Shan Mou

Diagnostic Value of Urinary Kidney Injury Molecule 1 for Acute Kidney Injury: A Meta-Analysis

Background Urinary Kidney Injury Molecule 1 (KIM-1) is a proximal tubular injury biomarker for early detection of acute kidney injury (AKI), with variable performance characteristics depending on clinical and population settings. Methods Meta-analysis was performed to assess the diagnostic value of urinary KIM-1 in AKI. Relevant studies were searched from MEDLINE, EMBASE, Pubmed, Elsevier Science Direct, Scopus, Web of Science, Google Scholar and Cochrane Library. Meta-analysis methods were used to pool sensitivity and specificity and to construct summary receiver operating characteristic (SROC) curves. Results A total of 2979 patients from 11 eligible studies were enrolled in the analysis. Five prospective cohorts, two cross-sectional and four case-control studies were identified for meta-analysis. The estimated sensitivity of urinary KIM-1 for the diagnosis of AKI was 74.0% (95% CI, 61.0%–84.0%), and specificity was 86.0% (95% CI, 74.0%–93.0%). The SROC analysis showed an area under the curve of 0.86(0.83–0.89). Subgroup analysis suggested that population settings and detection time were the key factors affecting the efficiency of KIM-1 for AKI diagnosis. Limitation Various population settings, different definition of AKI and Serum creatinine level used as the standard might have influence on AKI diagnosis. The relatively small number of studies and heterogeneity between them also affected the evaluation. Conclusion Urinary KIM-1 may be a promising biomarker for early detection of AKI with considerable predictive value, especially for cardiac surgery patients, and its potential value needs to be validated in large studies and across a broader scope of clinical settings.

Prevalence of non-diabetic renal disease in patients with type 2 diabetes

It is important to differentiate proteinuria from non-diabetic renal diseases (NDRD) or diabetic nephropathy in diabetic patients. The purpose of our study was to evaluate the prevalence of NDRD. A retrospective analysis was performed on diabetic patients who had undergone renal biopsy during a 6-year period. Our study revealed a high prevalence of NDRD in the diabetic population. Sixty-nine patients were investigated, 52.2% were diagnosed as NDRD and 47.8% as DN. Focal segmental glomerulosclerosis was the most common lesion found in patients with NDRD. We found a relationship between DN and fasting blood glucose level, systolic blood pressure, diastolic blood pressure, LVMI, intima-media thickening (IMT), and the presence of carotid plaques. Patients with NDRD had a lower incidence of diabetic retinopathy (DR). The absence of DR to differentiate NDRD had a sensitivity of 72.7%, a specificity 91.7%, and an ROC=0.822. Fasting blood glucose level had a sensitivity and specificity of 93.9% and 75%, respectively. Similarly, the use of IMT had sensitivity and specificity of 90% and 75.8%, respectively. In this study, we determined that the absence of DR, a lower fasting blood glucose level, and IMT is useful in differentiating NDRD from DN in diabetic patients with overt proteinuria.

Circulating levels of asymmetric dimethylarginine are an independent risk factor for left ventricular hypertrophy and predict cardiovascular events in pre-dialysis patients with chronic kidney disease.

BACKGROUND Several studies have related the circulating level of asymmetric dimethylarginine (ADMA) to cardiac remodeling and cardiovascular (CV) events in end-stage renal disease (ESRD) patients. Studies investigating this relationship in patients with pre-dialysis chronic kidney disease (CKD) are lacking. METHODS We enrolled 76 CKD patients (age, 46.7+/-14.3 years, 39 females) and 15 controls (age, 40.1+/-18.5 years, 6 females). Clinical parameters, blood biochemistry and echocardiographic findings were recorded, and plasma ADMA concentrations measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Patients were prospectively followed up for a median of 15 (range, 6-24) months. RESULTS Plasma ADMA was significantly elevated in CKD patients compared with controls (41.56+/-12.76 microg/mL vs 17.12+/-7.09 microg/mL, P<0.001), and correlated with the left ventricular mass index (LVMI) (r=0.597, P<0.001). During follow-up, 25 patients experienced new CV events and their plasma ADMA level was significantly elevated (48.27+/-13.70 vs 34.91+/-6.38 in CV event-free patients, P<0.001). Cox regression analysis further confirmed that ADMA was an independent risk factor for CVD (HR=1.175, 95%CI[1.070-1.290], P=0.001). CONCLUSION Similar to findings in ESRD patients, elevated circulating levels of ADMA may increase the risk of LVH and CV events in pre-dialysis CKD patients.

Astragaloside IV Ameliorates Renal Fibrosis via the Inhibition of Mitogen-Activated Protein Kinases and Antiapoptosis In Vivo and In Vitro

Apoptosis of renal tubular cells plays a crucial role in renal fibrosis. Astragaloside IV (AS-IV), a compound extracted from Radix Astragali, has been shown to inhibit renal tubular cell apoptosis induced by high glucose, but its role in preventing chronic renal fibrosis as well as the underlying molecular mechanisms involved still remain obscure. In this study, human kidney tubular epithelial cells induced by transforming growth factor-β1 (TGF-β1) were used to investigate the protective role of AS-IV in antifibrosis. As an in vivo model, mice subjected to unilateral ureteral obstruction (UUO) were administered AS-IV (20 mg/kg) by intraperitoneal injection for 7 days. AS-IV significantly alleviated renal mass loss and reduced the expression of α-smooth muscle actin, fibronectin, and collagen IV both in vitro and in vivo, suggesting that this compound functions in the inhibition of renal tubulointerstitial fibrosis. Furthermore, transferase-mediated dUTP nick-end labeling assay results both in vivo and in vitro showed that AS-IV significantly attenuated both UUO and TGF-β1–induced cell apoptosis and prevented renal tubular epithelial cell injury in a dose-dependent manner. Western blotting results also revealed that the antiapoptotic effect of AS-IV was reflected in the inhibition of caspase-3 activation, which might be mediated primarily by the downregulation of mitogen-activated protein kinase effectors phospho-p38 and phospho–c-Jun N-terminal kinase. These data infer that AS-IV effectively attenuates the progression of renal fibrosis after UUO injury and may have a promising clinical role as a potential antifibrosis treatment in patients with chronic kidney disease.

