Publications by authors named "Gianluigi Zaza"

120 Publications

Proteomic profile of mesothelial exosomes isolated from peritoneal dialysis effluent of children with focal segmental glomerulosclerosis.

Sci Rep 2021 Oct 21;11(1):20807. Epub 2021 Oct 21.

Dialysis Unit, Department of Pediatric, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Peritoneal dialysis (PD) is the worldwide recognized preferred dialysis treatment for children affected by end-stage kidney disease (ESKD). However, due to the unphysiological composition of PD fluids, the peritoneal membrane (PM) of these patients may undergo structural and functional alterations, which may cause fibrosis. Several factors may accelerate this process and primary kidney disease may have a causative role. In particular, patients affected by steroid resistant primary focal segmental glomerulosclerosis, a rare glomerular disease leading to nephrotic syndrome and ESKD, seem more prone to develop peritoneal fibrosis. The mechanism causing this predisposition is still unrecognized. To better define this condition, we carried out, for the first time, a new comprehensive comparative proteomic mass spectrometry analysis of mesothelial exosomes from peritoneal dialysis effluent (PDE) of 6 pediatric patients with focal segmental glomerular sclerosis (FSGS) versus 6 patients affected by other primary renal diseases (No FSGS). Our omic study demonstrated that, despite the high overlap in the protein milieu between the two study groups, machine learning allowed to identify a core list of 40 proteins, with ANXA13 as most promising potential biomarker, to distinguish, in our patient population, peritoneal dialysis effluent exosomes of FSGS from No FSGS patients (with 100% accuracy). Additionally, the Weight Gene Co-expression Network Analysis algorithm identified 17 proteins, with PTP4A1 as the most statistically significant biomarker associated to PD vintage and decreased PM function. Altogether, our data suggest that mesothelial cells of FSGS patients are more prone to activate a pro-fibrotic machinery. The role of the proposed biomarkers in the PM pathology deserves further investigation. Our results need further investigations in a larger population to corroborate these findings and investigate a possible increased risk of PM loss of function or development of encapsulating peritoneal sclerosis in FSGS patients, thus to eventually carry out changes in PD treatment and management or implement new solutions.
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http://dx.doi.org/10.1038/s41598-021-00324-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531449PMC
October 2021

The molecular mechanisms of inflammation and scarring in the kidneys of immunoglobulin A nephropathy : Gene involvement in the mechanisms of inflammation and scarring in kidney biopsy of IgAN patients.

Semin Immunopathol 2021 Oct 21;43(5):691-705. Epub 2021 Oct 21.

Department of Nephrology, University of Verona, Verona, Italy.

Kidney biopsy is the cornerstone for the diagnosis of immunoglobulin A nephropathy (IgAN). The immunofluorescence technique evidences the IgA deposits in the glomeruli; the routine histology shows degree of active and chronic renal lesions. The spectrum of renal lesions is highly variable, ranging from minor or no detectable lesions to diffuse proliferative or crescentic lesions. Over the past three decades, renal transcriptomic studies have been performed on fresh or frozen renal tissue, and formalin-fixed paraffin-embedded kidney tissue specimens obtained from archival histological repositories. This paper aims to describe (1) the transcriptomic profiles of the kidney biopsy and (2) the potential urinary biomarkers that can be used to monitor the follow-up of IgAN patients. The use of quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), microarrays and RNA-sequencing (RNA-seq) techniques on renal tissue and separated compartments of the nephron such as glomeruli and tubule-interstitium has clarified many aspects of the renal damage in IgAN. Recently, the introduction of the single-cell RNA-seq techniques has overcome the limitations of the previous methods, making that it is possible to study the whole renal tissue without the dissection of the nephron segments; it also allows better analysis of the cell-specific gene expression involved in cell differentiation. These gene products could represent effective candidates for urinary biomarkers for clinical decision making. Finally, some of these molecules may be the targets of old drugs, such as corticosteroids, renin-angiotensin-aldosterone blockers, and new drugs such as monoclonal antibodies. In the era of personalized medicine and precision therapy, high-throughput technologies may better characterize different renal patterns of IgAN and deliver targeted treatments to individual patients.
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http://dx.doi.org/10.1007/s00281-021-00891-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551145PMC
October 2021

[Immunosoppressivi alternativi ai CNI: Schemi terapeutici e tossicità].

