Serum Renal Biomarkers Research Articles

The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK.

Diclofenac sodium (DIC) is a widely used non-steroidal anti-inflammatory drug. Unfortunately, its prolonged use is associated with nephrotoxicity due to oxidative stress, inflammation, and fibrosis. We aimed to investigate the nephroprotective effects of vitamin B complex (B1, B6, B12) against DIC-induced nephrotoxicity and its impact on NOX4/RhoA/ROCK, a pathway that plays a vital role in renal pathophysiology. Thirty-two Wistar rats were divided into four groups: (1) normal control; (2) vitamin B complex (16 mg/kg B1, 16 mg/kg B6, 0.16 mg/kg B12, intraperitoneal); (3) DIC (10 mg/kg, intramuscular); and (4) DIC plus vitamin B complex group. After 14 days, the following were assayed: serum renal biomarkers (creatinine, blood urea nitrogen, kidney injury molecule-1), oxidative stress, inflammatory (tumor necrosis factor-α, interleukin-6), and fibrotic (transforming growth factor-β) markers as well as the protein levels of NOX4, RhoA, and ROCK. Structural changes, inflammatory cell infiltration, and fibrosis were detected using hematoxylin and eosin and Masson trichrome stains. Compared to DIC, vitamin B complex significantly decreased the renal function biomarkers, markers of oxidative stress and inflammation, and fibrotic cytokines. Glomerular and tubular damage, inflammatory infiltration, and excessive collagen accumulation were also reduced. Protein levels of NOX4, RhoA, and ROCK were significantly elevated by DIC, and this elevation was ameliorated by vitamin B complex. In conclusion, vitamin B complex administration could be a renoprotective approach during treatment with DIC via, at least in part, suppressing the NOX4/RhoA/ROCK pathway.

Weaning from Kidney Replacement Therapy in the Critically Ill Patient with Acute Kidney Injury.

Around 10% of critically ill patients suffer acute kidney injury (AKI) requiring kidney replacement therapy (KRT), with a mortality rate approaching 50%. Although most survivors achieve sufficient renal recovery to be weaned from KRT, there are no recognized guidelines on the optimal period for weaning from KRT. A systematic review was conducted using a peer-reviewed strategy, combining themes of KRT (intermittent hemodialysis, CKRT: continuous veno-venous hemo/dialysis/filtration/diafiltration, sustained low-efficiency dialysis/filtration), factors predictive of successful weaning (defined as a prolonged period without new KRT) and patient outcomes. Our research resulted in studies, all observational, describing clinical and biological parameters predictive of successful weaning from KRT. Urine output prior to KRT cessation is the most studied variable and the most widely used in practice. Other predictive factors, such as urinary urea and creatinine and new urinary and serum renal biomarkers, including cystatin C and neutrophil gelatinase-associated lipocalin (NGAL), were also analyzed in the light of recent studies. This review presents the rationale for early weaning from KRT, the parameters that can guide it, and its practical modalities. Once the patient's clinical condition has stabilized and volume status optimized, a diuresis greater than 500 mL/day should prompt the intensivist to consider weaning. Urinary parameters could be useful in predicting weaning success but have yet to be validated.

The protective impact of glutamine on anti-tuberculosis drug-induced nephrotoxicity in Wistar rats

This study assessed the protective effect of glutamine (GTN) against rifampicin/isoniazid/pyrazinamide/ethambutol (RIPE)-induced nephrotoxicity in rats. Thirty adult Wistar rats (200±20 g) of both sexes were grouped into 6 of 5 rats/group. The rats were treated daily for 30 days as follows: Group 1 (Vehicle control [normal saline 0.2mL]), group 2 (GTN 200 mg/kg), group 3 (RIPE 150, 75, 400 and 275 mg/kg in vehicle), group 4 (GTN 50 mg/kg +RIPE), group 5 (GTN 100 mg/kg +RIPE) and group 6 (GTN 200 mg/kg +RIPE). After treatment, blood samples were obtained and assessed for serum renal biomarkers. Kidneys were harvested, weighed and assessed for oxidative stress markers and histology. RIPE significantly (p<0.01) decreased body weight and significantly (p<0.01) increased kidney weight when compared to the control. Serum urea, creatinine, uric acid levels and kidney malondialdehyde levels were significantly (p<0.001) increased in RIPE-treated rats when compared to the control. Serum total protein, albumin, kidney glutathione, catalase, superoxide dismutase and glutathione peroxidase levels were significantly decreased (p<0.001) in RIPE-treated rats when compared to the control. RIPE caused tubular necrosis and collapsed glomeruli in the kidneys of rats. However, body and liver weights were significantly restored in GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05 and p<0.01, respectively when compared to RIPE. Serum and kidney oxidative stress markers were restored in GTN 50 mg/kg +RIPE, GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05, p<0.01 and p<0.001 respectively, when compared to RIPE. GTN restored kidney histology. GTN protects against RIPE-induced nephrotoxicity in a dose-related fashion.

