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Aim: The remote monitoring (RM) of cardiac implantable electronic devices (CIED) is standard of care. We describe an organizational and projection RM workload model. Methods: 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. Results: 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. Conclusion: We provide a descriptive analysis of remote monitoring management and workload estimation in a large cohort of CIED patients.

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. Keywords: Wearable cardioverter-defibrillator, Sudden arrhythmic death

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 Carto®3 (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

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.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.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 h5% 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.CI-AKI was associated with PRD in50% 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.

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. 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). 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. 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

Introduction The remote control (RC) of CIED has become necessary, though the human resources and technical facilities needed are limited. In most of Centers, the ratio of RC CIED /CIED with in-office follow up, is continuously increasing and is expected to reach the 100% of CIED remotely controlled. We sought assess an organizational model based on available facilities and a long-term projection of RC data burden. Pacemakers, ICD and implantable loop recorders were considered. Methods The total population served by the Hospital area has been obtained (271.260 citizens), timed at December 31st 2014. By checking our Hospital data files, the total number of followed up CIED patients timed at January 1st 2011 (3995; 1.47% of all population), was compared with the same data timed at January 1st 2015 (3902; 1.43% of all population), in order to the check for the “stability” of that data over time. At the analyzed time 1582/3902 (40,5%) of CIED were followed by RC. We have then considered an yearly average of 465 CIEDs implanted/replaced (yearly implants 2012 to 2015) and excluded a roughly 10% of them because not provided of RC facilities (unwilling patients or CIED not RC “ready”); all the other patients were provided with RC. On these basis, we can assume a ratio of RC CIEDs /non-RC CIED, deemed to increase by 10 to 11% per year, to reach the break-even of 100% of RC CIEDs, in 2021 (projection). The number of RC transmissions (Tx) have been gathered in 5 types of events (Fig. left upper). The timing of RC patient managing from opening the CIED web site to complete patient file assessment (RC file analysis) performed by expert nurses, was arbitrarily calculated over a sample of 10 Tx per day in 3 different days. Results Of 3902 CIED patient, 1582 (40.5%) were RC followed up (3261 pacemakers, 594 ICDs and 47 implantable loop recorder); the CIED brands were represented as follows: Medtronic 685 (43.3%); St. Jude 180 (11.4%), Boston Sc. 330 (20.8%), Biotronik 318 (20.1%) and Livanova (previously SorinGroup) 69 (4.4%). During the year 2015 we received a total number of 10396 Tx: 128 (1.2%) red alert; 1944 (18.6%) yellow alert, 141 (1.3%) atrial fibrillation; 403 (3.9%) lost Tx (disconnected transmitters or un-compliant patients for remote interrogation) and 7780 (75%) Tx “OK” with NO events. (Fig. right upper). The projection model at 2021 with 100% RC patients (break-even) shows a total 25990 Tx: 320 red alert; 1944 yellow alert, 352 atrial fibrillation; 1007 lost Tx and 19459 Tx “OK”. The 2021 monthly Tx would be 2320 (26 red alert; 405 yellow alert, 29 atrial fibrillation; 91 lost Tx and 1769 (75%) Tx “OK”) (Fig. both lower panels) The RC file analysis was roughly calculated around 3 minutes (116 hours/month); 5.8 hours/business day (Monday–Friday). Conclusion The rate of RC followed up CIEDs will inexorably increase by time. The projection management model presented could help to build a sustainable organization.

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

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. Electronic supplementary material The online version of this article (10.1186/s12967-019-1770-1) contains supplementary material, which is available to authorized users.

Most recent evidence suggest that mitochondrial dysfunction plays a primary role in the development of chronic kidney disease and of severe associated comorbidities. This raises the possibility of considering mitochondria as a new possible therapeutic target in this important pathological condition.A variety of natural extracts from plants in combination with conventional therapies and with a proper lifestyle could help doctors to reach the ambitious goal of preventing and slowing down chronic kidney disease progression. Herbal remedies, known during the centuries in traditional medicines of countries all around the world such as black cumin, turmeric, green tea, olive and others are potential resources for extraction and purification of antioxidants and mitochondria-modulating substances, as many studies, some of which reported below, have partly already shown, also in nephrology. Many of them are characteristic of the Mediterranean diet; this diet appears effective in terms of prevention and prognosis i...

