Publications by authors named "Antonio Lupo"

117 Publications

Bridge to avoid ICD implantation with wearable cardioverter defibrillators.

Postepy Kardiol Interwencyjnej 2020 Jun 23;16(2):227-228. Epub 2020 Jun 23.

Ospedale Civile, Mirano, Italy.

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http://dx.doi.org/10.5114/aic.2020.96072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333207PMC
June 2020

Cardiac implantable electronic device remote monitoring in a large cohort of patients and the need for planning.

Future Cardiol 2020 Sep 30;16(5):447-456. Epub 2020 Apr 30.

U.O.C. Cardiologia, Ospedale Civile Mirano, Mirano, Venezia, Italy.

The remote monitoring (RM) of cardiac implantable electronic devices (CIED) is standard of care. We describe an organizational and projection RM workload model. At the time of the analysis (2015), 3995 CIED patients were followed-up; 1582 (40.5%) with RM. All RM transmissions (Tx) have been gathered in five event types. We received 10,406 Tx, classified as: 128 (1.2%) red alerts, 141 (1.3%) atrial fibrillation episodes, 1944 (18.6%) yellow alerts, 403 (3.9%) lost Tx (disconnected/noncompliant patients) and 7790 (75.0%) Tx 'OK' (un-eventful Tx). At the time of 100% of remote CIED managed, we can expect a total of 25,990 Tx/year. We provide a descriptive analysis of remote monitoring management and workload estimation in a large cohort of CIED patients.
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http://dx.doi.org/10.2217/fca-2019-0039DOI Listing
September 2020

Single-center experience with wearable cardioverter-defibrillator as a bridge before definitive ICD implantation.

Indian Pacing Electrophysiol J 2020 Mar - Apr;20(2):60-63. Epub 2019 Dec 16.

Cardiac Pacing and Electrophysiology, Cardiology Department, Public Hospital of Mirano, Mirano, VE, Italy; Electrophysiology, Cardiology Department, Public Hospital of Gorizia, Gorizia, Italy.

Background: The wearable cardioverter-defibrillator (WCD) has been approved for patients with poor left ventricular ejection fraction (LVEF) who are at risk of sudden arrhythmic death for a limited period but are not candidates for a definitive implantable cardioverter-defibrillator (ICD). The present study sought to retrospectively analyse our single-centre experience.

Methods And Results: All consecutive WCDs applied between April 2017 and September 2018 in our centre were enrolled. An exercise test was performed in all patients in order to evaluate the absence of false detection of ventricular arrhythmias by the device. A total of 16 patients (57.7 ± 14.8 years old; 75% males) were taken into consideration for the analysis. Mean LVEF was 32 ± 11% at diagnosis and 42 ± 10% at last follow-up (mean, 3.1 ± 1.7 months; median, 3 months). At the end of the "wearing period" 11/16 patients (69%) did not have ICD implant indications and only 5 (31%) underwent ICD implantation. Neither appropriate nor appropriate shocks occurred during the follow up.

Conclusions: The WCD represents a useful tool to bridge a temporarily increased risk for sudden cardiac death. The proportion of patients with an improvement of LVEF> 35% beyond the WCD-application period was considerable.
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http://dx.doi.org/10.1016/j.ipej.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082683PMC
December 2019

Early Small Creatinine Shift Predicts Contrast-Induced Acute Kidney Injury and Persistent Renal Damage after Percutaneous Coronary Procedures.

Cardiovasc Revasc Med 2020 03 30;21(3):305-311. Epub 2019 May 30.

Division of Cardiology, Department of Medicine, Unirsity of Verona, Italy. Electronic address:

Purpose: Little is known on the impact of contrast-induced acute kidney injury (CI-AKI) on mid- and long-term renal function after percutaneous coronary procedure. The aim of the study was to investigate the incidence of persistent renal damage (PRD) after CI-AKI in a cohort of patients undergoing coronary angiography and/or intervention. Moreover, we sought to assess the predictive value of small creatinine change at 12-24 h (SCrΔ%12-24 h) from contrast exposure in predicting CI-AKI and PRD.

Methods: Complete clinical and biochemical data of 731 patients were retrospectively analyzed at sequential time intervals at baseline, 12-24 h and 48-72 h from the procedure. Data at 30 ± 10 days and 12-24 months were available in 59% and 49% of the cases respectively. Logistic regression was used to assess variables associated with CI-AKI and PRD. ROC analysis was used to test the diagnostic accuracy of SCrΔ%12-24 h in predicting CI-AKI and PRD.