Authors:
Gianluigi Zaza

G Ital Nefrol 2021 Sep 7;38(Suppl 77). Epub 2021 Sep 7.

Unità di Nefrologia, Dipartimento di Medicina, Università degli Studi di Verona, Verona, Italy.

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September 2021

mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis.

Front Pharmacol 2021 23;12:710543. Epub 2021 Aug 23.

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

Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis.
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http://dx.doi.org/10.3389/fphar.2021.710543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419255PMC
August 2021

Rapamycin promotes autophagy cell death of Kaposi's sarcoma cells through P75NTR activation.

Exp Dermatol 2021 Jul 31. Epub 2021 Jul 31.

Department of Nephrology, Dialysis and Transplantation, "Kidney and Transplantation" Research Centre, Annunziata Hospital, Cosenza, Italy.

The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi's Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study, we explored whether the activation of the autophagic pathway through the low-affinity receptor for nerve growth factor, p75 , may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75 via EGR1. Interestingly, p75 gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75 activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi's sarcoma, autophagy triggered by Rapamycin through p75 represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75 protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma.
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http://dx.doi.org/10.1111/exd.14438DOI Listing
July 2021

Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach.

Front Med (Lausanne) 2021 26;8:671798. Epub 2021 May 26.

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

Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated. Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort. Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: -1.8, < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN ( < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA. Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.
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http://dx.doi.org/10.3389/fmed.2021.671798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187918PMC
May 2021

Erratum.

Nephrol Dial Transplant 2021 Apr 14. Epub 2021 Apr 14.

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http://dx.doi.org/10.1093/ndt/gfaa345DOI Listing
April 2021

Endothelial Glycocalyx as a Regulator of Fibrotic Processes.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

Division of Nephrology and Dialysis, Department of Medicine, Piazzale A. Stefani 1, 37126 Verona, Italy.

The endothelial glycocalyx, the gel layer covering the endothelium, is composed of glycosaminoglycans, proteoglycans, and adsorbed plasma proteins. This structure modulates vessels' mechanotransduction, vascular permeability, and leukocyte adhesion. Thus, it regulates several physiological and pathological events. In the present review, we described the mechanisms that disturb glycocalyx stability such as reactive oxygen species, matrix metalloproteinases, and heparanase. We then focused our attention on the role of glycocalyx degradation in the induction of profibrotic events and on the possible pharmacological strategies to preserve this delicate structure.
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http://dx.doi.org/10.3390/ijms22062996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999025PMC
March 2021

Discovered cancers at postmortem donor examination: A starting point for quality improvement of donor assessment.

Transplant Rev (Orlando) 2021 04 20;35(2):100608. Epub 2021 Feb 20.

Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. Electronic address:

Background: clinical and imaging investigations allow a detailed assessment of an organ donor, but a quota of cancer still elude detection. Complete autopsy of donors is even less frequently performed, due to economic issues and increasing availability of high-quality imaging. The aim of this study is to gather evidence from the literature on donor malignancy discovered at autopsy following organ donation and to discuss the utility and limitations of autopsy practice in the field of transplantation.

Methods: A systematic search according to PRISMA guidelines was carried out in Pubmed and Embase databases until September 2020 to select articles with reporting of cancer discovered in a donor at postmortem examination. Cancer discover in not-transplant setting were excluded. A descriptive synthesis was provided.

Results: Of 7388 articles after duplicates removal, 56 were included. Fifty-one studies reported on complete autopsy, while 5 dealt only with limited autopsy (prostate and central nervous system). The number of autopsies ranged between 1 and 246 with a total of 823 autopsies performed. The most frequent cancer discovered at autopsy was lymphoma (n = 13, 15%), followed by renal cell carcinoma (RCC) (n = 11, 13%), non-small cell lung cancer (NSCLC) (n = 10, 11%), melanoma (n = 10, 11%), choriocarcinoma (n = 6, 7%) and glioblastoma (GBM) (n = 6, 7%).

Conclusions: Lymphoma and melanoma are still difficult-to-detect cancers both during donor investigation and at procurement, whilst prostate cancer and choriocarcinoma are almost always easily detected nowadays thank to blood markers and clinical examination. There have been improvements with time in pre-donation detection procedures which are now working well, particularly when complete imaging investigations are performed, given that detection rate of CT/MRI is high and accurate. Autopsy can play a role to help to establish the correct donor management pathways in case of cancer discover. Furthermore, it helps to better understand which cancers are still eluding detection and consequently to refine guidelines' assessment procedures.
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http://dx.doi.org/10.1016/j.trre.2021.100608DOI Listing
April 2021

Impact of renal replacement therapies on olfactory ability: results of a cross-sectional case control study.