Quercetin-loaded F127 nanomicelles: Antioxidant activity and protection against renal injury induced by gentamicin in rats

Quercetin (Q) is formulated into oil-in-water F127 microemulsions to improve its bioavailability. The size of the Q-loaded microemulsions system was about 8 nm by dynamic light scattering analysis. To compare antioxidant activity of bulk solution and microemulsion of Q, free radical scavenging activity was evaluated against 2,2-diphenyl-1-picrylhydrazyl (DPPH). The IC50 values were 56.77 and 187.68 μM, respectively. The drug in the bulk form released 16.34 times faster than microemulsion form. Although gentamicin (GM) has potent efficacy against gram-negative bacteria, it induces renal toxicity. Poor solubility and low bioavailability of Q as a bioflavonoid with potent antioxidant activity, limit its therapeutic application. We aimed to compare the effect of free Q and nanoencapsulated (NEQ) against GM-induced renal damage in Wistar rats. Forty-two animals were divided into six groups. Control and GM groups received apo-nanomicelles and GM (100 mg/kg) for 10 days. Two groups received Q (50 mg/kg, i.g.) and NEQ (50 mg/kg, i.g.) respectively for 10 days. Remaining two groups received Q and NEQ (50 mg/kg, i.g.) plus GM (100 mg/kg, i.p.) simultaneously for 10 days. After the experiments, serum and kidneys were used for biochemical, molecular and histological examinations. Immunohistochemical analysis was performed to explore kidney injury molecule-1 (KIM-1) expression as a specific protein biomarker of renal injury. Our findings indicated oxidative stress and altered histological features in renal tissue with deviated serum renal biomarkers in GM-treated rats. Although Q treatment in GM group tried to protect against GM-induced nephrotoxicity, but there were still differences compared to control rats. However, NEQ administration corrected elevations in the levels of urea, creatinine, uric acid and decrements in serum total proteins of GM group. Meanwhile, NEQ restored renal oxidative injury in GM rats through attenuation of lipid peroxidation and enhancement of antioxidant defense systems, glutathione, catalase and superoxide dismutase. NEQ could also normalize GM-induced abnormal renal histology features including fibrosis. Furthermore, the result of immunohistochemistry study confirmed these findings by undetecting KIM-1 expression in NEQ treated GM group, meanwhile showing this renal biomarker in GM and Q treated GM groups. Therefore, NEQ seems to be useful in protecting against renal oxidative stress and kidney damage in a rat model of GM nephrotoxicity which deserve further evaluations.

Effect of antioxidant-rich propolis and bee pollen extracts against D-glucose induced type 2 diabetes in rats