Results: CI-AKI occurred in 130/731 patients (17.8%). At 30 ± 10 days PRD occurred in 54.8% patients who developed CI-AKI. A SCrΔ%12-24 h >5% demonstrated independent predictive value (OR = 1.05, CI = 1.04-1.06, p < 0.001) and fair accuracy (AUC = 0.80, CI = 0.77-0.84) for CI-AKI.

Conclusion: CI-AKI was associated with PRD in >50% of the cases in this single centre cohort. A small and early SCrΔ%12-24 h demonstrated high predictive value for CI-AKI and may be used as a useful tool to unmask a group of patients at risk for PRD after percutaneous coronary procedures.
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http://dx.doi.org/10.1016/j.carrev.2019.05.021DOI Listing
March 2020

Proteomic Analysis of Urinary Microvesicles and Exosomes in Medullary Sponge Kidney Disease and Autosomal Dominant Polycystic Kidney Disease.

Clin J Am Soc Nephrol 2019 06 24;14(6):834-843. Epub 2019 Apr 24.

Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy; and

Background And Objectives: Microvesicles and exosomes are involved in the pathogenesis of autosomal dominant polycystic kidney disease. However, it is unclear whether they also contribute to medullary sponge kidney, a sporadic kidney malformation featuring cysts, nephrocalcinosis, and recurrent kidney stones. We addressed this knowledge gap by comparative proteomic analysis.

Design, Setting, Participants, & Measurements: The protein content of microvesicles and exosomes isolated from the urine of 15 patients with medullary sponge kidney and 15 patients with autosomal dominant polycystic kidney disease was determined by mass spectrometry followed by weighted gene coexpression network analysis, support vector machine learning, and partial least squares discriminant analysis to compare the profiles and select the most discriminative proteins. The proteomic data were verified by ELISA.

Results: A total of 2950 proteins were isolated from microvesicles and exosomes, including 1579 (54%) identified in all samples but only 178 (6%) and 88 (3%) specific for medullary sponge kidney microvesicles and exosomes, and 183 (6%) and 98 (3%) specific for autosomal dominant polycystic kidney disease microvesicles and exosomes, respectively. The weighted gene coexpression network analysis revealed ten modules comprising proteins with similar expression profiles. Support vector machine learning and partial least squares discriminant analysis identified 34 proteins that were highly discriminative between the diseases. Among these, CD133 was upregulated in exosomes from autosomal dominant polycystic kidney disease and validated by ELISA.

Conclusions: Our data indicate a different proteomic profile of urinary microvesicles and exosomes in patients with medullary sponge kidney compared with patients with autosomal dominant polycystic kidney disease. The urine proteomic profile of patients with autosomal dominant polycystic kidney disease was enriched of proteins involved in cell proliferation and matrix remodeling. Instead, proteins identified in patients with medullary sponge kidney were associated with parenchymal calcium deposition/nephrolithiasis and systemic metabolic derangements associated with stones formation and bone mineralization defects.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_24_CJASNPodcast_19_06_.mp3.
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http://dx.doi.org/10.2215/CJN.12191018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556712PMC
June 2019

Safety steps for a non-fluoroscopic approach in right-sided electrophysiology procedures: A point of view.

Indian Pacing Electrophysiol J 2019 Sep - Oct;19(5):183-188. Epub 2019 Mar 23.

U.O.C. Cardiologia, Ospedale Civile Mirano, Venezia, Italy.

Background: Electro-anatomic 3D mapping systems enable the fluoroscopy (FL) exposure to be reduced. In right-heart supraventricular tachycardia (SVT) procedures, FL could potentially be avoided. Our aim was to discuss some steps focusing on safety.

Methods And Results: The patient cohort comprised 70 consecutive SVT patients who underwent electrophysiologic (EP) catheterization. FL was routinely avoided in all cases (54.2% males, age 57.2 ± 13.3 years): 51 ablations and 19 EP study procedures. The Carto3 (Biosense Webster) mapping system was used in 17/70 cases (24.3%), and the EnSite Precision™ (Abbott) system in the remaining 53/70 (75.7%). The mean procedure time was 94.1 ± 33.2 min; no FL was used. No major complications occurred. Acute procedural success was achieved in all 51 patients who underwent ablation. Over 3-month follow-up, arrhythmia recurred in 1 patient. There were no significant differences in procedural times between the two mapping systems, except for the time dedicated to the full geometry creation, which was longer for the EnSite Precision™ system: 10 min (8.5-15 IQR) vs 8 min (5-10 IQR) for the Carto system (p < 0.001) mainly due to the sub-diaphragmatic navigation. The following procedural steps were considered critical in order to safely avoid FL use: "loop" advancing of catheters, the use of a fixed intracardiac reference, His signal landmark centered maps and the careful acquisition of sub-diaphragmatic extracardiac geometry.

