ResearchPad - renal-analysis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The precise long-term outcomes of adult IgA nephropathy by mail questionnaires: Better renal survival compared to earlier cohort studies]]> https://www.researchpad.co/article/elastic_article_14721 The estimated 20-year renal survival rate of immunoglobulin A (IgA) nephropathy is approx. 60%, but it is difficult to determine the 'big picture' for IgA nephropathy because a biopsy is essential for its diagnosis. Here we attempted to determine the longer and more precise renal prognosis of IgA nephropathy. We examined 310 patients with primary IgA nephropathy. Using the patients' clinical records and histological reports from our hospital and other clinics, we surveyed their renal prognoses and treatments within 1 year post-biopsy, and we sent questionnaires to the patients who had stopped visiting any hospital. We set renal death as the primary endpoint and analyzed factors related to renal death. The total patient cohort was 267: 159 males, 108 females; average age at biopsy, 37.7 years; average estimated glomerular filtration rate (eGFR), 69.7 mL/min/1.73m2; urinary protein, 1.3 g/day. The mean follow-up duration was prolonged to 13.8±8.9 years (vs. 9.2±8.5 years using only medical records). The 10- and 20-year follow-up rates were 61.7% and 27.3%. The 10-, 20-year renal survival rates were 83.6% and 72.5%. Lower eGFR, hypertension, and smoking were revealed as factors independently related to renal death. To study survival of relatively benign diseases such as IgA nephropathy, longer survival rate was affected by many censoring cases. The results regarding the long-term renal prognoses of IgA nephropathy patients (including those with a mild phenotype) obtained by our analysis of a questionnaire sent to the patients provided more precise and longer-term prognoses compared to earlier studies.

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<![CDATA[Low-molecular-weight heparin venous thromboprophylaxis in critically ill patients with renal dysfunction: A subgroup analysis of the PROTECT trial]]> https://www.researchpad.co/article/5c032e02d5eed0c4844f8af1

Introduction

There is concern about excessive bleeding when low-molecular-weight heparins (LMWHs) are used for venous thromboembolism (VTE) prophylaxis in renal dysfunction. Our objective was to evaluate whether LMWH VTE prophylaxis was safe and effective in critically ill patients with renal dysfunction by conducting a subgroup analysis of PROTECT, a randomized blinded trial.

Methods

We studied intensive care unit (ICU) patients with pre-ICU dialysis-dependent end-stage renal disease (ESRD; pre-specified subgroup; n = 118), or severe renal dysfunction at ICU admission (defined as ESRD or non-dialysis dependent with creatinine clearance [CrCl] <30 ml/min; post hoc subgroup; n = 590). We compared dalteparin, 5000 IU daily, with unfractionated heparin (UFH), 5000 IU twice daily, and considered outcomes of proximal leg deep vein thrombosis (DVT); pulmonary embolism (PE); any VTE; and major bleeding. Adjusted hazard ratios [HR] were calculated using Cox regression.

Results

In patients with ESRD, there was no significant difference in DVT (8.3% vs. 5.2%, p = 0.76), any VTE (10.0% vs. 6.9%; p = 0.39) or major bleeding (5.0% vs. 8.6%; p = 0.32) between UFH and dalteparin. In patients with severe renal dysfunction, there was no significant difference in any VTE (10.0% vs. 6.4%; p = 0.07) or major bleeding (8.9% vs. 11.0%; p = 0.66) but an increase in DVT with dalteparin (7.6% vs. 3.7%; p = 0.04). Interaction p-values for comparisons of HRs (ESRD versus not) were non-significant.

Conclusions

In critically ill patients with ESRD, or severe renal dysfunction, there was no significant difference in any VTE or major bleeding between UFH and dalteparin. Patients with severe renal dysfunction who received dalteparin had more proximal DVTs than those on UFH; this finding did not hold in patients with ESRD alone.

