Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review.

Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.

Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension.

In angiotensin II (Ang II)-dependent hypertension, Ang II activates angiotensin II type 1 receptors (AT1R) on renal vascular smooth muscle cells, leading to renal vasoconstriction with eventual glomerular and tubular injury and interstitial inflammation. While afferent arteriolar vasoconstriction is initiated by the increased intrarenal levels of Ang II activating AT1R, the progressive increases in arterial pressure stimulate the paracrine secretion of adenosine triphosphate (ATP), leading to the purinergic P2X receptor (P2XR)-mediated constriction of afferent arterioles. Thus, the afferent arteriolar tone is maintained by two powerful systems eliciting the co-existing activation of P2XR and AT1R. This raises the conundrum of how the AT1R and P2XR can both be responsible for most of the increased renal afferent vascular resistance existing in angiotensin-dependent hypertension. Its resolution implies that AT1R and P2XR share common receptor or post receptor signaling mechanisms which converge to maintain renal vasoconstriction in Ang II-dependent hypertension. In this review, we briefly discuss (1) the regulation of renal afferent arterioles in Ang II-dependent hypertension, (2) the interaction of AT1R and P2XR activation in regulating renal afferent arterioles in a setting of hypertension, (3) mechanisms regulating ATP release and effect of angiotensin II on ATP release, and (4) the possible intracellular pathways involved in AT1R and P2XR interactions. Emerging evidence supports the hypothesis that P2X1R, P2X7R, and AT1R actions converge at receptor or post-receptor signaling pathways but that P2XR exerts a dominant influence abrogating the actions of AT1R on renal afferent arterioles in Ang II-dependent hypertension. This finding raises clinical implications for the design of therapeutic interventions that will prevent the impairment of kidney function and subsequent tissue injury.

Exploring in vitro anti-proliferative and anti-inflammatory activities of Prasachandaeng remedy, and its bioactive compounds.

BACKGROUND: Prasachandaeng (PSD) remedy has been empirically used in Thai traditional medicine to treat fever in bile duct and liver and cancer patients through Thai folk doctors. However, there have been no scientific reports on the bioactive compounds and bioactivities related to inflammation-associated carcinogenesis or cytotoxicity against cancer cell lines. In this study, we investigated the chemical content of the remedy, and evaluated its cytotoxic activity against two cancer cell lines in comparison with a non-cancerous cell line and determined tumor necrosis factor-alpha (TNF-α) production in a murine macrophage cell line (RAW 264.7) to evaluate anti-inflammatory activity. A novel HPLC method was used for quality control of its chemical content. METHODS: Pure compounds from the EtOH extract of D. cochinchinensis were isolated using bioassay-guided fractionation and chemical content of the PSD remedy was determined using HPLC. The cytotoxic activity against the hepatocarcinoma cell line (HepG2) and cholangiocarcinoma cell line (KKU-M156), in comparison with non-cancerous cell line (HaCaT), were investigated using antiproliferative assay (SRB). The anti-inflammatory activity measured by TNF-α production in RAW 264.7 was determined using ELISA. RESULTS: All crude extracts and isolated compounds exhibited significant differences from vincristine sulfate (****p < 0.0001) in their cytotoxic activity against HepG2, KKU-M156, and HaCaT. The PSD remedy exhibited cytotoxic activity against HepG2 and KKU-M156 with IC50 values of 10.45 ± 1.98 (SI = 5.3) and 4.53 ± 0.74 (SI = 12.2) µg/mL, respectively. Some constituents from C. sappan, D. cochinchinensis, M. siamensis, and M. fragrans also exhibited cytotoxic activity against HepG2 and KKU-M156, with IC50 values less than 10 µg/mL. The isolated compounds, i.e., Loureirin B (1), 4-Hydroxy-2,4'-dimethoxydihydrochalcone (2), and Eucomol (3) exhibited moderate cytotoxicity against two cancer cell lines. None of the crude extracts and isolated compounds showed cytotoxicity against HaCaT. D. cochinchinensis and PSD remedy exhibited higher anti-inflammatory activity measured as TNF-α production than acetaminophen. CONCLUSION: The findings provide evidence of bioactivity for EtOH extracts of PSD remedy and the isolated compounds of D. Cochinchinensis. The results consistent the use clinical activity and use of PSD remedy as a antipyretic treatment for liver and bile duct cancer patients by Thai traditional practitioners.