J Nephrol 2021 Feb 24. Epub 2021 Feb 24.

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

Introduction: Several studies have suggested that chronic kidney disease (CKD) may be associated with olfactory impairment. However, to date, the impact of renal replacement therapies has only been partly defined.

Methods: We tested the olfactory function of 235 participants [50 kidney transplant recipients (KT), 49 hemodialyzed patients (HD), 30 peritoneal dialysis patients (PD), 51 patients with CKD not on dialysis (ND-CKD) and 55 healthy subjects (HS)] by the Sniffin' Sticks test (Burghardt®, Wedel, Germany), including the sub-tests for the determination of odor threshold (T), odor discrimination (D), odor identification (I). Each subtest result was then summed up to a composite score, known as the TDI score. The Sino-Nasal Outcome Test-22 (SNOT22), Montreal Cognitive Assessment (MoCA) test and olfactory function Visual Analogue Scale (ofVAS) were also performed.

Results: The mean TDI score was significantly lower (and consistent with hyposmia), in HD, PD and ND-CKD compared to HS and KT (ANOVA p < 0.001). Similar results were observed in the I and D tests, and with the T score, though with regard to the latter, only in PD and ND-CKD patients. Multiple comparisons among groups demonstrated no significant differences between KT and HS. After adjustments for confounding factors, a significant linear association was found between both urea (β - 0.03, p < 0.003) and eGFR (β 0.08, p < 0.001) with TDI score. No significant association was observed between the TDI score and the ofVAS score (p = 0.293).

Conclusions: Olfactory impairment affects a large number of CKD patients in the pre-dialysis phase as well as those on dialysis. Kidney transplantation may reverse this condition with a possible positive impact on the quality of life and social behaviors/relationships.
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http://dx.doi.org/10.1007/s40620-021-00983-6DOI Listing
February 2021

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

J Am Soc Nephrol 2021 Feb 17. Epub 2021 Feb 17.

Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.

Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry.

Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; =6.35×10) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract ( and ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; =1.86×10). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis.

Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.
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http://dx.doi.org/10.1681/ASN.2020050681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017540PMC
February 2021

Analysis of urinary exosomes applications for rare kidney disorders.

Expert Rev Proteomics 2020 10 4;17(10):735-749. Epub 2021 Jan 4.

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

: Exosomes are nanovesicles that play important functions in a variety of physiological and pathological conditions. They are powerful cell-to-cell communication tool thanks to the protein, mRNA, miRNA, and lipid cargoes they carry. They are also emerging as valuable diagnostic and prognostic biomarker sources. Urinary exosomes carry information from all the cells of the urinary tract, downstream of the podocyte. Rare kidney diseases are a subset of an inherited diseases whose genetic diagnosis can be unclear, and presentation can vary due to genetic, epigenetic, and environmental factors. : In this review, we focus on a group of rare and often neglected kidney diseases, for which we have sufficient available literature data on urinary exosomes. The analysis of their content can help to comprehend pathological mechanisms and to identify biomarkers for diagnosis, prognosis, and therapeutic targets. : The foreseeable large-scale application of system biology approach to the profiling of exosomal proteins as a source of renal disease biomarkers will be also useful to stratify patients with rare kidney diseases whose penetrance, phenotypic presentation, and age of onset vary sensibly. This can ameliorate the clinical management.
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http://dx.doi.org/10.1080/14789450.2020.1866993DOI Listing
October 2020

Hypomethylation of NLRP3 gene promoter discriminates glucocorticoid-resistant from glucocorticoid-sensitive idiopathic nephrotic syndrome patients.

Clin Transl Sci 2021 05 25;14(3):964-975. Epub 2021 Jan 25.

