remains controversial, partly because renal autophagy is usually examined at a certain time point. Therefore, monitoring of the whole time course of autophagy and apoptosis may help better understand the role of autophagy in renal I/R. Methods: Autophagy and apoptosis were detected after mice were subjected to bilateral renal ischemia followed by 0-h to 7-day reperfusion, exposure of TCMK-1 cells to 24-h hypoxia, and 2 to 24-h reoxygenation. The effect of autophagy on apoptosis was assessed in the presence of autophagy inhibitor 3-methyladenine (3-MA) and autophagy activator rapamycin. Results: Earlier than apoptosis, autophagy increased from 2-h reperfusion, reached the maximum at day 2, and then began declining from day 3 when renal damage had nearly recovered to normal. Exposure to 24-h hypoxia induced autophagy markedly, but it decreased drastically after 4 and 8-h reoxygenation, which was accompanied with increased cell apoptosis. Inhibition of autophagy with 3-MA increased the apoptosis of renal tubular cells during I/R in vivo and hypoxia/reoxygenation (H/R) in vitro. In contrast, activation of autophagy by rapamycin significantly alleviated renal tissue damage and tubular cell apoptosis in the two models. Conclusion: Autophagy was induced in a time-dependent manner and occurred earlier than the onset of cell apoptosis as an early response that played a renoprotective role during renal I/R and cell H/R. Up-regulation of autophagy may prove to be a potential strategy for the treatment of acute kidney injury.

Urinary neutrophil gelatinase-associated lipocalin and L-type fatty acid binding protein as diagnostic markers of early acute kidney injury after liver transplantation

Objective: We examined the value of two potential novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid binding protein (L-FABP), in diagnosing acute kidney injury (AKI) in liver transplant recipients. Methods: NGAL and L-FABP in urinary sample from Twenty-five patients before surgery and at 2, 4, 6, 12, 24, 48, 72 and 120 h after the anhepatic phase were tested. Standard statistics were used along with receiver-operating characteristic (ROC) analysis to evaluate the diagnostic value of selected markers. Results: Urinary NGAL was only slightly elevated at 2 h in the non-AKI group while rose and stayed high from 2–6 h in the AKI group. However, urinary L-FABP rose transiently in both groups 2–120 h following surgery. The level of urinary NGAL presented differences at 2–6 h (p < 0.05) and urinary L-FABP at 4 h (p < 0.05) between AKI and non-AKI groups. ROC analysis showed that area under the curves (AUCs) of NGAL were 0.766, 0.773, and 0.773 at 2, 4 and 6 h respectively while 0.760 of L-FABP at 4 h. Conclusion: Urinary NGAL rather than L-FABP appeared to be a sensitive and specific marker of AKI in liver transplant recipients.

Functional metabotropic glutamate receptors 1 and 5 are expressed in murine podocytes

In non-neuronal cells, glutamate is an extracellular signaling mediator. Since podocytes have glutamate-containing vesicles, we sought to determine glutamate receptor presence and action in glomerular cells. The metabotropic glutamate receptors (mGluR) 1, 5, 6, and 8 were found to be expressed in mouse brain and glomeruli; predominantly in podocytes. In two models of proteinuria (BalB/C mice with puromycin aminonucleoside- and doxorubicin-induced podocyte injury) we found that the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) attenuated albuminuria and improved the expression of the podocyte marker WT-1. TUNEL staining showed that the number of podocytes undergoing apoptosis was inversely correlated with the number of WT-1-positive cells in glomeruli. When podocytes were treated with DHPG in vitro, they generated cyclic AMP and activated CREB (cyclic AMP response element binding protein). The selective mGluR1/5 antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid, the adenylate cyclase inhibitor SQ22536, and RNA interference knockdown of mGluR1 or mGluR5 all prevented DHPG-induced cAMP generation and CREB activation. DHPG inhibited apoptosis and the decrease of aminonucleoside-induced mitochondrial membrane potential in podocytes but had no effect in the presence of SQ22536 with knockdown mGluR1 or mGluR5. Thus, functional mGluR1 and mGluR5 are expressed in podocytes and their activation protects against albuminuria and podocyte apoptosis, processes that are, at least in part, dependent on cAMP.