Investigations of the antipyretic effect and safety of Prasachandaeng, a traditional remedy from Thailand national list of essential medicines.

Prasachandaeng (PSD) remedy from the Thailand National List of Essential Medicines (NLEM) has been used as an antipyretic for chronic fever in both adults and children for centuries. Its therapeutic effect in treating fever and its safety have not been studied in animal models. We evaluated its antipyretic activity on lipopolysaccharide (LPS)-induced fever and safety in the liver in comparison with acetaminophen (ACP). Correlation between biochemistry of liver function and the level of cytochrome P450 (CYP2E1) was also evaluated using an ELISA kit. All doses of PSD powder (PSDP) and a 95% ethanol extract of PSD (PSDE) (50, 200, and 400 mg/kg) showed a significant antipyretic effect (* p < 0.05) as compared to ACP. We investigated clinical biochemistry of liver and kidney functions, histopathology, and concentrations of CYP2E1. All treatment groups demonstrated a normal range of clinical biochemistry of liver and kidney functions in comparison with ACP on days 1, 3, 7, and 10. Serum AST, ALP, and LDH levels of PSDE and PSDP showed mean values less than that of ACP on the corresponding days (* p < 0.05). None of the treatment groups showed evidence of hepatocellular damage, nor did they affect CYPE21. The results of histopathology on liver tissue correlated with the biochemistry of liver functions which indicated no hepatotoxicity effect in liver tissue during the seven day treatment. These findings suggest that both forms of PSD remedy possessed marked antipyretic activity and were not hepatotoxic during the seven days of administration in rats.

Associations of CB1 cannabinoid receptor (CNR1) gene polymorphisms with risk for alcohol dependence: Evidence from meta-analyses of genetic and genome-wide association studies.

OBJECTIVES: Reported associations of the cannabinoid receptor 1 (CNR1) single nucleotide polymorphisms (SNPs) with alcohol dependence (AD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. METHODS: A Boolean search of 4 databases (PubMed, Scopus, Google Scholar, and Mednar) sought articles that evaluated the association between CNR1 polymorphisms and risk of AD. We selected the articles with sufficient genotype frequency data to enable calculation of odds ratios (ORs) and 95% confidence intervals (CIs). Using the Population Intervention Comparators Outcome elements, AD patients (P) were compared by genotype data between AD-participants (I) and non-AD-participants (C) in order to determine the risk of AD (O) attributed to the CNR1 SNPs. Analyzing 4 SNPs (rs1049353, rs1535255, rs2023239, and rs806379) using standard genetic models, we examined associations where multiple comparisons were Holm-Bonferroni corrected. The pooled ORs were assessed for aggregate statistical power and robustness (sensitivity analysis). Subgroups were Caucasians and African-Americans. RESULTS: From 32 comparisons, 14 were significant indicating increased risk, from which 5 outcomes (P-value for association [Pa] = .003 to <.001) survived the Holm-Bonferroni-correction, which were deemed robust. In the rs1535255 outcomes, the codominant effect (OR = 1.43, 95% CIs = 1.24-1.65, Pa < .001) had greater statistical power than the dominant effect (OR = 1.30, 95% CI = 1.08-1.57, Pa = .006). In contrast, the rs2023239 codominant outcome was underpowered. Significance of both rs806379 Caucasian outcomes (ORs = 1.20-1.43, 95% CIs = 1.07-1.57, Pa = .003) contrasted with the null effects in African-Americans (ORs = 0.98-1.08, 95% CIs = 0.70-1.53). CONCLUSIONS: Three CNR1 SNPs (rs1535255, rs2023239, and rs806379) were implicated in their associations with development of AD: based on aggregate statistical power, rs1535255 presented greater evidence for associations than rs2023239; rs806379 implicated the Caucasian subgroup. Multiple statistical and meta-analytical features (consistency, robustness, and high significance) underpinned the strengths of these outcomes. Our findings could render the CNR1 polymorphisms useful in the clinical genetics of AD.