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

To assess whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid (GC)-resistant from GC-sensitive idiopathic nephrotic syndrome (INS), patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), we measured the methylation level of NLRP3 promoter in DNA from peripheral blood cells of 10 adult patients with GC-resistant FSGS already in hemodialysis and 18 patients with GC-sensitive INS (13 MCD/5 FSGS) and in 21 pediatric patients with INS with MCD/FSGS before starting any treatment. Association of NLRP3 inflammasome with GC resistance was recapitulated in vitro in monocytic cell lines (THP-1 and U937). In both adults and pediatric patients, NLRP3 promoter methylation was significantly reduced in GC-resistant compared with GC-sensitive patients. Indeed, NLRP3 methylation distinguished GC-resistant and GC-sensitive patients (area under the receiver operating characteristic curve [AUROC] 86.7% in adults, p = 0.00019, and 73.5% in children, p = 0.00097). NLRP3 knock-down augmented sensitivity to GCs in THP-1 cells, whereas NLRP3 inflammasome activation lowered GC receptor concentration, increasing GC resistance in U937 cells. Our results uncovered a new biological mechanism by which patients with INS may acquire GC resistance, that could be used in future as a novel noninvasive diagnostic tool. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Approximately 80% of patients with idiopathic nephrotic syndrome (INS) respond to glucocorticoids, with the remaining 20% being steroid-resistant. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid-resistant from glucocorticoid (GC)-sensitive INS. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ In both adults and children, NLRP3 promoter methylation was significantly reduced in leukocytes of patients with GC-resistant compared with GC-sensitive INS. NLRP3 inflammasome activation lowered GC receptor concentration and augmented GC resistance, whereas NLRP3 knockdown increased sensitivity to GCs in cell lines representative of monocytes (U937 and THP1). HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ Our findings uncovered a new biological mechanism whereby patients with INS may develop resistance to GCs that could be used in the future as a novel noninvasive diagnostic tool.
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http://dx.doi.org/10.1111/cts.12961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212736PMC
May 2021

The challenge of early glomerular filtration rate decline in response to antihypertensive treatment and chronic kidney disease outcomes.

Nephrol Dial Transplant 2020 Nov 6. Epub 2020 Nov 6.

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

Hypertension and chronic kidney disease (CKD) are closely linked pathological processes. Combating high blood pressure (BP) is an essential part of preventing CKD progression and reducing cardiovascular (CV) risk. Data from recent randomized controlled trials on patients at high CV risk showed the beneficial effects of intensive action to meet BP targets on mortality related to CV disease. The impact of meeting such targets on renal function is still unclear, however, particularly for patients with CKD. This issue has been the object of several post hoc analyses because lowering BP definitely has a nephroprotective role, but the early decline in glomerular filtration rate (GFR) associated with antihypertensive therapies and strict BP targets is still a concern in nephrology clinical practice. The present review discusses the results of studies on this topic, focusing specifically on the clinical significance of early GFR decline in response to treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or to different BP targets, in terms of renal and CV outcomes, and how this tips the balance towards continuing or discontinuing antihypertensive therapy.
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http://dx.doi.org/10.1093/ndt/gfaa171DOI Listing
November 2020

Formalin-fixed paraffin-embedded renal biopsy tissues: an underexploited biospecimen resource for gene expression profiling in IgA nephropathy.

Sci Rep 2020 09 16;10(1):15164. Epub 2020 Sep 16.

Schena Foundation, Research Center of Kidney Diseases, Strada Provinciale Valenzano-Casamassima Km. 3.00, 70100, Valenzano, Bari, Italy.

Primary IgA nephropathy (IgAN) diagnosis is based on IgA-dominant glomerular deposits and histological scoring is done on formalin-fixed paraffin embedded tissue (FFPE) sections using the Oxford classification. Our aim was to use this underexploited resource to extract RNA and identify genes that characterize active (endocapillary-extracapillary proliferations) and chronic (tubulo-interstitial) renal lesions in total renal cortex. RNA was extracted from archival FFPE renal biopsies of 52 IgAN patients, 22 non-IgAN and normal renal tissue of 7 kidney living donors (KLD) as controls. Genome-wide gene expression profiles were obtained and biomarker identification was carried out comparing gene expression signatures a subset of IgAN patients with active (N = 8), and chronic (N = 12) renal lesions versus non-IgAN and KLD. Bioinformatic analysis identified transcripts for active (DEFA4, TNFAIP6, FAR2) and chronic (LTB, CXCL6, ITGAX) renal lesions that were validated by RT-PCR and IHC. Finally, two of them (TNFAIP6 for active and CXCL6 for chronic) were confirmed in the urine of an independent cohort of IgAN patients compared with non-IgAN patients and controls. We have integrated transcriptomics with histomorphological scores, identified specific gene expression changes using the invaluable repository of archival renal biopsies and discovered two urinary biomarkers that may be used for specific clinical decision making.
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http://dx.doi.org/10.1038/s41598-020-72026-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494931PMC
September 2020

Recent Advances in the Role of Natural Killer Cells in Acute Kidney Injury.