Background Acute kidney injury (AKI) after liver transplantation (LT) is a frequent and serious complication. The incidence of AKI requiring continuous renal replacement therapy (CRRT) ranges from 10% to 30%. Kidney Disease: Improving Global Outcomes guidelines indicate the use of citrate as a locoregional anticoagulant drug for CRRT regardless of the patient's hemorrhagic risk. Despite this indication, however, the use of citrate is still under debate in patients with liver failure and/or LT owing to the potential risk of plasmatic citrate accumulation due to reduced liver clearance. The aim of this study was to evaluate the safety and efficacy of citrate as a locoregional anticoagulation drug in CRRT for AKI after LT. Methods A retrospective analysis was performed in patients with AKI after liver transplantation who were treated with CRRT using citrate as local anticoagulant. Five patients were enrolled from January to December 2015. Results No patients showed complications related to citrate (metabolic acidosis, hyperlactatemia, hypercalcemia, or hypernatremia). All treatments with heparin were stopped owing to circuit clotting. Treatments with citrate was interrupted where it was no longer needed or when other examinations had to be made. None were stopped because of circuit coagulation. Conclusions At our center, 5 patients have been successfully treated with the use of CRRT with citrate for AKI during the post-LT course. Our results, though on a small series of patients, provide evidence that CRRT with citrate can be a safe and promising treatment for AKI after LT.

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.

Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn–Tolosa–Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.

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

Il trattamento poli-farmacologico ha determinato, nel corso degli anni, un significativo rallentamento della progressione della malattia renale cronica verso lo stadio di uremia terminale, ma siamo ancora distanti dallo sviluppo di interventi terapeutici in grado di bloccare questo inesorabile e irreversibile processo. Studi clinico-patologici hanno chiaramente dimostrato che il principale elemento coinvolto nel danno renale è la fibrosi tubulo-interstiziale e che il meccanismo patogenetico alla base di questa condizione ha inizio in larga parte nel compartimento tubulare. In particolare, il processo di transizione epitelio-mesenchimale gioca un ruolo importante nella genesi del danno cronico. Durante questo processo, le cellule epiteliali tubulari subiscono un incremento significativo di markers di superficie di natura mesenchimale e, grazie al rimodellamento del citoscheletro e alla degradazione della membrana basale, sono in grado di migrare nell'interstizio dove svolgono un ruolo chiave nel processo patogenetico. In questo contesto, sembra avere un ruolo chiave l'enzima eparanasi, una endo-β-D-glucuronidasi che taglia le catene dell'eparan-solfato a livello di siti specifici intracatena, e partecipa attivamente alla degradazione e al rimodellamento della matrice extracellulare. La degradazione dei vari costituenti dell'ECM, inclusi i proteoglicani eparan-solfato fa-vorisce il rilascio di fattori trofici quali il FGF-2 che induce l'espressione dei marcatori mesenchimali alfa-SMA, VIM e FN, porta alla degradazione della membrana basale mediante la secrezione di metalloproteinasi della matrice ed aumenta la motilità cellulare. L'epressione dell'eparanasi è regolata da fattori di trascrizione, dalla metilazione del DNA e da varie molecole endogene. L'importanza di questo enzima è stata confermata clinicamente dal riscontro di una sua iperespressione in preparati istologici di biopsie effettuate in soggetti affetti da nefropatie croniche (per esempio, nefropatia diabetica). Pertanto visto l'importante ruolo dell'eparanasi sono in fase di standardizzazione numerose strategie per inibire la sua espressione genica e/o la sua attività enzimatica. Infine, è stato proposto il suo possibile utilizzo come biomarker di progressione del danno tubulo-interstiziale da utilizzare routinariamente in ambito nefrologico.

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 in vivo 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 in vivo 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.

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. 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. 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. 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.

Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control biopsies. We conclude that type I interferon signalling may represent the molecular signature of CAMR.

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.