An Updated Meta-Analysis of Controlling Myopia with Auricular Acupoint Stimulation.

Objective: Myopia prevalence mostly affects young people, particularly in Asia. Of the several recommendations addressing the myopia epidemic, auricular acupoint stimulation (AAS) has been proposed and investigated. However, reported outcomes have been inconsistent, prompting a meta-analysis to obtain more precise estimates. Materials and Methods: Twelve articles were included in a meta-analysis, wherein each article was evaluated for risk of bias. Summary effects were calculated using odds ratios (ORs) and 95% confidence intervals (CIs). Outlier and sensitivity treatments as well as publication bias assessment were applied. Results: Risk of bias among the articles was low in random sequence but generally unclear judgments for the other bias criteria. AAS outcomes were significant (P a [P-value for association] <0.00001-0.003) when random and fixed effects favored the treated groups (ORs: 2.87-3.42; 95% CIs: 1.44-5.75). Conclusions: This meta-analysis showed evidence of AAS being effective for controlling myopia. Substantial magnitude (up to 3.4-fold), robustness, and lack of bias strengthened this effect.

Influence of polymorphisms in the vascular endothelial growth factor gene on allograft rejection after kidney transplantation: a meta-analysis.

Background: Reported associations of allograft rejection in kidney transplant patients with VEGF single nucleotide polymorphisms (SNPs) have been inconsistent between studies, which prompted a meta-analysis to obtain more precise estimates. Methods: Using the PICO elements, kidney transplant patients (P) were compared by genotype data between rejectors (I) and non-rejectors (C) in order to determine the risk of allograft rejection (O) attributed to the VEGF SNPs. Literature search of four databases yielded seven articles. To calculate risks for allograft rejection, four SNPs were examined. Using the allele-genotype model we compared the variant ( var) with the wild-type ( wt) and heterozygous ( var- wt) alleles. Meta-analysis treatments included outlier and subgroup analyses, the latter was based on ethnicity (Indians/Caucasians) and rejection type (acute/chronic). Multiple comparisons were corrected with the Bonferroni test. Results: Five highly significant outcomes (P a < 0.01) survived Bonferroni correction, one of which showed reduced risk for the var allele (OR 0.61, 95% CI 0.45-0.82). The remaining four indicated increased risk for the wt allele where the chronic rejection (OR 2.10, 95% CI 1.36-3.24) and Indian (OR 1.44, 95% CI 1.13-1.84) subgroups were accorded susceptibility status. Conclusions: Risk associations for renal allograft rejection were increased and reduced on account of the wt and var alleles, respectively. These findings could render the VEGF polymorphisms useful in the clinical genetics of kidney transplantation.

Ultrafiltration rates and intradialytic hypotension: A case-control sampling of pooled haemodialysis data.

BACKGROUND: Intradialytic hypotension (IDH) is one of the most critical adverse events during maintenance haemodialysis. Previous studies reported the association of fluid removal rate with the occurrence of IDH. OBJECTIVE: We aimed to identify the optimal threshold of ultrafiltration rate to prevent the occurrence of IDH events. DESIGN, PARTICIPANTS AND MEASUREMENTS: Prognostic factor research with a retrospective case-control design was conducted. Patient data were gathered from four haemodialysis units from January to December 2017. All the haemodialysis records were independently justified, whether IDH occurred or not, based on the standard definition. A total of 10 haemodialysis sessions were sampled from each patient's pool based on the incidence of events. The association of ultrafiltration rates and IDH events was explored by multivariable multilevel logistic regression. RESULTS: A total of 1080 haemodialysis sessions from 108 patients were included: 149 (13.8%) with IDH and 931 (86.2%) without IDH. After adjusting for all pre-specified risk factors and imbalance baselines, the odds ratio of IDH were 1.22 (95% confidence interval [CI]: 0.59, 2.52) for rate 10-12 ml/kg/h; 2.52 (95% CI: 1.20, 5.29) for rate 12-14 ml/kg/h; 4.02 (95% CI: 1.61, 10.03) for rate 14-16 ml/kg/h; and 7.41 (95% CI: 2.53, 21.68) for rate >16 ml/kg/h comparing to the referent rate of <10 ml/kg/h. CONCLUSION: The ultrafiltration rate should be limited to 12 ml/kg/h. If a higher rate of fluid removal was indicated, it should not exceed 16 ml/kg/h to avoid the occurrence of IDH.

