Galectin-3 pharmacological inhibition attenuates early renal damage in spontaneously hypertensive rats.

BACKGROUND: The pharmacological blockade of galectin-3 (Gal-3), a ß-galactoside-binding lectin, reduces renal impairment in acute kidney injury, hyperaldosteronism or nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in renal damage in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Gal-3 inhibition did not modify blood pressure levels in 30-week-old SHR. Kidney weight was higher in SHR, with no effect of MCP treatment (100 mg/kg/day in the drinking water). Plasma creatinine and albuminuria were slightly but significantly increased in SHR and reduced by MCP, as well as plasma and urinary neutrophil gelatinase-associated lipocalin. In kidney from SHR, Gal-3 was upregulated, as well as the fibrotic markers (collagen type I, TGF-ß and connective tissue growth factor) and tubulointerstitial fibrosis. MCP treatment reduced Gal-3 levels and fibrosis. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, α-smooth muscle actin and ß-catenin) were modified in SHR and normalized by Gal-3 inhibition. The inflammatory mediators (monocyte chemoattractant protein-1, osteopontin, cd68, cd80, cd44 and cd45) were elevated in SHR and attenuated by MCP. Renal damage markers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were augmented in SHR and improved by MCP. In renal epithelial normal rat kidney-52E cells, Gal-3 treatment induced EMT markers, whereas Gal-3 silencing attenuated EMT. CONCLUSION: Gal-3 inhibition attenuated early renal damage in SHR as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, EMT and inflammation, independently of blood pressure levels. These data suggest that Gal-3 could be a potential therapeutic candidate for the prevention of early renal alterations in hypertension.

Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double-blinded, placebo-controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24-48 h before the initiation of cisplatin infusion and continuing to the end of three 21-day cisplatin-containing chemotherapy courses on cisplatin-induced renal electrolytes wasting and kidney function were assessed. Cisplatin-associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase-associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin-induced urine electrolyte wasting or renal function impairment.

Preliminary study of Huai Qi Huang granules delay the development of primary glomerular diseases in human.

OBJECTIVE: To evaluate the effects of Huai Qi Huang (HQH) granules on primary glomerulonephritis patients, and to discuss its possible mechanisms. METHOD: Sixteen patients diagnosed with primary glomerular disease between December 2011 and December 2012 were enrolled. Their blood and urine samples were collected at day 0 (the baseline levels), 30, and 90 of receiving HQH granules orally. Levels of creatinine and cystatin C (Cys-C) in serum and urine, and total protein and albumin in urine were measured by automatic biochemical analyzer. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine was tested by ELISA; serum malondialdehyde (MDA) was measured by thiobarbituric acid method, the erythrocyte count in urine was calculated under light microscope. RESULTS: Serum levels of creatinine, MDA, Cys-C and NGAL at day 30 and 90 were significantly lower than the baseline levels. Urinary levels of Cys-C, NGAL, total protein, albumin and erythrocyte counts were also decreased; level of estimated glomerular filtration (eGFR) was increased. CONCLUSION: HQH granules have certain effect on delaying the development of primary glomerular disease with mild proteinuria and hematuresis in patients. This study may supply a new treatment for primary glomerular diseases.

Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs.

As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-ß-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The results showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs=1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species.

Effects of Schizolobium parahyba extract on experimental Bothrops venom-induced acute kidney injury.

BACKGROUND: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. METHODOLOGY: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). PRINCIPAL FINDINGS: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. CONCLUSION: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.

Role of dongchongxiacao (Cordyceps) in prevention of contrast-induced nephropathy in patients with stable angina pectoris.

OBJECTIVE: To study the preventative effects of Dongchongxiacao (Cordyceps) on contrast-induced nephropathy (CIN) in patients with stable angina pectoris (SAP). METHODS: One-hundred and three SAP inpatients were divided randomly into two groups: basic treatment (n = 51) and Dongchongxiacao (Cordyceps) treatment (n = 52); corbrin capsules (3 g; t.d.s.) were used 3 days before angioplasty and 3 days after angioplasty). Serum creatinine (Scr) was assessed at the time of hospital admission and 1, 2, and 3 days after angioplasty. Values of kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin (IL) 18 in the kidney were detected before angioplasty and 1 day after angioplasty in the patients of both groups. The prevalence of CIN between the two groups was then compared. RESULTS: CIN occurred in 9 of 103 patients (8.74%). The prevalence of CIN in the Dongchongxiacao (Cordyceps) treatment group was lower than that of the basic treatment group (5.77% vs 11.76%) but the difference was not significant (P > 0.05). The post-procedure mean peak of Scr, post-procedure increase in Scr levels from baseline, and urine levels of KIM-1, NGAL and IL18 after the procedure in the Dongchongxiacao (Cordyceps) treatment group were significantly lower than those in the basic treatment group (P < 0.05). CONCLUSION: Prophylactic treatment with Dongchongxiacao (Cordyceps) in SAP patients who undergo coronary angiography or coronary intervention could prevent contrast-induced renal impairment.

