Yucheng Yan

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.

Urinary L-FABP and its combination with urinary NGAL in early diagnosis of acute kidney injury after cardiac surgery in adult patients

Background/Aim: The early detection of acute kidney injury (AKI) may be become possible by several promising early biomarkers which may facilitate the early detection, differentiation and prognosis prediction of AKI. In this study, we investigated the value of urinary liver-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL) and their combination in predicting the occurrence and the severity of AKI following cardiac surgery. Methods: We prospectively followed 109 patients undergoing open heart surgery and identified 26 that developed AKI, defined as an increase in serum creatinine of ≥0.3 mg/dl or ≥150% of baseline creatinine. Serum creatinine (SCr), urinary L-FABP, and NGAL corrected by urine creatinine were tested pre-operation, at 0 hour and 2 hours post-operation. Each marker was assessed at each time point between patients with and without AKI. Receiver operating characteristic (ROC) curves and area under curves (AUC) were used to evaluate the diagnostic accuracy of urinary L-FABP, NGAL and their combination for predicting AKI. Results: Patients were aged 63.0 ± 11.3 years, 66.1% were male and baseline SCr was 70.5 ± 19.1 umol/L. Of 109 patients, 26(23.9%) developed AKI (AKIN stage I, II and III were 46.2%, 34.6% and 19.2% separately). The levels of urinary L-FABP and NGAL were significantly higher in AKI patients than non-AKI patients at 0 hour and 2 hours postoperative. AUCs for L-FABP was 0.844 (sensitivity (ST) 0.846, specificity (SP) 0.819, cut-off (CO) 2226.50 μg/g Ucr) at 0 hours and 0.832 at 2 hours (ST 0.808, SP 0.747, CO 673.09 μg/g Ucr) while 0.866 for NGAL at 0 hours (ST 0.769, SP 0.819, CO 131.12 μg/g Ucr) and 0.871 at 2 hours (ST 0.808, SP 0.831, CO 33.73 μg/g Ucr) to predict AKI occurrence. Using a combination of L-FABP and NGAL analyzed at the same timepoint as above, we were able to obtain an AUC of 0.911–0.927, p < 0.001. Similar AUCs of 0.81–0.87 were found to predict AKI stage II–III. Conclusions: Urinary L-FABP and NGAL increased at an early stage after cardiac surgery. The combination of the two biomarkers enhanced the accuracy of the early detection of postoperative AKI after cardiac surgery before a rise in SCr.

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.

Two-times weekly hemodialysis in China: frequency, associated patient and treatment characteristics and Quality of Life in the China Dialysis Outcomes and Practice Patterns study

BACKGROUND Renal replacement therapy is rapidly expanding in China, and two-times weekly dialysis is common, but detailed data on practice patterns are currently limited. Using cross-sectional data from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), we describe the hemodialysis practice in China compared with other DOPPS countries, examining demographic, social and clinical characteristics of patients on two-times weekly dialysis. METHODS The DOPPS protocol was implemented in 2011 among a cross-section of 1379 patients in 45 facilities in Beijing, Guangzhou and Shanghai. Data from China were compared with a cross section of 11 054 patients from the core DOPPS countries (collected 2009-11). Among China DOPPS patients, logistic and linear regression were used to describe the association of dialysis frequency with patient and treatment characteristics and quality of life. RESULTS A total of 26% of the patients in China were dialyzing two times weekly, compared with < 5% in other DOPPS regions. Standardized Kt/V was lowest in China (2.01) compared with other regions (2.12-2.27). Female sex, shorter dialysis vintage, lower socioeconomic status, less health insurance coverage, and lack of diabetes and hypertension were associated with dialyzing two times weekly (versus three times weekly). Patients dialyzing two times per week had longer treatment times and lower standardized Kt/V, but similar quality of life scores. CONCLUSIONS Two-times weekly dialysis is common in China, particularly among patients, who started dialysis more recently, have a lower comorbidity burden and have financial constraints. Quality of life scores do not differ between the two-times and three-times weekly groups. The effect on clinical outcomes merits further study.