The present study was designed to investigate the preventive effect of propolis, bee pollen and their combination on Type 2 diabetes induced by D-glucose in rats. The study was carried out by feeding daily two concentrations (100 and 200 mg/Kg BW) of propolis or bee pollen (or their combination to normal (non-diabetic) and diabetic rats for a period of 16 weeks. In vivo biochemical changes associated to diabetes are induced by drinking a solution containing 10% of D-glucose (diabetic rats). The in vitro antioxidant activity was also evaluated and the chemical composition of propolis and bee pollen extracts was determined by UHPLC-DAD. Phytochemical composition of propolis and bee pollen revealed the presence of several natural antioxidants, such as hydroxycinnamic acids, hydroxybenzoic acids, flavonoids, flavan-3-ols and stilbens. The major antioxidant compound present in propolis was Naringin (290.19 ± 0.2 mg/Kg) and in bee pollen was apigenin (162.85 ± 17.7 mg/Kg). These results have been related with a high antioxidant activity, more intense in propolis extract. In rats, the administration of D-glucose had induced hyperglycemia (13.2 ± 0.82 mmol/L), increased plasmatic insulin levels (25.10 ± 2.12 U/L) and HOMA-IR index (14.72 ± 0.85) accompanied with dyslipidemia, elevation of hepatic enzyme levels, and a change in both serum renal biomarkers and plasmatic calcium. The co-administration of propolis and bee pollen extracts alone or in combination restored these biochemical parameters and attenuated the deleterious effects of D-glucose on liver and kidney functions. Furthermore, these effects were better attenuated in the combined therapy-prevented diabetic rats. Hence, it is possible to conclude that propolis and bee pollen can be used as a preventive natural product against diabetes induced dyslipidemia and hepato-renal damage.

First-year profile of biomarkers for early detection of renal injury in infants with congenital urinary tract obstruction.

Diagnosis of renal function impairment and deterioration in congenital urinary tract obstruction (UTO) continues to be extremely challenging. Use of renal biomarkers in this setting may favor early renal injury detection, allowing for a reliable choice of optimal therapeutic options and prevention or minimization of definitive renal damage. This longitudinal, prospective study analyzed the first-year profile of two serum renal biomarkers: creatinine (sCr) and cystatin C (sCyC); and six urinary renal biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), transforming growth factor beta-1 (TGF-β1), retinol-binding protein (RBP), cystatin C (uCyC), and microalbuminuria (μALB) in a cohort of 37 infants with UTO divided into three subgroups: 14/37 with unilateral hydro(uretero)nephrosis, 13/37 with bilateral hydro(uretero)nephrosis, and 10/37 patients with lower urinary tract obstruction (LUTO), compared with 24 healthy infants matched by gestational age and birth weight. All urine biomarkers showed significantly higher values at the first month of life (p ≤ 0.009), while NGAL (p = 0.005), TGF-ß1 (p < 0.001), and μALB (p < 0.001) were high since birth compared to controls. Best single biomarker performances were RBP in bilateral hydronephrosis and LUTO subgroups and KIM-1 in unilateral hydronephrosis subgroup. Best biomarker combination results for all subgroups were obtained by matching RBP with TGF-ß1 or KIM-1 and NGAL with CyC ([AUC] ≤ 0.934; sensitivity ≤ 92.4%; specificity ≤ 92.8%). RBP, NGAL, KIM-1, TGF-ß1, and CyC, alone and especially in combination, are relatively efficient in identifying surgically amenable congenital UTO and could be of practical use in indicating on-time surgery.

Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection

IntroductionSerum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. ObjectiveTo determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. DesignSecondary analysis of a prospective multicentre observational study. Setting148 Spanish ICUs. PatientsICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60–2.50mg/dL and Cr≥2.51–3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. InterventionsNone. ResultsOut of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60–10.0]ng/mL vs. 0.40 [0.13–1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). ConclusionsAlthough PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection.

Lycium europaeum Linn as a source of polysaccharide with in vitro antioxidant activities and in vivo anti-inflammatory and hepato-nephroprotective potentials