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<![CDATA[Association of the Ratio of Early Mitral Inflow Velocity to the Global Diastolic Strain Rate with a Rapid Renal Function Decline in Atrial Fibrillation]]> https://www.researchpad.co/article/5989d9d3ab0ee8fa60b64e76

The ratio of early mitral inflow velocity (E) to the global diastolic strain rate (E’sr) has been correlated with left ventricular filling pressure and predicts adverse cardiac outcomes in atrial fibrillation (AF). The relationship between the E/E’sr ratio and renal outcomes in AF has not been evaluated. This study examined the ability of the E/E’sr ratio in predicting progression to the renal endpoint, which is defined as a ≥ 25% decline in the estimated glomerular filtration rate in patients with AF. Comprehensive echocardiography was performed on 149 patients with persistent AF, and E’sr was assessed from three standard apical views using the index beat method. During a median follow-up period of 2.3 years, 63 patients (42.3%) were reaching the renal endpoint. Multivariate analysis showed that an increased E/E’sr ratio (per 10 cm) (hazard ratio, 1.230; 95% confidence interval, 1.088 to 1.391; p = 0.001) was associated with an increased renal endpoint. In a direct comparison, the E/E’sr ratio outperformed the ratio of E to early diastolic mitral annular velocity (E’) in predicting progression to the renal endpoint in both univariate and multivariate models (p ≤ 0.039). Moreover, adding the E/E’sr ratio to a clinical model and echocardiographic parameters provided an additional benefit in the prediction of progression to the renal endpoint (p = 0.006). The E/E’sr ratio is a useful parameter and is stronger than the E/E’ ratio in predicting the progression to the renal endpoint, and it may offer an additional prognostic benefit over conventional clinical and echocardiographic parameters in patients with AF.

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<![CDATA[Representation and reporting of kidney disease in cerebrovascular disease: A systematic review of randomized controlled trials]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc2ab

Patients with kidney disease (KD) are at increased risk for cerebrovascular disease (CVD) and CVD patients with KD have worse outcomes. We aimed to determine the representation of KD patients in major randomized controlled trials (RCTs) of CVD interventions. We searched MEDLINE for reports of major CVD trials published through February 9, 2017. We excluded trials that did not report mortality outcomes, enrolled fewer than 100 participants, or were subgroup, follow-up, or post-hoc analyses. Two independent reviewers performed study selection and data extraction. We included 135 RCTs randomizing 194,977 participants. KD patients were excluded in 48 (35.6%) trials, but were less likely to be excluded from trials of class I/II recommended interventions (n = 7; 15.9%; p = 0.001) and more likely to be excluded in trials with registered protocols (45.5% vs. 22.4%; p = 0.007). Exclusion was lower in trials supported by academic or governmental grants compared to industry or combined funding (21.2% vs. 42.0% and 47.8%; p = 0.033 and 0.028, respectively). Among trials excluding KD patients, 24 (50.0%) used serum creatinine, 7 (14.6%) used estimated glomerular filtration rate or creatinine clearance, 7 (14.6%) used renal replacement therapy, and 19 (39.6%) used non-specific kidney-related criteria. Only 4 (3.0%) trials reported baseline renal function. No trials prespecified or reported subgroup analyses by baseline renal function. Although 19 (14.1%) trials reported the incidence of acute kidney injury, no trial examined adverse event rates according to renal function. In summary, more than one third of major CVD trials excluded patients with KD, primarily based on serum creatinine or non-specific criteria, and outcomes were not stratified by renal parameters. Therefore, purposeful efforts to increase inclusion of KD patients in CVD trials and evaluate the impact of renal function on efficacy and safety are needed to improve the quality of evidence for interventions in this vulnerable population.