The First Asian Kidney Transplantation Prediction Models for Long-term Patient and Allograft Survival.

BACKGROUND: Several kidney transplantation (KT) prediction models for patient and graft outcomes have been developed based on Caucasian populations. However, KT in Asian countries differs due to patient characteristics and practices. To date, there has been no equation developed for predicting outcomes among Asian KT recipients. METHODS: We developed equations for predicting 5- and 10-year patient survival (PS) and death-censored graft survival (DCGS) based on 6662 patients in the Thai Transplant Registry. The cohort was divided into training and validation data sets. We identified factors significantly associated with outcomes by Cox regression. In the validation data set, we also compared our models with another model based on KT in the United States. RESULTS: Variables included for developing the DCGS and PS models were recipient and donor age, background kidney disease, dialysis vintage, donor hepatitis C virus status, cardiovascular diseases, panel reactive antibody, donor types, donor creatinine, ischemic time, and immunosuppression regimens. The C statistics of our model in the validation data set were 0.69 (0.66-0.71) and 0.64 (0.59-0.68) for DCGS and PS. Our model performed better when compared with a model based on US patients. Compared with tacrolimus, KT recipients aged ≤44 years receiving cyclosporine A had a higher risk of graft loss (adjusted hazard ratio = 1.26; P = 0.046). The risk of death was higher in recipients aged >44 years and taking cyclosporine A (adjusted hazard ratio = 1.44; P = 0.011). CONCLUSIONS: Our prediction model is the first based on an Asian population, can be used immediately after transplantation. The model can be accessed at www.nephrochula.com/ktmodels.

Corrigendum to "Dual Inhibiting Senescence and Epithelial-to-Mesenchymal Transition by Erythropoietin Preserve Tubular Epithelial Cell Regeneration and Ameliorate Renal Fibrosis in Unilateral Ureteral Obstruction".

[This corrects the article DOI: 10.1155/2013/308130.].

Dialysate White Blood Cell Change after Initial Antibiotic Treatment Represented the Patterns of Response in Peritoneal Dialysis-Related Peritonitis.

Background. Patients with peritoneal dialysis-related peritonitis usually have different responses to initial antibiotic treatment. This study aimed to explore the patterns of response by using the changes of dialysate white blood cell count on the first five days of the initial antibiotic treatment. Materials and Methods. A retrospective cohort study was conducted. All peritoneal dialysis-related peritonitis episodes from January 2014 to December 2015 were reviewed. We categorized the patterns of antibiotic response into 3 groups: early response, delayed response, and failure group. The changes of dialysate white blood cell count for each pattern were determined by multilevel regression analysis. Results. There were 644 episodes in 455 patients: 378 (58.7%) of early response, 122 (18.9%) of delayed response, and 144 (22.3%) of failure episodes. The patterns of early, delayed, and failure groups were represented by the average rate reduction per day of dialysate WBC of 68.4%, 34.0%, and 14.2%, respectively (p value < 0.001 for all comparisons). Conclusion. Three patterns, which were categorized by types of responses, have variable rates of WBC declining. Clinicians should focus on the delayed response and failure patterns in order to make a decision whether to continue medical therapies or to aggressively remove the peritoneal catheter.

Erythropoietin Administration Promotes Expression of VEGF in Renal Ischemic­Reperfusion Injury in Rat Model.