Conclusions: A routine zero X-ray approach by means of electro-anatomic 3D mapping systems is safe and effective in right-atrium procedures. Some ad-hoc discussed procedural steps may enhance safety.
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http://dx.doi.org/10.1016/j.ipej.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823685PMC
March 2019

In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells.

J Transl Med 2019 01 7;17(1):12. Epub 2019 Jan 7.

Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy.

Background: The epithelial to mesenchymal transition (EMT) is a multi-factorial biological mechanism involved in renal and hepatic fibrosis and the IL-1 beta has been assumed as a mediator of this process although data are not exhaustive. Therefore, the aim of our study was to evaluate the role of this cytokine in the EMT of renal proximal tubular epithelial cells (HK-2) and stellate cells (LX-2) and the protective/anti-fibrotic effect of its inhibition by Canakinumab (a specific human monoclonal antibody targeted against IL-1beta).

Methods: Both cell types were treated with IL-1 beta (10 ng/ml) for 6 and 24 h with and without Canakinumab (5 μg/ml). As control we used TGF-beta (10 ng/ml). Expression of EMT markers (vimentin, alpha-SMA, fibronectin) were evaluated through western blotting and immunofluorescence. Genes expression for matrix metalloproteinases (MMP)-2 was measured by Real-Time PCR and enzymatic activity by zymography. Cellular motility was assessed by scratch assay.

Results: IL-1 beta induced a significant up-regulation of EMT markers in both cell types and increased the MMP-2 protein expression and enzymatic activity, similarly to TGF-beta. Moreover, IL-1 beta induced a higher rate of motility in HK-2. Canakinumab prevented all these modifications in both cell types.

Conclusions: Our results clearly demonstrate the role of IL-1 beta in the EMT of renal/stellate cells and it underlines, for the first time, the therapeutic potential of its specific inhibition on the prevention/minimization of organ fibrosis.
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http://dx.doi.org/10.1186/s12967-019-1770-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323803PMC
January 2019

Inhibition of heparanase protects against chronic kidney dysfunction following ischemia/reperfusion injury.

Oncotarget 2018 Nov 16;9(90):36185-36201. Epub 2018 Nov 16.

Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy.

Renal ischemia/reperfusion (I/R) injury occurs in patients undergoing renal transplantation and with acute kidney injury and is responsible for the development of chronic allograft dysfunction as characterized by parenchymal alteration and fibrosis. Heparanase (HPSE), an endoglycosidase that regulates EMT and macrophage polarization, is an active player in the biological response triggered by ischemia/reperfusion (I/R) injury. I/R was induced by clamping left renal artery for 30 min in wt C57BL/6J mice. Animals were daily treated and untreated with Roneparstat (an inhibitor of HPSE) and sacrificed after 8 weeks. HPSE, fibrosis, EMT-markers, inflammation and oxidative stress were evaluated by biomolecular and histological methodologies together with the evaluation of renal histology and measurement of renal function parameters. 8 weeks after I/R HPSE was upregulated both in renal parenchyma and plasma and tissue specimens showed clear evidence of renal injury and fibrosis. The inhibition of HPSE with Roneparstat-restored histology and fibrosis level comparable with that of control. I/R-injured mice showed a significant increase of EMT, inflammation and oxidative stress markers but they were significantly reduced by treatment with Roneparstat. Finally, the inhibition of HPSE almost restored renal function as measured by BUN, plasma creatinine and albuminuria. The present study points out that HPSE is actively involved in the mechanisms that regulate the development of renal fibrosis arising in the transplanted organ as a consequence of ischemia/reperfusion damage. HPSE inhibition would therefore constitute a new pharmacological strategy to reduce acute kidney injury and to prevent the chronic pro-fibrotic damage induced by I/R.
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http://dx.doi.org/10.18632/oncotarget.26324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281411PMC
November 2018

Interleukin-27 is a potential marker for the onset of post-transplant malignancies.

Nephrol Dial Transplant 2019 01;34(1):157-166

Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

Background: Malignancies represent the third leading cause of post-transplant mortality worldwide. The main challenge for transplant physicians is a timely diagnosis of this condition. The aim of the study was to identify a soluble diagnostic marker for monitoring the development of post-transplant malignancies.