Prevalence of Acute Kidney Injury following Cardiac Surgery and Related Risk Factors in Chinese Patients

Background/Aims: Acute kidney injury (AKI) following surgery is a major complication, but the prevalence and risk factors in the Asian population are unclear. Recently, a consensus definition of AKI (AKIN) was proposed. We studied a cohort of cardiac surgery patients and identified AKI by AKIN and associated risk factors. Methods: We retrospectively evaluated 1,056 consecutive patients undergoing cardiac surgery in Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from January 1, 2004 to June 30, 2007. We recorded AKIN stage, clinical characteristics, perioperative variables and complications, as well as clinical outcomes. Univariate and multivariate regression as well as survival analysis was performed. Results: AKI occurred in 328 (31.1%) patients, stage 1 in 21.1%, stage 2 in 6.3% and stage 3 in 3.7%. Patients with AKI were older (65.8 vs. 53.5 years, p < 0.001), more often male (66.8 vs. 54.1%, p < 0.001), and had higher Charlson Comorbidity Index (CCI) (CCI >2: 22.6 vs. 7.8%, p < 0.001). In logistic regression, advanced age (OR 1.48 per decade, 95% CI 1.32–1.67), CCI >2 (OR 2.82, 95% CI 1.80–4.41), hypertension (OR 2.13, 95% CI 1.47–3.09), left ventricular ejection fraction (LVEF) <45% (OR 1.97, 95% CI 1.14–3.40), postoperative central venous pressure (CVP) <6 cm H2O (OR 13.28, 95% CI 8.72–20.14) and postoperative use of ACEI/ARB (OR 1.90, 95% CI 1.27–2.85) were risk factors of AKI. Mortality rose progressively with increased AKIN stage (non-AKI 0.7%, stage 1 4.9%, stage 2 12.1% and stage 3 48.7%). In ROC analysis, AKIN classification was identified to be associated with in-hospital mortality with an AUC of 0.865 (95% CI 0.801–0.929, sensitivity 0.884, specificity 0.714, p < 0.001). Finally, in a Cox proportional hazards model, AKIN stage (HR 2.40, p < 0.001), re-exploration (HR 6.30, p = 0.002) and multiple organ dysfunction syndrome (MODS) (HR 4.42, p = 0.001) were associated risk factors for in-hospital mortality. Conclusion: We evaluated AKIN as a marker of AKI and mortality risk in a large, unselected Chinese cohort of incident patients undergoing cardiac surgery. AKI following cardiac surgery was diagnosed by AKIN criteria in around one third of the patients, and AKI may be associated with outcome. The value of preventative strategies to reduce AKI and their effect on in-hospital mortality should be studied.

Daily peritoneal ultrafiltration predicts patient and technique survival in anuric peritoneal dialysis patients

BACKGROUND Maintenance dialysis therapy is the only way to remove excess fluid in patients with anuric end-stage renal disease. The optimal ultrafiltration (UF) volume in patients on peritoneal dialysis (PD) remains controversial. METHODS We retrospectively analysed a cohort of 86 prevalent anuric PD patients followed up for a median of 25.3 months (range, 6 to 54 months). Clinical and PD parameters were recorded yearly. Kaplan-Meier analysis and Cox proportional hazards models were used to identify risk factors of mortality and technique failure in patients with a UF >/=1 L/24 h or <1 L/24 h. RESULTS When compared to those with a UF <1 L/24 h, patients with a UF >/=1 L/24 h had significantly higher haemoglobin levels (101.9 +/- 20.5 vs 89.3 +/- 20.2 g/L, P < 0.05) and tended to be younger (55.0 +/- 12.5 vs 60.6 +/- 16.1 years, P = 0.10). Also, while Kt/V and CCr were stable over time, UF decreased significantly over the study period (baseline, 1205.5 +/- 327.3 ml/24 h vs after 3 years, 870.6 +/- 439.8 ml/24 h; P < 0.001). Using Kaplan-Meier analysis, patients with baseline UF <1 L/24 h had significantly worse outcome (survival, 27.2 +/- 3.9 vs 42.4 +/- 1.9 months; P < 0.001). In multivariate Cox regression analysis, age, time-dependent UF volume and serum albumin were independent predictors of mortality, while UF independently predicted technique failure. CONCLUSIONS The present study demonstrates a strong predictive value of daily peritoneal UF for both technique and patient survival in prevalent anuric PD patients. Identifying markers of satisfactory fluid status, as well as optimizing therapy to meet UF goals, remains an important clinical target.

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.