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<![CDATA[The Protective Role of Fucosylated Chondroitin Sulfate, a Distinct Glycosaminoglycan, in a Murine Model of Streptozotocin-Induced Diabetic Nephropathy]]> https://www.researchpad.co/article/5989daefab0ee8fa60bc0ae0

Background

Heparanase-1 activation, albuminuria, and a decrease in glomerular heparan sulfate (HS) have been described in diabetic nephropathy (DN). Glycosaminoglycan (GAG)-based drugs have been shown to have renoprotective effects in this setting, although recent trials have questioned their clinical effectiveness. Here, we describe the effects of fucosylated chondroitin sulfate (FCS), a novel GAG extracted from a marine echinoderm, in experimentally induced DN compared to a widely used GAG, enoxaparin (ENX).

Methods

Diabetes mellitus (DM) was induced by streptozotocin in male Wistar rats divided into three groups: DM (without treatment), FCS (8 mg/kg), and ENX (4 mg/kg), administered subcutaneously. After 12 weeks, we measured blood glucose, blood pressure, albuminuria, and renal function. The kidneys were evaluated for mesangial expansion and collagen content. Immunohistochemical quantifications of macrophages, TGF-β, nestin and immunofluorescence analysis of heparanase-1 and glomerular basement membrane (GBM) HS content was also performed. Gene expression of proteoglycan core proteins and enzymes involved in GAG assembly/degradation were analyzed by TaqMan real-time PCR.

Results

Treatment with GAGs prevented albuminuria and did not affect the glucose level or other functional aspects. The DM group exhibited increased mesangial matrix deposition and tubulointerstitial expansion, and prevention was observed in both GAG groups. TGF-β expression and macrophage infiltration were prevented by the GAG treatments, and podocyte damage was halted. The diabetic milieu resulted in the down-regulation of agrin, perlecan and collagen XVIII mRNAs, along with the expression of enzymes involved in GAG biosynthesis. Treatment with FCS and ENX positively modulated such changes. Heparanase-1 expression was significantly reduced after GAG treatment without affecting the GBM HS content, which was uniformly reduced in all of the diabetic animals.

Conclusions

Our results demonstrate that the administration of FCS prevented several pathological features of ND in rats. This finding should stimulate further research on GAG treatment for this complication of diabetes.

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<![CDATA[Potential Use of Autologous Renal Cells from Diseased Kidneys for the Treatment of Renal Failure]]> https://www.researchpad.co/article/5989dabeab0ee8fa60bafaea

Chronic kidney disease (CKD) occurs when certain conditions cause the kidneys to gradually lose function. For patients with CKD, renal transplantation is the only treatment option that restores kidney function. In this study, we evaluated primary renal cells obtained from diseased kidneys to determine whether their normal phenotypic and functional characteristics are retained, and could be used for cell therapy. Primary renal cells isolated from both normal kidneys (NK) and diseased kidneys (CKD) showed similar phenotypic characteristics and growth kinetics. The expression levels of renal tubular cell markers, Aquaporin-1 and E-Cadherin, and podocyte-specific markers, WT-1 and Nephrin, were similar in both NK and CKD kidney derived cells. Using fluorescence- activated cell sorting (FACS), specific renal cell populations were identified and included proximal tubular cells (83.1% from NK and 80.3% from CKD kidneys); distal tubular cells (11.03% from NK and 10.9% from CKD kidneys); and podocytes (1.91% from NK and 1.78% from CKD kidneys). Ultra-structural analysis using scanning electron microscopy (SEM) revealed microvilli on the apical surface of cultured cells from NK and CKD samples. Moreover, transmission electron microscopy (TEM) analysis showed a similar organization of tight junctions, desmosomes, and other intracellular structures. The Na+ uptake characteristics of NK and CKD derived renal cells were also similar (24.4 mmol/L and 25 mmol/L, respectively) and no significant differences were observed in the protein uptake and transport characteristics of these two cell isolates. These results show that primary renal cells derived from diseased kidneys such as CKD have similar structural and functional characteristics to their counterparts from a normal healthy kidney (NK) when grown in vitro. This study suggests that cells derived from diseased kidney may be used as an autologous cell source for renal cell therapy, particularly in patients with CKD or end-stage renal disease (ESRD).