Methods: This is a multicentre, observational, perspective, case-control study. We enrolled 47 patients with post-transplant solid neoplasia. As a control group we employed 106 transplant recipients without a history of neoplasia and matched them with cases for the main demographic and clinical features. We investigated the transcriptomic profiles of peripheral blood mononuclear cells from kidney graft recipients with and without post-transplant malignancies enrolled in two of the participating centres, randomly selected from the whole study population. Microarray results were confirmed by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) in the remaining patients from the same transplant centres and validated in a further independent group enrolled in two different transplant centres.

Results: We identified 535 differentially expressed genes comparing patients with and without post-transplant malignancies (fold change ≥2.5; false discovery rate <5%). The cancer pathway was closely related to gene expression data, and one of the most down-regulated genes in this pathway was interleukin-27 (IL-27), a cytokine regulating anti-tumour immunity. Quantitative PCR and ELISA confirmed the microarray data. Interestingly, IL-27 plasma levels were able to discriminate patients with post-transplant neoplasia with a specificity of 80% and a sensitivity of 81%. This observation was confirmed in an independent set of patients from two different transplant centres.

Conclusions: Our data suggest that IL-27 may represent a potential immunological marker for the timely identification of post-transplant neoplasia.
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http://dx.doi.org/10.1093/ndt/gfy206DOI Listing
January 2019

In Vitro Identification of New Transcriptomic and miRNomic Profiles Associated with Pulmonary Fibrosis Induced by High Doses Everolimus: Looking for New Pathogenetic Markers and Therapeutic Targets.

Int J Mol Sci 2018 Apr 20;19(4). Epub 2018 Apr 20.

Renal Unit, Department of Medicine, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy.

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (α-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets.
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http://dx.doi.org/10.3390/ijms19041250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979287PMC
April 2018

Assessment of physical performance and body composition in male renal transplant patients.

J Nephrol 2018 08 17;31(4):613-620. Epub 2018 Mar 17.

Division of Geriatrics, Department of Medicine, University of Verona, Verona, Italy.

Background: Renal transplant (RTX) recipients seem to experience a better quality of life compared to dialysis patients. However, the factors responsible for this positive effect are not completely defined. Conceivably, a change in the physical performance of these patients could play a role.

Methods: To assess this, we measured: (1) waist circumference, fat mass and appendicular fat-free mass (aFFM) by dual-energy X-ray densitometry, (2) physical performance with the Short Physical Performance Battery, and (3) muscle strength with the handgrip test, in 59 male RTX, 11 chronic kidney disease in conservative treatment (CKD) and 10 peritoneal dialysis (PD) patients.

Results: Surprisingly, anthropometric characteristics and body composition were similar among the three groups. However, despite a low aFFM, muscle strength was higher in stable RTX recipients > 5 years after transplantation than in dialyzed patients. Instead, CKD (wait-listed for RTX) had similar muscle strength to RTX patients. Waist circumference in RTX recipients showed a redistribution of body fat with increased central adipose tissue allocation compared to PD. At linear regression analysis, age, weight, height, aFFM, hemoglobin and transplant age were independent predictors of handgrip strength, explaining about 37% of the variance. Age and transplant age accounted for 18 and 12% of variance, respectively.

Conclusions: Our study demonstrates, for the first time, that clinically stable RTX recipients have greater muscle strength than dialyzed patients and suggests that the handgrip test could be an effective and easy-to-perform tool to assess changes in physical performance in this large patient population.
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http://dx.doi.org/10.1007/s40620-018-0483-5DOI Listing
August 2018

mTOR Inhibition Role in Cellular Mechanisms.

Transplantation 2018 02;102(2S Suppl 1):S3-S16

Renal Unit, Department of Medicine, University of Verona, Verona, Italy.

The mammalian target of rapamycin inhibitors (mTOR-I), drugs widely used in transplant medicine and oncology, exert their function by inhibiting a serine/threonine kinase with a pivotal role in cellular metabolism and in a wide range of eukaryotic biological/cellular functions and signaling networks. Additionally, as largely described, the inhibition of mTOR has a major impact on cellular metabolism by stimulating synthesis of proteins and lipids, inhibiting catabolic processes, such as lysosome biogenesis and autophagy, and controlling cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis. All these biological functions are essential to guarantee body homeostasis and survival. Therefore, it is necessary for clinicians and researchers to better understand this complex pathway to ameliorate patients' treatment empathizing therapeutic effects to minimize/avoid toxicities and to propose new valuable research strategies.The aim of this article has been to underline the complexity of the mTOR pathway and to review the recent literature describing the consequences of its inhibition on several cellular functions including (a) protein synthesis, (b) cell cycle,
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http://dx.doi.org/10.1097/TP.0000000000001806DOI Listing
February 2018

Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.