Clinical metabolomics and urinary NGAL for the early prediction of chronic kidney disease in healthy adults born ELBW.

BACKGROUND: Clinical metabolomics is a recent "omic" technology which is defined as a global holistic overview of the personal metabolic status (fingerprinting). This technique allows to prove metabolic differences in different groups of people with the opportunity to explore interactions such as genotype-phenotype and genotype-environment type, whether normal or pathological. AIM: To study chronic kidney injury 1) using urine metabolomic profiles of young adults born extremely low-birth weight (ELBW) and 2) correlating a biomarker of kidney injury, urinary neutrophil gelatinase-associated lipocalin (NGAL), in order to confirm the metabolomic injury profile. METHOD: Urine samples were collected from a group of 18 people (mean: 24-year-old, std: 4.27) who were born with ELBW and a group of 13 who were born at term appropriate for gestational age (AGA) as control (mean 25-year-old, std: 5.15). Urine samples were analyzed by (1)H-nuclear magnetic resonance spectroscopy, and then submitted to unsupervised and supervised multivariate analysis. Urine NGAL (uNGAL) was measured using ARCHITECT (ABBOTT diagnostic NGAL kit). RESULTS: With a multivariate approach and using a supervised analysis method, PLS-DA, (partial least squares discriminant analysis) we could correlate ELBW metabolic profiles with uNGAL concentration. Conversely, uNGAL could not be correlated to AGA. CONCLUSIONS: This study demonstrates the relevance of the metabolomic technique as a predictive tool of the metabolic status of exELBW. This was confirmed by the use of uNGAL as a biomarker which may predict a subclinical pathological process in the kidney such as chronic kidney disease.

Urinary neutrophil gelatinase-associated lipocalin: A potential biomarker for predicting rapid progression of drug-induced chronic tubulointerstitial nephritis.

INTRODUCTION: The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in drug-induced chronic tubulointerstitial nephritis (D-CTIN) has not been well described. METHODS: A total of 36 patients with D-CTIN were enrolled in the study. The baseline urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL), alpha1-microglobin (alpha1-MG), albumin (mAlb) and total protein were measured, and estimated glomerular filtration rate change rates within a period of 6 to 33 (mean: 24 months) follow-up months were recorded. RESULTS: Areas under the receiver-operator characteristic curve of urinary NGAL, alpha1-MG, mAlb and total protein for predicting deterioration of estimated glomerular filtration rate were 0.707, 0.631, 0.685 and 0.678, respectively. The cutoff points that maximized the combined sensitivity and specificity for NGAL, alpha1-MG, mAlb and total protein were 37.71 ng/mL, 33.20 microg/mL, 6.91 mg/L and 60.00 mg/L, respectively. At these thresholds, the sensitivity and specificity was 64.7% and 78.9% for NGAL, 66.7% and 50.0% for alpha1-MG, 80.0% and 50.0% for mAlb and 70.6% and 63.2% for total protein, respectively. The median renal survival time (years) of patients with urinary NGAL level exceeding 37.705 ng/mL was shorter than that of patients with urinary NGAL level below 37.705 ng/mL (1.59 +/- 0.79 versus 2.09 +/- 0.63, P = 0.040, chi(2) = 4.218). CONCLUSIONS: Increase of baseline urinary NGAL was better than alpha1-MG, mAlb and total protein in predicting renal function deterioration in patients with D-CTIN. This noninvasive approach has potential to serve as a practical tool in D-CTIN prognosis.

Evaluation of the ARCHITECT urine NGAL assay: assay performance, specimen handling requirements and biological variability.

OBJECTIVES: NGAL (Neutrophil Gelatinase-Associated Lipocalin) has emerged as a new biomarker for the identification of acute kidney injury. Reliable clinical evaluations require a simple, robust test method for NGAL, and knowledge of specimen handling and specimen stability characteristics. We evaluated the performance of a new urine NGAL assay on the ARCHITECT analyzer. METHODS: Assay performance characteristics were evaluated using standard protocols. Urine specimen storage requirements were determined and biological variability was assessed in a self-declared apparently healthy population. RESULTS: Assay performance data showed good precision, sensitivity and lot-to-lot reproducibility. There was good short term 2-8 degrees C sample stability, however, long term storage samples must be kept at -70 degrees C or colder. The largest variance component in a biological variance study was within-day. CONCLUSIONS: The ARCHITECT NGAL assay proved to be a precise and reproducible assay for the determination of urine NGAL.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.

Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-D-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.