Ethnopharmacological relevanceLycium europaeum Linn. is widely used to treat the burning of the skin and well-known as a medicinal plant having various biological activities. Aims of the studyThe purpose of the present study is to characterize the polysaccharide from L. europaeum L. leaves (LEP) and to explore its antioxidant, anti-inflammatory and hepato-nephroprotective properties. Materials and methodsThe structural and functional characteristics of LEP were investigated using X-ray diffraction techniques (XRD), Scanning Electron Microscopy (SEM), and FT-IR Spectroscopy. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl and hydrogen peroxide scavenging assays. Hepato-renal effects were studied using CCl4 and cisplatin-induced liver and kidney injuries in mice, respectively. Anti-inflammatory activity was assessed on carrageenan-induced paw edema. ResultsThe LEP showed an interesting water-holding capacity and effective foaming and emulsifying properties. XRD analysis suggested that LEP form a semi-crystalline polymer with an amorphous structure. FT-IR profile showed the presence of pyranose ring in LEP. SEM and helix-coil transition analyses indicated that LEP had a lamellar structure with angular edges and didn't present a triple helical conformation in solution. In vitro, LEP indicated significant concentration-dependent antioxidant activity. In vivo, LEP treatment significantly reduced the effects of CCl4 intoxication on serum liver biomarkers (AST, ALT, LDH, and GGT) and the effect of cisplatin on serum renal biomarkers (urea, blood urea nitrogen, creatinine, and uric acid). Meanwhile, LEP diminishes significantly the effect of CCl4 and cisplatin on the level of lipid peroxidation in liver and kidney tissues, respectively. Additionally, the normal histological structure of liver and kidney was restored after treatment with the polysaccharide. LEP possessed a significant anti-inflammatory activity on acute inflammation induced by carrageenan in mice. ConclusionOverall, the findings of this study support the traditional use of L. europaeum L. This plant may also be used as a good agent for protection against inflammatory diseases and hepato-renal injuries in patients with cancer.

Relationship between acute kidney injury and serum procalcitonin (PCT) concentration in critically ill patients with influenza infection

IntroductionSerum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. ObjectiveTo determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. DesignSecondary analysis of a prospective multicentre observational study. Setting148 Spanish ICUs. PatientsICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60–2.50mg/dL and Cr≥2.51–3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. InterventionsNone. ResultsOut of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60–10.0]ng/mL vs. 0.40 [0.13–1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). ConclusionsAlthough PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection.

Lycium europaeum Extract: A New Potential Antioxidant Source against Cisplatin-Induced Liver and Kidney Injuries in Mice.

This study was designed to assess the protective effects of Lycium europaeum methanol extract (LEM) on liver and kidney injuries induced by cisplatin. The phytochemical composition, the antioxidant activity, and hepatorenal injury biomarkers were investigated. Results revealed that LEM exhibited a significant antioxidant activity in vitro on DPPH radical and H2O2 scavenging assays. In the animal studies, treatment with LEM significantly reduced the effects of cisplatin intoxication on serum liver biomarkers and serum renal biomarkers. Meanwhile, LEM diminishes significantly the effect of cisplatin on the level of lipid peroxidation in liver and kidney tissues. The activities of the antioxidant enzymes (reduced glutathione, glutathione peroxidase, superoxide dismutase, and catalase) were increased in groups pretreated with LEM and quercetin. Additionally, the normal histological structures of the liver and kidney were restored after treatment with LEM. This work clearly demonstrated that L. europaeum may be useful as a drug with hepato-nephroprotective potentials.

Phytochemical characterization and bioactivity of Lycium europaeum: A focus on antioxidant, antinociceptive, hepatoprotective and nephroprotective effects

In this study, the antioxidant, antinociceptive, hepatoprotective, nephroprotective properties and the bioactive composition of Lycium europaeum were investigated. Polyphenols and total tannin contents were measured by colorimetric methods The antioxidant activity in vitro was evaluated using the reducing power, 2,2-diphenyl-1-picrylhydrazyl radical and phosphomolybdenum assays. The hepatotoxicity and nephrotoxicity effects were studied using carbon tetrachloride (CCl4)-induced liver and renal injuries in mice. The analgesic activity was explored using the hot-plate and acetic acid tests in mice. Results showed that the methanol fraction of L. europaeum (LEM) had the highest level of total phenolic, total tannin, and flavonoid. HPLC-DAD analysis revealed the presence of twelve compounds among them caffeic acid was the major compound (140.18μg/g of extract). This fraction also showed the best antioxidant activity in vitro in the three used assays.In vivo, in the mice studies, CCl4 administration induced hepatotoxicity and nephrotoxicity by a significant rise in the levels of serum liver biomarkers (gamma glutamyl transferase, lactate dehydrogenase, and aminotransferases) and serum renal biomarkers (urea, creatinine, and uric acid). Similarly, levels of lipid peroxidation (MDA) in both tissues were found increased by CCl4 intoxication. Pretreatment with LEM and quercetin significantly restored the majority of these biological parameters to normal levels, as well as an improvement of histopathological changes. In addition, LEM showed an interesting analgesic activity. LEM decreased significantly the number of writhing induced by acetic acid and prolonged the reaction time in response to thermal stimulus in mice. Therefore, it was speculated that the obtained results highlighted the potential use of L. europaeum as a source of bioactive compounds with pharmacological advantages