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<![CDATA[Effect of Proteinuria and Glomerular Filtration Rate on Renal Outcome in Patients with Biopsy-Proven Benign Nephrosclerosis]]> https://www.researchpad.co/article/5989da87ab0ee8fa60b9ca17

Background

Reduced estimated glomerular filtration rate (eGFR) and proteinuria are risk factors for end-stage renal disease (ESRD), of which benign nephrosclerosis is a common cause. However, few biopsy-based studies have assessed these associations.

Methods

We performed retrospective cohort study of 182 Japanese patients who underwent renal biopsy from June 1985 through March 2014 and who were diagnosed with benign nephrosclerosis. Competing risk regression analyses were used to investigate the effect of eGFR and proteinuria levels at the time of renal biopsy on the risk for renal events (ESRD or a 50% decline in eGFR from baseline).

Results

During a median 5.8-year follow-up, 63 (34.6%) patients experienced renal events. The incidence of renal events increased with lower baseline eGFR and greater baseline proteinuria levels. After adjustment for baseline covariates, lower eGFR levels (subhazard ratios [SHRs], 1.30; 95% confidence interval [CI], 1.01–1.67, per 10 mL/min/1.73 m2) and higher proteinuria levels (SHR, 1.52; 95% CI, 1.23–1.87, per 1.0 g/day) at the time of renal biopsy were associated independently with higher risk for renal events. Lower levels of serum albumin (SHR, 2.07; 95% CI, 1.20–3.55 per 1.0 g/dL) were also associated with renal events. Patients with both eGFR <30 mL/min/1.73 m2 and proteinuria ≥0.5 g/day had a 26.7-fold higher risk (95% CI, 3.97–179.4) of renal events than patients with both eGFR ≥60 mL/min/1.73 m2 and proteinuria <0.5 g/day.

Conclusions

Reduced eGFR and increased proteinuria as well as lower serum albumin at the time of renal biopsy are independent risk factors for renal events among patients with biopsy-proven benign nephrosclerosis.

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<![CDATA[Development of Glomerulus-, Tubule-, and Collecting Duct-Specific mRNA Assay in Human Urinary Exosomes and Microvesicles]]> https://www.researchpad.co/article/5989da95ab0ee8fa60ba16c0

Urinary exosomes and microvesicles (EMV) are promising biomarkers for renal diseases. Although the density of EMV is very low in urine, large quantity of urine can be easily obtained. In order to analyze urinary EMV mRNA, a unique filter device to adsorb urinary EMV from 10 mL urine was developed, which is far more convenient than the standard ultracentrifugation protocol. The filter part of the device is detachable and aligned to a 96-well microplate format, therefore multiple samples can be processed simultaneously in a high throughput manner following the isolation step. For EMV mRNA quantification, the EMV on the filter is lysed directly by adding lysis buffer and transferred to an oligo(dT)-immobilized microplate for mRNA isolation followed by cDNA synthesis and real-time PCR. Under the optimized assay condition, our method provided comparable or even superior results to the standard ultracentrifugation method in terms of mRNA assay sensitivity, linearity, intra-assay reproducibility, and ease of use. The assay system was applied to quantification of kidney-specific mRNAs such as NPHN and PDCN (glomerular filtration), SLC12A1 (tubular absorption), UMOD and ALB (tubular secretion), and AQP2 (collecting duct water absorption). 12-hour urine samples were collected from four healthy subjects for two weeks, and day-to-day and individual-to-individual variations were investigated. Kidney-specific genes as well as control genes (GAPDH, ACTB, etc.) were successfully detected and confirmed their stable expressions through the two-week study period. In conclusion, this method is readily available to clinical studies of kidney diseases.