Background: Acute ischemia-reperfusion (I/R) injury is the most common causes of acute renal failure in daily clinical practice. It has been recognized that endothelial cell dysfunction and microvascular injury as the pathophysiological changes during I/R injury. Protective effects of erythropoietin (EPO) have been demonstrated in various experimental models of I/R induced injury. Therefore, the aim of the present study was to investigate whether EPO administration has renoprotective effect against acute renal failure I/R injury in rats by promotion of endothelial progenitor cells (EPCs) mobilization and neovascularization. Material and Method: Male Sprague-Dawley rats were pretreated with EPO (1,000 IU/kg/day, ip); or the placebo for 3 days before the induction of I/R procedure. On day 4, the bilateral renal occlusion for 30 min operations to produce renal I/R injury or treatment with EPO 30 min before the initiation of I/R were done. At the end of the reperfusion period at day 1 day 2 and day 4, blood and renal tissues were collected to investigate renal function and pathohistological examination. The expression levels of CAV-1 and CD34 were determined for circulating of EPCs in blood, while CD34, CAV-1 and VEGFR-2 were investigated for mobilized EPCs in kidney, using real time PCR. The expression level of VEGF was also examined to indicate the angiogenesis in kidney using real time PCR and western blotting. Results: In the I/R group, the significantly increased values of serum urea and creatinine were found on Day 1 after ischemia, as compared to sham group. The development of tubular epithelial cell necrosis, peritubular capillary congestion and mild interstitial infiltration has been observed in this group. Administration of EPO in I/R rat was significantly improved renal function and significantly less the tubular damage. The treatment with EPO significantly increased in expression levels of CD34 and CAV-1 in blood, and also CAV-1, VEGFR-2 and VEGF in kidney tissue in this group, as compared to the I/R group. Conclusion: These results suggest that treatment with EPO protects the kidney from ischemic acute renal injury via increasing the mobilization and recruitment of EPCs, resulting in the induction of expression of VEGF that might play an important role in the repair response.

Glucose-Lowering Efficacy of Water Extract of Malvastrum coromandelianum in Type 2 Diabetes Subjects: A Double Blind, Randomized Controlled Trial.

BACKGROUND: Water extract from Malvastrum coromandelianum (Linn.) Garcke (MC) has been shown to have glucose lowering effect, short- and long-term safety in animal studies. A preliminary study in human reveals safety and its potential use as an adjunctive treatment to antihyperglycemic medications. OBJECTIVE: To investigate the glycemic-lowering efficacy ofMC in type 2 diabetes subjects. MATERIAL AND METHOD: A multicenter randomized, double-blind, placebo-controlled trial was conducted. Seventy-one diabetes subjects, who were treated with either diet control or single oral anti-diabetic drug (sulphonylurea or biguanide) with HbA1C between 6.5-9%, were recruited. Subjects were randomized to take MC tablets in a total dose of 1,200 mg/day or placebo for 12 weeks. Clinical parameters, glycemic control, HOMA-IR and HOMA-ß were assessed. RESULTS: Both MC (n = 34) and placebo (n = 37) groups had comparable baseline characteristics with a mean baseline HbA1C of 7.6 ± 0.82 vs. 7.5 ± 0.8%, respectively. During the study, HbA1C did not differ statistically after 4, 8 and 12 weeks of treatment (7.7 ± 0.97 vs. 7.6 ± 1.0, 7.9 ± 1.09 vs. 7.8 ± 1.03 and 7.8 ± 1.1 vs. 7.6 ± 1.1%, respectively). The body weight, insulin resistance and insulin secretion were also similar between groups (p > 0.05). No episode of hypoglycemia was reported. CONCLUSION: MC in a dosage of 1,200 mg/day does not have glucose lowering efficacy in type 2 diabetes.

Mycophenolic acid AUC in Thai kidney transplant recipients receiving low dose mycophenolate and its association with UGT2B7 polymorphisms.