Abstract 12845: Renal Biomarkers Predict Long-Term Adverse Events in Patients With Type 2 Diabetes Mellitus and Recent Acute Coronary Syndrome: Insights From the EXAMINE Trial

Introduction: Prediction of cardiovascular (CV) risk in patients with type 2 diabetes mellitus (T2DM) remains incomplete. Measurement of renal biomarkers may facilitate early risk stratification in high-risk patients with T2DM. Methods: We evaluated the prognostic performance of 4 urinary and 1 serum renal biomarkers for major cardiovascular events in 5,380 patients with T2DM and recent acute coronary syndrome (ACS, within 15-90d) enrolled in the EXAMINE trial. Patients requiring dialysis within 14d of screening were excluded. Cystatin C, markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 protein, and indices of urinary protein excretion were measured at randomization (a median of 45 days after ACS). CV events at 24-mo were estimated by the Kaplan-Meier method. Single- and multi-biomarker covariate-adjusted Cox proportional hazards models were created to predict times to events. Results: In EXAMINE, median age was 61y, 68% were male, and median baseline estimated glomerular filtration rate (eGFR) was 71.2 ml/min/1.73 m 2 . During follow-up, 326 (6.1%) patients had died. All renal biomarkers were robustly associated with long-term adverse CV events in graded fashion (P≤0.006 for all trends; Table ). Risk prediction for all 5 renal biomarkers was independent of major covariates including baseline eGFR for all major clinical endpoints ( Table ). However, when simultaneously accounting for all biomarkers, only Cystatin C (standardized) was predictive of all-cause mortality (HR 1.51 [1.30, 1.74]; p≤0.001), heart failure hospitalization (HR 1.20 [0.96, 1.49]; p=0.107), and major CV events (HR 1.28 [1.14, 1.45]; p≤0.001). Conclusions: These data from the EXAMINE trial represent one of the largest experiences to support the prognostic value of multiple novel and traditional renal biomarkers in predicting long-term adverse CV events in high-risk patients with T2DM, beyond baseline eGFR.

Relationship between lean body mass and serum renal biomarkers in healthy dogs.

BackgroundSymmetric dimethylarginine (SDMA) is an accurate and precise biomarker for estimating glomerular filtration rate (GFR) in humans and cats. Serum creatinine (sCr) also correlates with GFR, but has limitations as a biomarker of renal function because nonrenal factors can influence its concentration.HypothesisDifferences in lean body mass (LBM) influence sCr, but not serum SDMA concentrations.AnimalsForty‐one healthy Beagles, mean age 9.9 years (range: 3.1–14.8 years), were studied over a 6 month period.MethodsSerum biomarkers of renal function were measured prospectively at baseline, and 1, 3, and 6 months. SDMA concentrations were measured by liquid chromatography‐mass spectroscopy and sCr concentrations by enzymatic colorimetry. Body composition was determined by dual energy x‐ray absorptiometry.Results LBM (P < .001) and age (P = .006) were significant explanatory variables for sCr concentration (R 2 = 0.38), but not SDMA concentration. Time on food was the only significant explanatory variable for SDMA concentration (R 2 = 0.49). SDMA concentrations decreased across time (P < .001). LBM was affected by sex (males > females; P = .02). Mature adult dogs (<8 years) had greater LBM compared with geriatric dogs (≥8 years; P < .001).Conclusion and Clinical Importance sCr concentrations, but not SDMA concentrations, are influenced by LBM, which limits sCr utility as a biomarker for monitoring renal function in dogs with decreased LBM. Reductions in LBM can lower sCr concentration and overestimate GFR. SDMA concentrations, but not sCr concentrations were influenced by time on food. SDMA could have clinical advantages over sCr in monitoring response to nutritional interventions.