Survey of Acute Kidney Injury and Related Risk Factors of Mortality in Hospitalized Patients in a Third-Level Urban Hospital of Shanghai

Objective: The main aim of this study is to investigate the incidence and prognosis of acute kidney injury (AKI) and to clarify the risk factors associated with the prognosis of AKI in hospitalized patients. Method: All patients hospitalized from January 1st to December 31st 2012 in Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University were screened by the Lab Administration Network. All the patients with an intact medical history of AKI according to the Acute Kidney Injury Network (AKIN) were enrolled in the study cohort. AKIs incidence and etiology, as well as the patients characteristics and prognosis, were retrospectively analyzed. Logistic regression analysis was used to investigate the risk factors on the patient prognosis and renal outcome. Results: 934 AKI patients were enrolled. The incidence of AKI in hospitalized patients was 2.41%. The ratio of males to females of patients was 1.88:1 and the mean age was 60.82 w 16.94. The incidence of AKI increased with increase in age. Among hospitalized patients, 63.4% were from the surgical department, 35.4% from the internal medicine department, and 1.2% from the obstetric and gynecologic department. Regarding the cause of AKI, pre-renal AKI, acute tubular necrosis (ATN), acute glomerulonephritis and vasculitis (AGV), acute interstitial nephritis (AIN), and post-renal AKI contributed with 51.7, 37.7, 3.8, 3.5, and 3.3%, respectively. The survival rate on the day 28 after AKI was 71.8%. In addition, 65.7% patients got complete renal recovery, while 16.9% got partial renal recovery and 17.4% got renal loss. The mortality of AKI in hospitalized patients at Stage I, Stage II and Stage III was 24.8, 31.2 and 43.7%, respectively. Multivariate Logistic regression analysis showed that use of nephrotoxic drugs, [Odds Ratio (OR) = 2.313], hypotension in the previous week (OR = 4.482), oliguria (OR = 5.267), the number of extra-renal organ failures (OR = 1.376), and need for renal replacement therapy (RRT) (OR = 4.221) were independent risk factors for mortality. The number of extra-renal organ failures (OR = 1.529) and RRT (OR = 2.117) were independent risk factors for renal loss. Conclusion: AKI is one of the most common complications in hospitalized patients. The mortality is high and renal prognosis is poor after AKI. The prognosis is closely associated with the severity of AKI. Nephrotoxic drugs, hypotension within the last week, oliguria, the number of extra-renal organ failures, and RRT are independent risk factors for mortality, while the number of extra-renal organ failures and RRT are independent risk factors for renal loss. i 2014 S. Karger AG, Basel

Analysis of the Urine Proteome of Human Contrast-Induced Kidney Injury Using Two-Dimensional Fluorescence Differential Gel Electrophoresis/Matrix-Assisted Laser Desorption Time-of-Flight Mass Spectrometry/Liquid Chromatography Mass Spectrometry

Background: The pathogenesis of contrast-induced nephropathy (CIN) remains unclear and is defined by changes in serum creatinine which is not a sensitive biomarker for acute kidney injury. Search for differentially expressed urinary protein or peptide could contribute to further understanding of the disease and may provide new biomarkers. Methods: This is a small sample research. Urine samples were obtained from patients who underwent percutaneous coronary intervention and were labeled with 3 different fluorescent dyes. After 2-dimensional electrophoresis was run, the differentially regulated spots were picked out and identified by mass spectrometry. Another 31 patients were used as validation group. Results: Among 56 significantly changed spots, mannose-binding lectin (MBL) and MBL-associated serine protease 2 were both significantly upregulated. Compared to the baseline value, urinary MBL was significantly increased in the CIN group (2.08, 1.42–5.72, vs. 1.09, 0.516–1.411; p < 0.01). Postprocedure urinary MBL in the CIN group was also significantly higher than that in the non-CIN group (2.08, 1.42–5.72, vs. 1.057, 0.738–1.885; p < 0.05). Conclusion: The studies suggested that MBL may be associated with contrast-induced acute kidney injury. It leads to an attempt to define a new pathogenesis and a novel biomarker for CIN.