Soluble urokinase plasminogen activator receptor is associated with cardiovascular calcification in peritoneal dialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is an important cause of morbidity and mortality in peritoneal dialysis (PD) patients. Cardiovascular calcification (CVC) is highly prevalent in PD patients and could predict their cardiovascular mortality. Soluble urokinase plasminogen activator receptor (suPAR) is closely associated with coronary artery calcification in hemodialysis patients and is an important predictor of CVD. However, the role of suPAR in PD patients is poorly understood. We investigated the relationship between serum suPAR and CVC in PD patients. METHODS: Abdominal aortic calcification (AAC) was assessed by lateral lumbar radiography, coronary artery calcification (CAC) by multi-slice computed tomography, and cardiac valvular calcification (ValvC) by echocardiography. CVC was defined as confirmed presence of calcification in one site (AAC, CAC, or ValvC). Patients were divided into CVC group and non-CVC group. Demographic characteristics, biochemical variables, comorbidities, PD regimen, serum suPAR, and medication were compared between the two groups. Logistic regression was conducted to determine association between serum suPAR and presence of CVC. The receiver-operator curve (ROC) was plotted to calculate the area under the curve (AUC) for suPAR to identify CVC and ValvC. RESULTS: Of 226 PD patients, 111 (49.1%) had AAC, 155 (68.6%) had CAC, and 26 (11.5%) had ValvC. There were significant differences in age, BMI, diabetes, white blood cell, phosphorus, hs-CRP, suPAR, time on dialysis, total volume of dialysate, ultrafiltration, volume of urine, and Kt/V between CVC and non-CVC group. Serum suPAR was associated with CVC by multivariate logistic regression analysis in PD patients, especially in elderly patients. The levels of serum suPAR were closely related to the degree of AAC, CAC, and ValvC in PD patients. The incidence of CVC was higher in patients with higher levels of suPAR. The ROC curve showed that serum suPAR had a predictive value for CVC (AUC = 0.651), especially for ValvC (AUC = 0.828). CONCLUSION: Cardiovascular calcification is prevalent in PD patients. High levels of serum suPAR are associated with cardiovascular calcification in PD patients, especially in elderly patients.

PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells.

BACKGROUND: Cisplatin-induced injury of renal proximal tubular cells results basically from increased apoptosis via mitochondrial damage, and is mitigated by appropriate enhancement of autophagy. Peroxisome proliferator-activated receptor-delta (PPAR-δ) reportedly protects against not only mitochondrial damages but also enhances autophagy. Thus, PPAR-δ may protect against cisplatin-induced kidney injury. METHODS: We examined the protective effects of PPAR-δ activation on cisplatin-induced cellular injury and their detailed mechanisms in a murine renal proximal tubular (mProx) cell line using GW0742, an authentic PPAR-δ activator. Cisplatin-induced cell damages were evaluated by TUNEL assay and immunoblot analyses for p53, 14-3-3, Bax, Bcl2, cytochrome C, and activated caspases. Autophagy status was examined by immunoblot analyses for p62 and LC3. RESULTS: GW0742 suppressed cisplatin-induced apoptosis of mProx cells by reducing the activation of caspase-3 via attenuating the phosphorylation of p53 and 14-3-3, mitochondrial Bax accumulation, cytochrome C release from mitochondria to the cytosol and ensuing cytosolic caspase-9 activation. In contrast, GW0742 did not diminish cisplatin-enhanced activation of caspases-8 or -12 as extrinsic or endothelium reticulum apoptotic pathways, respectively. The inhibitory effect of GW0742 on cisplatin-induced caspase-3 activation was significantly diminished by silencing of the PPAR-δ gene expression. GW0742 itself had no influence on starvation-stimulated or cisplatin-induced autophagy in mProx cells, suggesting that the protective effects were not mediated by autophagy modification. CONCLUSION: Our results indicate that GW0742 may serve as a candidate agent to mitigate cisplatin nephrotoxicity via inhibiting the mitochondrial apoptotic pathway considerably depending on PPAR-δ, without modulating autophagy.

Implications of the changes in serum neutrophil gelatinase-associated lipocalin and cystatin C in patients with chronic kidney disease.

AIM: Early intervention in patients with chronic kidney disease (CKD) significantly improves the prognosis. The present widely used markers of renal function, such as serum creatinine (sCr), fail to reflect early renal damage and predict the progression of disease. The authors aimed to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL), a novel specific biomarker of acute kidney injury, could predict the progression of CKD. METHODS: We identified 92 patients with stage 2-4 CKD caused by primary chronic glomerulonephritis. The patients were followed for 2 years, the changes in NGAL levels in the progressive and non-progressive groups were compared. RESULTS: First, the serum NGAL levels of patients with stage 2-4 CKD were significantly increased compared with the control group. Second, based on Pearson correlation analysis, positive correlations existed between NGAL and cystatin C levels and between NGAL and sCr levels. Third, bounded by the progress of renal function, the area under the curve of serum NGAL was 0.872 (95% confidence interval, 0.786-0.933), which suggests a blood NGAL cut-off level of 246 ng/mL (sensitivity 85.19%, specificity 81.54%). Fourth, Kaplan-Meier survival curve analysis showed that the serum NGAL level was closely related to the end-point of renal function in patients with CKD. Fifth, Cox multivariate regression analysis showed that the estimated glomerular filtration rate and blood NGAL are associated with progression of CKD. CONCLUSION: Serum NGAL is an effective biomarker for detecting early-stage renal damage in CKD patients. Serum NGAL was significantly correlated with the severity of renal damage and the progression of renal function deterioration.