HEPATOCYTE GROWTH FACTOR SUPPRESSES TRANSFORMING GROWTH FACTOR-BETA-1 AND TYPE III COLLAGEN IN HUMAN PRIMARY RENAL FIBROBLASTS

Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor‐beta‐1 (TGF‐β1) is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF) has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF‐β1‐mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c‐Met) and TGF‐β1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF‐β1 expression were studied by RT‐PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high‐glucose condition, the expression of HGF and c‐Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF‐β1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose‐dependently inhibited TGF‐β1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF‐β1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF‐β1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.

Up-regulation of Serum MiR-130b-3p Level is Associated with Renal Damage in Early Lupus Nephritis

Systemic lupus erythematosus (SLE) is a common but severe autoimmune systemic inflammatory disease. Lupus nephritis (LN) is a serious complication of SLE,affecting up to 70% of SLE patients. Circulating microRNAs (miRNA) are emerging as biomarkers for pathological conditions and play significant roles in intercellular communication. In present research, serum samples from healthy control, early and late stage LN patients were used to analyze the expression profile of miRNAs by microarray. Subsequent study demonstrated that miR-130b-3p in serum of patients with early stage LN were significantly up-regulated when compared with healthy controls. In addition,we have also observed that the expression of a large amount of circulating microRNAs significantly decreased in patients with late stage LN. The further analysis found that the expression of serum miR-130b-3p was positively correlated with 24-hour proteinuria and renal chronicity index in patients with early stage LN.Transfection of renal tubular cellline(HK-2)with miR-130b-3p mimics can promote epithelial-mesenchymal transition (EMT). The opposite effects were observed when transfected with miR-130b-3p inhibitors. MiR-130b-3p negatively regulated ERBB2IP expression by directly targeting the 3′-UTR of ERBB2IP The circulating miR-130b-3p might serve as a biomarker and play an important role in renal damage in early stage LN patients.

L-FABP: A novel biomarker of kidney disease

Human liver-type fatty acid-binding protein (hL-FABP), which is found in both the normal and the diseased human kidney, has been observed to bind free fatty acids. Recently, the predictive and prognostic value of L-FABP in kidney diseases has attracted considerable attention. Numerous studies have demonstrated that L-FABP is a promising biomarker of several kidney diseases, and it has also been shown to attenuate renal injury. We performed a literature review regarding the ability of L-FABP to identify patients at risk of developing kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD) and to protect the kidneys in the course of kidney disease.

Urinary excretion of liver-type fatty acid-binding protein as a marker of progressive kidney function deterioration in patients with chronic glomerulonephritis.

BACKGROUND To evaluate the value of basal urinary L-FABP (uL-FABP) excretion as a prognostic indicator of the progression of kidney function impairment in patients with chronic glomerulonephritis (CGN). METHODS One hundred twenty-three patients with newly diagnosed, biopsy-proven primary CGN were included. In all patients, and in 28 healthy subjects, uL-FABP was measured using an ELISA. Risk factors of the progression of kidney function were evaluated. The patients were in follow-up for at least 5 years. RESULTS uL-FABP in the patients with CGN (76.58±17.3 μg/g.cr) was greater than in the healthy subjects. A significant positive correlation between uL-FABP and proteinuria (R=0.501, P<0.01), serum creatinine (R=0.601, P<0.01) were found. Kaplan-Meier analysis revealed that uL-FABP >76.58 μg/g.cr predicts progression of renal function. The cut off values for L-FABP at 119.8 μg/g.cr was found to be more sensitive, area under the curve (AUC) was 0.95. CONCLUSION Urinary L-FABP may be a useful clinical biomarker for monitoring chronic glomerular disease. Urinary L-FABP can help predict the progression of chronic glomerular disease.

Serum IL-18 Is Closely Associated with Renal Tubulointerstitial Injury and Predicts Renal Prognosis in IgA Nephropathy

Background. IgA nephropathy (IgAN) was thought to be benign but recently found it slowly progresses and leads to ESRD eventually. The aim of this research is to investigate the value of serum IL-18 level, a sensitive biomarker for proximal tubule injury, for assessing the histopathological severity and disease progression in IgAN. Methods. Serum IL-18 levels in 76 IgAN patients and 36 healthy blood donors were measured by ELISA. We evaluated percentage of global and segmental sclerosis (GSS) and extent of tubulointerstitial damage (TID). The correlations between serum IL-18 levels with clinical, histopathological features and renal prognosis were evaluated. Results. The patients were 38.85 ± 10.95 years old, presented with 2.61 (1.43∼4.08) g/day proteinuria. Serum IL-18 levels were significantly elevated in IgAN patients. Baseline serum IL-18 levels were significantly correlated with urinary protein excretion (r = 0.494, P = 0.002), Scr (r = 0.61, P < 0.001), and eGFR (r = −0.598, P < 0.001). TID scores showed a borderline significance with serum IL-18 levels (r = 0.355, P = 0.05). During follow-up, 26 patients (34.21%) had a declined renal function. Kaplan-Meier analysis found those patients with elevated IL-18 had a significant poor renal outcome (P = 0.03), and Cox analysis further confirmed that serum IL-18 levels were an independent predictor of renal prognosis (β = 1.98, P = 0.003).

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.