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<![CDATA[Impact of High-Cut-Off Dialysis on Renal Recovery in Dialysis-Dependent Multiple Myeloma Patients: Results from a Case-Control Study]]> https://www.researchpad.co/article/5989da56ab0ee8fa60b8edf5

Background

High-cut-off hemodialysis (HCO-HD) can effectively reduce high concentrations of circulating serum free light chains (sFLC) in patients with dialysis-dependent acute kidney injury (AKI) due to multiple myeloma (MM). Therefore, the aim of this study was to analyze renal recovery in a retrospective single-center cohort of dialysis-dependent MM patients treated with either conventional HD (conv. HD) or HCO-HD.

Methods and Results

The final cohort consisted of 59 patients treated with HCO-HD (n = 42) or conv. HD (n = 17). A sustained sFLC response was detected in a significantly higher proportion of HCO-HD patients (83.3%) compared with conv. HD patients (29.4%; p = 0.007). The median duration of sFLC required to reach values <1000 mg/l was 14.5 days in the HCO-HD group and 36 days in the conv. HD group. The corresponding rates of renal recovery were 64.3% and 29.4%, respectively (chi-squared test, p = 0.014). Multivariate regression and decision tree analysis (recursive partitioning) revealed HCO-HD (adjusted odds ratio [OR] 6.1 [95% confidence interval (CI) 1.5–24.5], p = 0.011) and low initial uric acid values (adjusted OR 1.3 [95%CI 1.0–1.7], p = 0.045) as independent and paramount variables associated with a favorable renal outcome.

Conclusions

In summary, the results from this retrospective case-control study suggest in addition to novel agent-based chemotherapy a benefit of HCO-HD in sFLC removal and renal outcome in dialysis-dependent AKI secondary to MM. This finding was especially pertinent in patients with low initial uric acid values, resulting in a promising renal recovery rate of 71.9%. Further prospective studies are warranted.

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<![CDATA[GSTA3 Attenuates Renal Interstitial Fibrosis by Inhibiting TGF-Beta-Induced Tubular Epithelial-Mesenchymal Transition and Fibronectin Expression]]> https://www.researchpad.co/article/5989da7dab0ee8fa60b99415

Tubular epithelial-mesenchymal transition (EMT) has been widely accepted as the underlying mechanisms of renal interstitial fibrosis (RIF). The production of reactive oxygen species (ROS) plays a vital role in tubular EMT process. The purpose of this study was to investigate the involved molecular mechanisms in TGF-beta-induced EMT and identify the potential role of glutathione S-transferase alpha 3 (GSTA3) in this process. The iTRAQ screening was performed to identify protein alterations of the rats underwent unilateral-ureteral obstruction (UUO). Protein expression of GSTA3 in patients with obstructive nephropathy and UUO rats was detected by immunohistochemistry. Protein and mRNA expression of GSTA3 in UUO rats and NRK-52E cells were determined by Western blot and RT-PCR. siRNA and overexpression plasmid were transfected specifically to assess the role of GSTA3 in RIF. The generation of ROS was measured by dichlorofluorescein fluorescence analysis. GSTA3 protein and mRNA expression was significantly reduced in UUO rats. Immunohistochemical analysis revealed that GSTA3 expression was reduced in renal cortex in UUO rats and patients with obstructive nephropathy. Treating with TGF-β1 down-regulated GSTA3 expression in NRK-52E cells, which have been found to be correlated with the decreased expression in E-cadherin and megalin and increased expression in α-smooth muscle actin. Furthermore, knocking down GSTA3 in NRK-52 cells led to increased production of ROS and tubular EMT, whereas overexpressing GSTA3 ameliorated ROS production and prevented the occurrence of tubular EMT. GSTA3 plays a protective role against tubular EMT in renal fibrosis, suggesting GSTA3 is a potential therapeutic target for RIF.