FASEB J 2018 02 4;32(2):742-756. Epub 2018 Jan 4.

Department of Biomedical Sciences Padova, University of Padova, Padua, Italy.

Heparanase (HPSE) is part of the biologic network triggered by ischemia/reperfusion (I/R) injury, a complication of renal transplantation and acute kidney injury. During this period, the kidney or graft undergoes a process of macrophages recruitment and activation. HPSE may therefore control these biologic effects. We measured the ability of HPSE and its inhibitor, SST0001, to regulate macrophage polarization and the crosstalk between macrophages and HK-2 renal tubular cells during in vitro hypoxia/reoxygenation (H/R). Furthermore, we evaluated in vivo renal inflammation, macrophage polarization, and histologic changes in mice subjected to monolateral I/R and treated with SST0001 for 2 or 7 d. The in vitro experiments showed that HPSE sustained M1 macrophage polarization and modulated apoptosis, the release of damage associated molecular patterns in post-H/R tubular cells, the synthesis of proinflammatory cytokines, and the up-regulation of TLRs on both epithelial cells and macrophages. HPSE also regulated M1 polarization induced by H/R-injured tubular cells and the partial epithelial-mesenchymal transition of these epithelial cells by M1 macrophages. All these effects were prevented by inhibiting HPSE. Furthermore, the inhibition of HPSE in vivo reduced inflammation and M1 polarization in mice undergoing I/R injury, partially restored renal function and normal histology, and reduced apoptosis. These results show for the first time that HPSE regulates macrophage polarization as well as renal damage and repair after I/R. HPSE inhibitors could therefore provide a new pharmacologic approach to minimize acute kidney injury and to prevent the chronic profibrotic damages induced by I/R.-Masola, V., Zaza, G., Bellin, G., Dall'Olmo, L., Granata, S., Vischini, G., Secchi, M. F., Lupo, A., Gambaro, G., Onisto, M. Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury.
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http://dx.doi.org/10.1096/fj.201700597RDOI Listing
February 2018

Naturally Occurring Compounds: New Potential Weapons against Oxidative Stress in Chronic Kidney Disease.

Int J Mol Sci 2017 Jul 10;18(7). Epub 2017 Jul 10.

Renal Unit, Department of Medicine, University-Hospital of Verona, Verona 37126, Italy.

Oxidative stress is a well-described imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system of cells and tissues. The overproduction of free radicals damages all components of the cell (proteins, lipids, nucleic acids) and modifies their physiological functions. As widely described, this condition is a biochemical hallmark of chronic kidney disease (CKD) and may dramatically influence the progression of renal impairment and the onset/development of major systemic comorbidities including cardiovascular diseases. This state is exacerbated by exposure of the body to uremic toxins and dialysis, a treatment that, although necessary to ensure patients' survival, exposes cells to non-physiological contact with extracorporeal circuits and membranes with consequent mitochondrial and anti-redox cellular system alterations. Therefore, it is undeniable that counteracting oxidative stress machinery is a major pharmacological target in medicine/nephrology. As a consequence, in recent years several new naturally occurring compounds, administered alone or integrated with classical therapies and an appropriate lifestyle, have been proposed as therapeutic tools for CKD patients. In this paper, we reviewed the recent literature regarding the "pioneering" in vivo testing of these agents and their inclusion in small clinical trials performed in patients affected by CKD.
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http://dx.doi.org/10.3390/ijms18071481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535971PMC
July 2017

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

PLoS One 2017 24;12(5):e0178228. Epub 2017 May 24.

Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy.

Background: The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.

Methods: We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group).

Results: A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.

Conclusions: Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443527PMC
September 2017

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545.

Oncotarget 2017 May;8(21):34191-34204

Department of Medicine, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy.

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.
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http://dx.doi.org/10.18632/oncotarget.16573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470960PMC
May 2017

A single dialysis session of hemodiafiltration with sorbent-regenerated endogenous ultrafiltrate reinfusion (HFR) removes hepcidin more efficiently than bicarbonate hemodialysis: a new approach to containing hepcidin burden in dialysis patients?

J Nephrol 2018 04 28;31(2):297-306. Epub 2017 Mar 28.

Emodialisi Borgo Roma, Nephrology Section, Department of Medicine, University of Verona, Piazzale LA Scuro 10, 37134, Verona, Italy.