BACKGROUND: Despite use of a lower mycophenolate dose in Thai kidney transplant patients, acceptable graft and patient outcomes can be achieved. We therefore examined the pharmacokinetics of mycophenolic acid (MPA) by area under the curve (AUC) and investigated genetic contribution in mycophenolate metabolism in this population. METHODS: Kidney transplant recipients with stable graft function who were receiving mycophenolate mofetil 1,000 mg/d in combination with either cyclosporine or tacrolimus, and prednisolone were studied. The MPA concentration was measured by fluorescence polarization immunoassay (FPIA), at predose and 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. Genetic polymorphisms in UGT1A8, UGT1A9, and UGT2B7 were examined by denaturing high-performance liquid chromatography (DHPLC)-based single-base extension (SBE) analysis. RESULTS: A total 138 patients were included in study. The mean AUC was 39.49 mg-h/L (28.39-89.58 mg-h/L), which was in the therapeutic range. The correlation between the predose MPA concentration and AUC was poor. The mean AUC in the tacrolimus group was higher than that in the cyclosporine group. Polymorphisms in UGT2B7 showed significant association with AUC. CONCLUSION: Most of our patients with reduced mycophenolate dose had the AUC within the therapeutic range. Genetic polymorphisms in UGT2B7 may play a role in MPA metabolism in Thai kidney transplant patients.

Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention.

Radiocontrast media (RCM) are medical drugs used to improve the visibility of internal organs and structures in X-ray based imaging techniques. They may have side effects ranging from itching to a life-threatening emergency, known as contrast-induced nephropathy (CIN). We define CIN as acute renal failure occurring within 24-72 hrs of exposure to RCM that cannot be attributed to other causes. It usually occurs in patients with preexisting renal impairment and diabetes. The mechanisms underlying CIN include reduction in medullary blood flow leading to hypoxia and direct tubule cell damage and the formation of reactive oxygen species. Identification of patients at high risk for CIN is important. We have reviewed the risk factors and procedures for prevention, providing a long list of references enabling readers a deep evaluation of them both. The first rule to follow in patients at risk of CIN undergoing radiographic procedure is monitoring renal function by measuring serum creatinine and calculating the eGFR before and once daily for 5 days after the procedure. It is advised to discontinue potentially nephrotoxic medications, to choose radiocontrast media at lowest dosage, and to encourage oral or intravenous hydration. In high-risk patients N-acetylcysteine may also be given.

Pharmacological strategies to prevent contrast-induced acute kidney injury.

Contrast-induced acute kidney injury (CI-AKI) is the most common iatrogenic cause of acute kidney injury after intravenous contrast media administration. In general, the incidence of CI-AKI is low in patients with normal renal function. However, the rate is remarkably elevated in patients with preexisting chronic kidney disease, diabetes mellitus, old age, high volume of contrast agent, congestive heart failure, hypotension, anemia, use of nephrotoxic drug, and volume depletion. Consequently, CI-AKI particularly in high risk patients contributes to extended hospitalizations and increases long-term morbidity and mortality. The pathogenesis of CI-AKI involves at least three mechanisms; contrast agents induce renal vasoconstriction, increase of oxygen free radicals through oxidative stress, and direct tubular toxicity. Several strategies to prevent CI-AKI have been evaluated in experimental studies and clinical trials. At present, intravascular volume expansion with either isotonic saline or sodium bicarbonate solutions has provided more consistent positive results and was recommended in the prevention of CI-AKI. However, the proportion of patients with risk still develops CI-AKI. This review critically evaluated the current evidence for pharmacological strategies to prevent CI-AKI in patients with a risk of developing CI-AKI.

Antioxidant effect of Phyllanthus emblica extract prevents contrast-induced acute kidney injury.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) occurs after the administration of intravenous iodinated contrast agents. Oxidative stress has been proposed as one of the most important mechanisms in the pathogenesis of CI-AKI. The objective of this study was to investigate the antioxidant effect of the extract from Phyllanthus emblica (PE) in preventing CI-AKI. METHODS: Male Sprague Dawley rats were subjected into eight groups, were given water (control) or PE extract (125 or 250 or 500 mg/kg/day) for 5 days before the induction of CI-AKI. Renal function and oxidative stress markers; malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT) activity were determined in plasma and renal tissue. Kidney sections were performed for histopathological examination. RESULTS: In the contrast media (CM) group, increases in blood urea nitrogen and serum creatinine were demonstrated which correlated with severity of tubular necrosis, peritubular capillary congestion and interstitial edema. Moreover, an increase in MDA and a decrease in TAC SOD and CAT activity in CM group were significantly changed when compared with the control (P<0.05). In contrast, CI-AKI-induced rats administrated with PE extract 250 and 500 mg/kg/day significantly preserved renal function and attenuated the severity of pathological damage (P<0.05) as well as significantly lower MDA and higher TAC, SOD and CAT than the CM group (P<0.05). CONCLUSIONS: This study demonstrated the protective role of PE extract against CI-AKI.