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<![CDATA[Change in iron metabolism in rats after renal ischemia/reperfusion injury]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc3fb

Previous studies have indicated that hepcidin, which can regulate iron efflux by binding to ferroportin-1 (FPN1) and inducing its internalization and degradation, acts as the critical factor in the regulation of iron metabolism. However, it is unknown whether hepcidin is involved in acute renal ischemia/reperfusion injury (IRI). In this study, an IRI rat model was established via right renal excision and blood interruption for 45 min in the left kidney, and iron metabolism indexes were examined to investigate the change in iron metabolism and to analyze the role of hepcidin during IRI. From 1 to 24 h after renal reperfusion, serum creatinine and blood urea nitrogen were found to be time-dependently increased with different degrees of kidney injury. Regular variations in iron metabolism indexes in the blood and kidneys were observed in renal IRI. Renal iron content, serum iron and serum ferritin increased early after reperfusion and then declined. Hepcidin expression in the liver significantly increased early after reperfusion, and its serum concentration increased beginning at 8 h after reperfusion. The splenic iron content decreased significantly in the early stage after reperfusion and then increased time-dependently with increasing reperfusion time, and the hepatic iron content showed a decrease in the early stage after reperfusion. The early decrease of the splenic iron content and hepatic iron content might indicate their contribution to the increase in serum iron in renal IRI. In addition, the duodenal iron content showed time-dependently decreased since 12 h after reperfusion in the IRI groups compared to the control group. Along with the spleen, the duodenum might contribute to the decrease in serum iron in the later stage after reperfusion. The changes in iron metabolism indexes observed in our study demonstrate an iron metabolism disorder in renal IRI, and hepcidin might be involved in maintaining iron homeostasis in renal IRI. These findings might suggest a self-protection mechanism regulating iron homeostasis in IRI and provide a new perspective on iron metabolism in attenuating renal IRI.

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<![CDATA[Initial computed tomography imaging details during first-line systemic therapy is of significant prognostic value in patients with naïve, unresectable metastatic renal cell carcinoma]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be00eb

Purpose

We aimed to determine the prognostic significance of computed tomography imaging parameters of unresectable primary renal tumor lesions, obtained at baseline and at first follow-up, on overall survival in naïve, unresectable metastatic renal cell carcinoma patients during first-line systemic therapy.

Materials and methods

Clinicopathological parameters of 56 patients treated between 2007 and 2015, including imaging parameters (such as the longest tumor diameter, necrotic area diameter, and attenuation in primary renal tumor lesions on baseline vs. follow-up computed tomography), were retrospectively reviewed to derive predictive factors of overall survival. The best overall response was measured according to the RECIST v1.1.

Results

The median treatment period was 206.3 days and the median follow-up was 14.6 months. Forty-four (78.6%) patients progressed after a median 4.6 months of progression-free survival, and 6 (10.7%) patients survived with a median overall survival of 12.5 months. Multivariate analysis showed that the baseline tumor diameter (hazard ratio [HR] 0.903) and mean attenuation (HR 0.936), change of tumor diameter (HR 0.714) and necrosis diameter (HR 0.861), change in the percentage of tumor diameter (HR 1.483) and of necrosis diameter (HR 1.028) between baseline and follow-up computed tomography images; treatment duration (HR 0.986) and baseline serum hemoglobin (HR 1.790) and albumin level (HR 0.060) were significant factors for overall survival (p<0.05).

Conclusion

The study showed that baseline and first follow-up computed tomography findings of primary renal lesions during first-line systemic therapy are useful and significant predictors of OS in patients with naïve unresectable mRCC.

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<![CDATA[Circulating Level of Neutrophil Extracellular Traps Is Not a Useful Biomarker for Assessing Disease Activity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis]]> https://www.researchpad.co/article/5989dad3ab0ee8fa60bb6d8b