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 (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1

// Zaid Abassi 1,2 , Shadi Hamoud 3 , Ahmad Hassan 4 , Iyad Khamaysi 5 , Omri Nativ 1 , Samuel N. Heyman 6 , Rabia Shekh Muhammad 3 , Neta Ilan 7 , Preeti Singh 7 , Edward Hammond 8 , Gianluigi Zaza 9 , Antonio Lupo 9 , Maurizio Onisto 10 , Gloria Bellin 9 , Valentina Masola 9 , Israel Vlodavsky 7 and Giovani Gambaro 11 1 Department of Physiology, The Rappaport Faculty of Medicine, Technion, Haifa, Israel 2 Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel 3 Department of Internal Medicine E, Rambam Health Care Campus, Haifa, Israel 4 Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel 5 Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel 6 Department of Internal Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel 7 Department of Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel 8 Zucero Therapeutics, Brisbane, Queensland, Australia 9 Department of Medicine, Renal Unit, Verona, Italy 10 Department of Biomedical Sciences, University of Padova, Catholic University of the Sacred Heart, Roma, Italy 11 Department of Medicine, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy Correspondence to: Zaid Abassi, email: // Israel Vlodavsky, email: // Keywords : acute kidney injury, heparanase, ischemia, inflammation, PG545 Received : February 09, 2017 Accepted : March 16, 2017 Published : March 25, 2017 Abstract 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.

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.

Kidney stone disease is associated with a higher incidence of cardio-vascular (CV) events for still unclear reasons. Reduced bone density is also a frequent finding in calcium kidney stones. The association of reduced bone density with increased vascular stiffness and calcification has been discovered in a number of conditions. We investigated the hypothesis that patients with calcium kidney stones have increased arterial stiffness, which would be associated with reduced bone density and higher CV risk. We compared measures of arterial stiffness [carotid-radial pulse-wave velocity (CR-PWV), carotid-femoral pulse-wave velocity (CF-PWV) and augmentation index (AI)] and of bone density (T-scores determined at lumbar spine, neck and hip) among 42 idiopathic calcium stone formers compared with 42 age- and sex-matched healthy volunteers. Stone formers had higher values of CR-PWV, CF-PWV and AI, and lower values of all T-scores. Furthermore, the prevalence of abnormal arterial stiffness and reduced bone density was significantly higher among stone formers. Statistical adjustment for age, sex, body mass index and other covariates did not change the results. Our study confirms that stone formers have increased arterial stiffness and reduced bone density. Abnormal arterial stiffness appears to be independent of reduced bone density and may explain the higher CV risk observed in stone formers.

Mammalian target of rapamycin inhibitors (mTOR-I), everolimus and sirolimus, are immunosuppressive drugs extensively used in renal transplantation. Their main mechanism of action is the inhibition of cell signaling through the PI3 K/Akt/mTOR pathway. This interesting mechanism of action confers to these medications both great immunosuppressive potential and important anti-neoplastic properties. Although the clinical utility of this drug category, as with other antineoplastic/immunosuppressants, is clear, the use of mTOR-I commonly results in the development of several complications. In particular, these agents may determine severe renal toxicity that, as recent studies report, seems clearly correlated to dose and duration of drug use. The mTOR-I-induced renal allograft spectrum of toxicity includes the enhanced incidence of delayed graft function, nephrotoxicity in particular when co-administered with calcineurin inhibitors (CNI) and onset of proteinuria. The latter effect appears highly frequent in patients undergoing mTOR-I treatment and significantly associated with a rapid graft lost. The damage leading to this complication interests both the glomerular and tubular area. mTOR-I cause an inhibition of proliferation in podocytes and the epithelial-to-mesenchymal transition in tubular cells. Interestingly, all these side effects are mostly reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to maximize their important and specific therapeutic effects while minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in a CNI-free immunosuppressive protocol.

A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.

Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium nephrolithiasis. Approximately 12% of recurrent stone formers have MSK, which is generally considered a sporadic disorder. Since its discovery, three pedigrees have been described in which an apparently autosomal dominant inheritance was suggested. Here, family members of 50 patients with MSK were systematically investigated by means of interviews, renal imaging, and biochemical studies in an effort to establish whether MSK is an inheritable disorder. Twenty-seven MSK probands had 59 first- and second-degree relatives of both genders with MSK in all generations. There were progressively lower mean levels of serum calcium, urinary sodium, pH, and volume, combined with higher serum phosphate and potassium from probands to relatives with bilateral, to those with unilateral, and to those unaffected by MSK. This suggests that most affected relatives have a milder form of MSK than the probands, which would explain why they had not been so diagnosed. Thus, our study provides strong evidence that familial clustering of MSK is common, and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity.

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.

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 (

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.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.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.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.