Urinary Neutrophil Gelatinase-Associated Lipocalin predicts the severity of contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) particularly in high risk patients with chronic kidney disease (CKD), increases morbidity and mortality. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein excreted by the kidney during AKI. There are no urine (u) NGAL data as an early CI-AKI marker in CKD patients undergoing coronary procedures. METHODS: This prospective study enrolled 130 patients with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² undergoing elective coronary procedures. Serial urine samples, obtained at baseline and 3, 6, 12, 18, and 24 h post contrast administration were analyzed by NGAL ELISA kit. AKI was defined as an increase in serum creatinine (SCr) of ≥ 0.3 mg/dl or ≥ 1.5 times baseline SCr within 48 h per 2012 KDIGO guidelines. Receiver operator characteristic curve analyses identified optimal uNGAL and delta of uNGAL values for diagnosing CI-AKI. RESULTS: The uNGAL was significantly and inverse correlated with eGFR (R = 0.25, P < 0.005). CI-AKI developed in 16/130 (12.31%) patients: 13 and 3 in CI-AKI stages I and II, respectively. uNGAL and delta of uNGAL were significantly higher in the CI-AKI group when compared with the No CI-AKI group (P < 0.05). The best uNGAL cut-off for optimal sensitivity 94%, specificity 78%, and area under the curve 0.84 for predicting CI-AKI was 117 ng/mL at 6 h, respectively. Corresponding values for predicting CI-AKI stage II were 100%, 87% and 0.9 when using an uNGAL of 264 ng/mL at 6 h. CONCLUSIONS: Monitoring of uNGAL levels not only provide the early detecting CI-AKI but also predict the severity of CI-AKI in CKD patients undergoing elective coronary procedures.

Dual inhibiting senescence and epithelial-to-mesenchymal transition by erythropoietin preserve tubular epithelial cell regeneration and ameliorate renal fibrosis in unilateral ureteral obstruction.

This study aims to investigate the renoprotective effect of recombinant human erythropoietin (rhEPO) treatment could preserve tubular epithelial cell regeneration and ameliorate renal fibrosis by dual inhibition of stress-induced senescence and EMT in unilateral ureteric obstruction (UUO) mouse model. UUO or sham-operated mice were randomly assigned to receive rhEPO or vehicle treatment and were sacrificed on days 3, 7, and 14. Kidney specimens were fixed for histopathological and immunohistochemical study. The expression of S100A4, TGF-ß1, BMP-7, Smad2/3, Smad1/5/8, and p16(INK4a) was determined by western blot and real-time RT-PCR. Vehicle treated UUO mice had increased tubular atrophy and interstitial fibrosis within 3 to 14 days. An increase in TGF-ß1, Smad2/3, S100A4, and p16(INK4a) expression and a decrease in BMP-7 and Smad1/5/8 expression were observed in the obstructed kidneys. p16(INK4a) was positively correlated with TGF-ß1/Smad2/3 and negatively correlated with BMP-7/Smad1/5/8 in UUO mice. rhEPO treatment significantly suppressed the upregulation of TGF-ß, Smad2/3, S100A4, and p16(INK4a) and preserved the downregulation of BMP-7 and Smad1/5/8, resulting in markedly reduced TA/IF compared to the vehicle treated mice. The renoprotective effects of rhEPO could ameliorate renal TA/IF by modulating senescence and EMT which could be a part of therapeutic option in patients with chronic kidney disease.