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening disorders, and frequently affects the kidneys. This study investigated whether the circulating neutrophil extracellular traps (NETs) levels were associated with disease activity of AAV. We collected serum samples from 34 patients with AAV in active stage and 62 patients with AAV in remission. Cell free DNA in serum was quantified using the Quant-iT PicoGreen assay. NETs associated MPO-DNA complexes, citrullinated-histone H3-DNA (cit-H3-DNA) complexes and the concentration of deoxyribonuclease I (DNase I) were quantified using ELISA. The activity of DNase I was quantified using radial enzyme-diffusion method. Associations between circulating levels of NETs with clinico-pathological parameters were analyzed. Serum levels of NETs in active AAV patients were significantly higher than those in healthy controls, and the level of cell free DNA correlated with C-reactive protein (CRP). However, no correlation was found between MPO-DNA complexes or cit-H3-DNA complexes level and CRP. Also there was no significant correlation between NETs level and initial serum creatinine, estimated glomerular filtration rate (eGFR), crescents formation or Birmingham Vasculitis Activity Score (BVAS). Furthermore, there was no significant difference of serum levels of cell free DNA or MPO-DNA complexes between active stage and remission of AAV. In conclusion, circulating levels of NETs cannot be used as a biomarker to assess disease activity in AAV patients.

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<![CDATA[Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity]]> https://www.researchpad.co/article/5989db1dab0ee8fa60bce93b

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.

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<![CDATA[Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients]]> https://www.researchpad.co/article/5aafc76d463d7e7d7e2e8771

The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme-2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease.

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<![CDATA[Renal Fibrosis mRNA Classifier: Validation in Experimental Lithium-Induced Interstitial Fibrosis in the Rat Kidney]]> https://www.researchpad.co/article/5989d9dfab0ee8fa60b6920b

Accurate diagnosis of fibrosis is of paramount clinical importance. A human fibrosis classifier based on metzincins and related genes (MARGS) was described previously. In this investigation, expression changes of MARGS genes were explored and evaluated to examine whether the MARGS-based algorithm has any diagnostic value in a rat model of lithium nephropathy. Male Wistar rats (n = 12) were divided into 2 groups (n = 6). One group was given a diet containing lithium (40 mmol/kg food for 7 days, followed by 60mmol/kg food for the rest of the experimental period), while a control group (n = 6) was fed a normal diet. After six months, animals were sacrificed and the renal cortex and medulla of both kidneys removed for analysis. Gene expression changes were analysed using 24 GeneChip® Affymetrix Rat Exon 1.0 ST arrays. Statistically relevant genes (p-value<0.05, fold change>1.5, t-test) were further examined. Matrix metalloproteinase-2 (MMP2), CD44, and nephroblastoma overexpressed gene (NOV) were overexpressed in the medulla and cortex of lithium-fed rats compared to the control group. TGFβ2 was overrepresented in the cortex of lithium-fed animals 1.5-fold, and 1.3-fold in the medulla of the same animals. In Gene Set Enrichment Analysis (GSEA), both the medulla and cortex of lithium-fed animals showed an enrichment of the MARGS, TGFβ network, and extracellular matrix (ECM) gene sets, while the cortex expression signature was enriched in additional fibrosis-related-genes and the medulla was also enriched in immune response pathways. Importantly, the MARGS-based fibrosis classifier was able to classify all samples correctly. Immunohistochemistry and qPCR confirmed the up-regulation of NOV, CD44, and TGFβ2. The MARGS classifier represents a cross-organ and cross-species classifier of fibrotic conditions and may help to design a test to diagnose and to monitor fibrosis. The results also provide evidence for a common pathway in the pathogenesis of fibrosis.

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<![CDATA[Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens]]> https://www.researchpad.co/article/5989db17ab0ee8fa60bcd67a

Objectives

Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs).

Methods

This cohort study used US health insurance data spanning the years 2008–2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs).

Results

We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD −3.96; 95% CI: −7.31, −1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD −3.85; 95% CI: −5.02, −2.78).

Conclusions

In this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower or similar to those for all HIV patients, with the lowest IRs observed among patients receiving EFV/FTC/TDF. Compared with all HIV patients, the observed IR for fracture was higher with EVG/COBI/FTC/TDF, comparable with RPV/FTC/TDF, and lower with EFV/FTC/TDF.