Background: Most hemodialysis patients have high Hepcidin-25 levels, which may be involved in the pathogenesis of several uremic complications related to an altered iron biology. The hemodialysis procedure itself can influence Hepcidin-25 levels by removing Hepcidin-25 and maybe stimulating its production due to a pro-inflammatory effect.

Methods: To assess the relationship between dialysis-related inflammation and intradialysis changes in Hepcidin-25, we performed a crossover trial in 28 hemodialysis patients to compare the effects on serum levels of Hepcidin-25 and inflammatory markers activated during dialysis [Tumor Necrosis Factor-α (TNF-α), Interleukin-6, C-reactive protein (CRP), Pentraxin-3] of a single dialysis session using a technique capable of reducing inflammation, HFR (Hemo Filtrate Reinfusion: a hemodiafiltration system combining convection, diffusion and adsorption) or bicarbonate-dialysis using either the same low-flux membrane as in the diffusion stage of HFR (LFBD) or a high-flux membrane (HFBD).

Results: HFR achieved a greater reduction in Hepcidin-25 levels than both LFBD [-72% (95% CI: -11 to -133), p = 0.022] and HFBD [-137% (95% CI: -2 to -272), p = 0.047], conceivably due to both a greater removal (because of its convective/adsorptive component) and a lower inflammation-related Hepcidin-25 production. HFR also led to a greater decrease in TNF-α than LFBD [-277% (95% CI: -59 to -494), p = 0.014], while the two methods induced similar changes in Interleukin-6, CRP and Pentraxin-3 levels.

Conclusions: Our findings suggest that a single bicarbonate-dialysis session can upregulate Hepcidin-25 synthesis and that HFR can fully overcome this effect, enabling a greater Hepcidin-25 removal during dialysis. Adequately-designed studies are needed, however, to establish whether the beneficial effect of HFR emerging from our study could reduce Hepcidin-25 (and TNF-α) burden and improve clinically-relevant outcomes.

Trial Registration: ISRCTN15957905.
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http://dx.doi.org/10.1007/s40620-017-0383-0DOI Listing
April 2018

[HFR aequilibrium can be an answer to malnutrition and hypotension in dialisys: case report].

G Ital Nefrol 2016 Nov-Dec;33(6)

The interdialytic hypotension is still the most frequent complication during the hemodialysis. A-HFR has dynamic profiles of ultrafiltration and conductivity of the dialysate that ensure a better refilling and reduce compliance during the dialysis treatment, furthermore reduce the amino acid loss and has a lower inflammatory effect. In our Center, we wanted to analyze the impact of this kind of dialysis on intradialytic tolerance and nutritional status in two malnourished patients with encouraging data on the use of AHFR in malnutrition and disequilibrium syndromes.
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October 2017

Specific heparanase inhibition reverses glucose-induced mesothelial-to-mesenchymal transition.

Nephrol Dial Transplant 2017 Jul;32(7):1145-1154

Renal Unit, Department of Medicine, Verona University Hospital, Verona, Italy.

Background: Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells induced by high glucose (HG) levels is a major biological mechanism leading to myofibroblast accumulation in the omentum of patients on peritoneal dialysis (PD). Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate chains, is involved in the EMT of several cell lines, and may have a major role in this pro-fibrotic process potentially responsible for the failure of dialysis. Its specific inhibition may therefore plausibly minimize this pathological condition.

Methods: An in vitro study employing several biomolecular strategies was conducted to assess the role of HPSE in the HG-induced mesothelial EMT process, and to measure the effects of its specific inhibition by SST0001, a N-acetylated glycol-split heparin with a strong anti-HPSE activity. Rat mesothelial cells were grown for 6 days in HG (200 mM) culture medium with or without SST0001. Then EMT markers (VIM, α-SMA, TGF-β) and vascular endothelial growth factor (VEGF) (a factor involved in neoangiogenesis) were measured by real-time PCR and immunofluorescence/western blotting. As a functional analysis, trans-epithelial resistance (TER) and permeability to albumin were also measured in our in vitro model using a Millicell-ERS ohmmeter and a spectrophotometer, respectively.

Results: Our results showed that 200 mM of glucose induced a significant gene and protein up-regulation of VEGF and all EMT markers after 6 days of culture. Intriguingly, adding SST0001 on day 3 reversed these biological and cellular effects. HPSE inhibition also restored the normal TER and permeability lost during the HG treatment.