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<![CDATA[Renal Dysfunction during Tenofovir Use in a Regional Cohort of HIV-Infected Individuals in the Asia-Pacific]]> https://www.researchpad.co/article/5989d9d7ab0ee8fa60b6616d

Background

In resource-limited settings, routine monitoring of renal function during antiretroviral therapy (ART) has not been recommended. However, concerns for tenofovir disoproxil fumarate (TDF)-related nephrotoxicity persist with increased use.

Methods

We investigated serum creatinine (S-Cr) monitoring rates before and during ART and the incidence and prevalence of renal dysfunction after starting TDF by using data from a regional cohort of HIV-infected individuals in the Asia-Pacific. Time to renal dysfunction was defined as time from TDF initiation to the decline in estimated glomerular filtration rate (eGFR) to <60 ml/min/1.73m2 with >30% reduction from baseline using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or the decision to stop TDF for reported TDF-nephrotoxicity. Predictors of S-Cr monitoring rates were assessed by Poisson regression and risk factors for developing renal dysfunction were assessed by Cox regression.

Results

Among 2,425 patients who received TDF, S-Cr monitoring rates increased from 1.01 to 1.84 per person per year after starting TDF (incidence rate ratio 1.68, 95%CI 1.62–1.74, p <0.001). Renal dysfunction on TDF occurred in 103 patients over 5,368 person-years of TDF use (4.2%; incidence 1.75 per 100 person-years). Risk factors for developing renal dysfunction included older age (>50 vs. ≤30, hazard ratio [HR] 5.39, 95%CI 2.52–11.50, p <0.001; and using PI-based regimen (HR 1.93, 95%CI 1.22–3.07, p = 0.005). Having an eGFR prior to TDF (pre-TDF eGFR) of ≥60 ml/min/1.73m2 showed a protective effect (HR 0.38, 95%CI, 0.17–0.85, p = 0.018).

Conclusions

Renal dysfunction on commencing TDF use was not common, however, older age, lower baseline eGFR and PI-based ART were associated with higher risk of renal dysfunction during TDF use in adult HIV-infected individuals in the Asia-Pacific region.

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<![CDATA[Kidney dysfunction and cerebral microbleeds in neurologically healthy adults]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc34a

Introduction

Cerebral microbleed (CMB) is a potent risk factor for overt cerebrovascular disease. Although some studies indicated the possible role of renal dysfunction as a risk factor of CMB, the findings could not be generalized. This study aimed to investigate the association between renal dysfunction and cerebral microbleed (CMB) in neurologically healthy adults.

Materials and methods

A total of 2,518 subjects who underwent brain MRI as part of health screening were involved in the study. CMBs were defined as well-demarcated focal areas of low signal intensity with associated blooming on the T2-weighted MRI measuring less than 5mm in diameter. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease formula. Kidney function was classified as normal (≥90), mild (60 to 89.9), moderate (30 to 59.9), and severe (<30 mL/min/1.73 m2) renal dysfunction according to the GFR.

Results

The mean age of the participants was 57.5 ± 8.3 years (ranged 40 to 79), and 1,367 subjects (54.3%) were male. The mean GFR level was 81.5 ± 15.5, and the prevalence of CMB was 4.1% (n = 103). Subjects with CMB demonstrated a higher proportion of moderate-to-severe renal dysfunction than those without CMB (15.5% vs. 5.0%, p < 0.001). In the multivariate logistic regression analysis, moderate-to-severe renal dysfunction showed a significant association with CMB (adjusted odd ratio = 2.63; p = 0.008). Furthermore, a decrease in the GFR level was associated with an increasing trend of the presence of CMB (p for trend = 0.031) and number of CMB lesions (p for trend = 0.003).

Conclusions

Renal dysfunction was significantly associated with the presence of CMB in neurologically healthy adults. More studies are needed to evaluate if treatment of kidney disease and risk factor modification may prevent further progress of CMB.

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