Conclusion: Taken together, our data confirm that HG can induce EMT of mesothelial cells, and that HPSE plays a central part in this process. Our findings also suggest that pharmacological HPSE inhibition could prove a valuable therapeutic tool for minimizing fibrosis and avoiding a rapid decline in the efficacy of dialysis in patients on PD, though clinical studies and/or trials would be needed to confirm the clinical utility of this treatment.
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http://dx.doi.org/10.1093/ndt/gfw403DOI Listing
July 2017

and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

J Am Soc Nephrol 2017 Mar 5;28(3):981-994. Epub 2016 Dec 5.

Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
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http://dx.doi.org/10.1681/ASN.2016020131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328154PMC
March 2017

Proteomic-based research strategy identified laminin subunit alpha 2 as a potential urinary-specific biomarker for the medullary sponge kidney disease.

Kidney Int 2017 02 1;91(2):459-468. Epub 2016 Dec 1.

Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy. Electronic address:

Medullary sponge kidney (MSK) disease, a rare kidney malformation featuring recurrent renal stones and nephrocalcinosis, continues to be diagnosed using expensive and time-consuming clinical/instrumental tests (mainly urography). Currently, no molecular diagnostic biomarkers are available. To identify such we employed a proteomic-based research strategy utilizing urine from 22 patients with MSK and 22 patients affected by idiopathic calcium nephrolithiasis (ICN) as controls. Notably, two patients with ICN presented cysts. In the discovery phase, the urine of 11 MSK and 10 controls, were randomly selected, processed, and analyzed by mass spectrometry. Subsequently, several statistical algorithms were undertaken to select the most discriminative proteins between the two study groups. ELISA, performed on the entire patients' cohort, was used to validate the proteomic results. After an initial statistical analysis, 249 and 396 proteins were identified exclusive for ICN and MSK, respectively. A Volcano plot and ROC analysis, performed to restrict the number of MSK-associated proteins, indicated that 328 and 44 proteins, respectively, were specific for MSK. Interestingly, 119 proteins were found to differentiate patients with cysts (all patients with MSK and the two ICN with renal cysts) from ICN without cysts. Eventually, 16 proteins were found to be common to three statistical methods with laminin subunit alpha 2 (LAMA-2) reaching the higher rank by a Support Vector Machine, a binary classification/prediction scheme. ELISA for LAMA-2 validated proteomic results. Thus, using high-throughput technology, our study identified a candidate MSK biomarker possibly employable in future for the early diagnosis of this disease.
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http://dx.doi.org/10.1016/j.kint.2016.09.035DOI Listing
February 2017

Everolimus-induced epithelial to mesenchymal transition (EMT) in bronchial/pulmonary cells: when the dosage does matter in transplantation.

J Nephrol 2016 Dec 29;29(6):881-891. Epub 2016 Mar 29.

Department of Medicine, Renal Unit, University of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy.

Background: Everolimus (EVE) is a mammalian target of rapamycin inhibitor (mTOR-I) widely used in transplantation that may determine some severe adverse events, including pulmonary fibrosis. The pathogenic mechanism of mTOR-I-associated pulmonary toxicity is still unclear, but epithelial to mesenchymal transition (EMT) of bronchial/pulmonary cells may play a role.

Methods: Three cell lines-human type II pneumocyte-derived A549, normal bronchial epithelial, and bronchial epithelial homozygous for the delta F508 cystic fibrosis-causing mutation-were treated with EVE or tacrolimus at different concentrations. Real-time polymerase chain reaction and immunofluorescence were used to evaluate mRNA and protein levels of EMT markers (alpha-SMA, vimentin, fibronectin). Subsequently, in 13 EVE- and 13 tacrolimus-treated patients we compared the rate of lung fibrosis, estimated by an arbitrary pulmonary fibrosis index score (PFIS).

Results: Biomolecular experiments demonstrated that high doses of EVE (100 nM) up-regulated EMT markers in all cell lines at both gene- and protein level. High concentrations of EVE were also able to reduce the mRNA levels of epithelial markers (E-cadherin and ZO-1) and to induce the phosphorylation of AKT. In the in vivo part of the study, PFIS was significantly higher in the EVE-group than the tacrolimus-group (p = 0.03) and correlated with trough levels (R = 0.35).

Conclusions: Our data reveal, for the first time, a dose-dependent EVE-induced EMT in airway cells. They suggest that clinicians should employ, wherever possible, low dosages of mTOR-Is in transplant recipients, assessing periodically their pulmonary function.
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http://dx.doi.org/10.1007/s40620-016-0295-4DOI Listing
December 2016

New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers.

Urolithiasis 2017 Aug 29;45(4):359-362. Epub 2016 Aug 29.

Division of Nephrology, Department of Medical Sciences, Catholic University of the Sacred Heart, Rome, Italy.

Medullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET-GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.
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http://dx.doi.org/10.1007/s00240-016-0913-6DOI Listing
August 2017

Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury.

PLoS One 2016 28;11(7):e0160074. Epub 2016 Jul 28.

Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Background: Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFβ-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models.

Methods: Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies.

Results: In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48-72 h. Noteworthy, these effects were absent in WT animals.

Conclusions: In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160074PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965068PMC
August 2017

Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease.

Biomed Res Int 2016 21;2016:9290857. Epub 2016 Jun 21.

Renal Unit, Department of Medicine, University Hospital of Verona, Piazzale Stefani 1, 37126 Verona, Italy.

Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The "omics" techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other "omics" methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients.
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http://dx.doi.org/10.1155/2016/9290857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932167PMC
February 2017

[Cystinic nephrolythiasis: clinical experience and new diagnostic and therapeutic perspectives].

G Ital Nefrol 2016 May-Jun;33(3)

Cystinuria is an inherited autosomal recessive disease with a prevalence 1:7000 and typical age of onset in the second decade of life. This nephrolithiasis is not always well known and well studied and for this reason it is often underdiagnosed. Cystinuria is characterized by increased urinary excretion of cystine and dibasic amino acids (lysine, ornithine, arginine) caused by defective transport of these amino acids across the luminal membrane of proximal tubule and small intestine cells. Two mutated genes responsible of this tubular defect are SLC3A1 on chromosome 2 and SLC7A9 on chromosome 19. Clinical manifestations of cystinuria are essentially those related to stones formation and their movement across the urinary tract, like flank pain/abdomen pain and hematuria, as occurred in other nephrolithiasis types. Diagnosis is based on biochemical urine analysis, stone analysis and imaging. Genetic study of this disease may be a new and stimulating approach to better understand the defects and identify new therapeutic targets. A wider knowledge and a more detailed approach to cystinuria may help to ameliorate patients quality of life, to prevent recurrences and complications and to develop more specific and adequate treatments.
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November 2017

Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects.

Int J Mol Sci 2016 May 14;17(5). Epub 2016 May 14.

Renal Unit, Department of Medicine, University/Hospital of Verona, 37126 Verona, Italy.

Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific "SRL/EVR genes-focused pathway", possibly employable as a starting point for future in-depth research projects.
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http://dx.doi.org/10.3390/ijms17050735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881557PMC
May 2016

Long-Term (3 Years) Prognosis of Contrast-Induced Acute Kidney Injury After Coronary Angiography.

Am J Cardiol 2016 Jun 23;117(11):1741-6. Epub 2016 Mar 23.

Department of Cardiology, University of Verona, Italy. Electronic address:

Contrast-induced acute kidney injury (CI-AKI) after coronary angiography or interventions is relatively frequent and portends adverse outcomes. The lack of a "universally accepted" definition, however, limits the integration and comparison of available data. We aimed to detect the CI-AKI definition that best correlates with the occurrence of clinical events at long-term in a 3-year follow-up study of patients at intermediate-to-high risk for CI-AKI. Furthermore, we sought to describe the incidence and long-term evolution of persistent renal damage (PRD) after CI-AKI and clarify the role of early (<12 hours) increments of serum creatinine (SCr) in CI-AKI prediction. Among a total of 216 patients enrolled at our center and followed for a median of 37 months, CI-AKI was diagnosed in 18.1% of cases (SCr increment ≥25% of baseline), 7.4% (SCr increment ≥0.5 mg/dl), and in 17.1% (SCr increment ≥0.3 mg/dl), according to 3 different definitions. The third definition was the only one significantly associated with the occurrence of events at 3 years (Cox regression, p = 0.04). PRD at 30 days, as detected by the same cutoff, significantly and independently identified patients at risk of worst outcomes at 3 years (p = 0.04 at multivariate Cox regression). Furthermore, a slight 5% to 10% increment of SCr compared with baseline, occurring as early as 12 hours postprocedure, was confirmed as a strong predictor of inhospital CI-AKI occurrence. In conclusion, an absolute increase in SCr ≥0.3 mg/dl seems to be most clinically informative cutoff for CI-AKI and PRD detection.
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http://dx.doi.org/10.1016/j.amjcard.2016.03.008DOI Listing
June 2016

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Nat Commun 2016 Jan 21;7:10023. Epub 2016 Jan 21.

Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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http://dx.doi.org/10.1038/ncomms10023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735748PMC
January 2016