Front Immunol 2020 4;11:1484. Epub 2020 Aug 4.

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

Growing evidence is revealing a central role for natural killer (NK) cells, cytotoxic cells belonging to the broad family of innate lymphoid cells (ILCs), in acute and chronic forms of renal disease. NK cell effector functions include both the recognition and elimination of virus-infected and tumor cells and the capability of sensing pathogens through Toll-like receptor (TLR) engagement. Notably, they also display immune regulatory properties, exerted thanks to their ability to secrete cytokines/chemokines and to establish interactions with different innate and adaptive immune cells. Therefore, because of their multiple functions, NK cells may have a major pathogenic role in acute kidney injury (AKI), and a better understanding of the molecular mechanisms driving NK cell activation in AKI and their downstream interactions with intrinsic renal cells and infiltrating immune cells could help to identify new potential biomarkers and to select clinically valuable novel therapeutic targets. In this review, we discuss the current literature regarding the potential involvement of NK cells in AKI.
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http://dx.doi.org/10.3389/fimmu.2020.01484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438947PMC
May 2021

Mortality from cancer is not increased in elderly kidney transplant recipients compared to the general population: a competing risk analysis.

J Nephrol 2020 Dec 3;33(6):1309-1319. Epub 2020 Sep 3.

Section of Dermatology, Dermatology Unit, Department of Medicine, University of Verona, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126, Verona, VR, Italy.

Background: The impact of cancer on death of elderly kidney transplant recipients has been extensively investigated, but with conflicting results. Unlike their younger counterparts, in elderly kidney transplant recipients cardiovascular and infectious disease may outweigh cancer in causing the patient's death.

Methods: Using competing risk analysis on a large retrospective cohort of kidney transplant recipients, we estimated the cause-specific cumulative incidence and hazard of death in different age categories and calculated standardized mortality ratios (SMRs) to compare mortality rates with the general population.

Results: Six thousand seven hundred eighty-nine kidney transplant recipients were followed-up for a median of 9 years. Ten years after transplantation, in transplant recipients aged 20-39, 40-59, and 60+, the cumulative incidence of cancer-related death was 0.6 (95% confidence interval [CI]: 0.3-1.0), 2.9 (2.3-3.6) and 5.3% (3.5-7.5), whereas the SMR was 9.1 (5.5-15.0), 2.0 (1.6-2.5), and 0.8 (0.6-1.0), respectively. At variance with young recipients, the hazard and the cumulative incidence of cardiovascular-related death in elderly recipients was well above that of cancer-related death.

Conclusions: Relative to the general population, cancer-related death is increased in young but not in elderly kidney transplant recipients because of the more marked increased incidence of competing cause of death in the latter category.
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http://dx.doi.org/10.1007/s40620-020-00847-5DOI Listing
December 2020

COVID-19 and the Kidneys: An Update.

Front Med (Lausanne) 2020 21;7:423. Epub 2020 Jul 21.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

The new coronavirus disease 2019 (COVID-19) has become a world health emergency. The disease predominantly effects individuals between 30 and 79 years of age with 81% of cases being classified as mild. Despite the majority of the general population displaying symptoms similar to the common cold, COVID-19 has also induced alveolar damage resulting in progressive respiratory failure with fatalities noted in 6.4% of cases. Direct viral injury, uncontrolled inflammation, activation of coagulation, and complement cascades are thought to participate in disease pathogenesis. Patients with COVID-19 have displayed kidney damage through acute kidney injury, mild proteinuria, hematuria, or slight elevation in creatinine possibly as consequence of kidney tropism of the virus and multiorgan failure. The impact of COVID-19 on patients with pre-existing kidney impairment, including those with chronic kidney disease, kidney transplant recipients, and individuals on hemodialysis (HD) has not yet been clearly established. No specific treatments for COVID-19 have been found yet. Research has revealed several agents that may have potential efficacy against COVID-19, and many of these molecules have demonstrated preliminary efficacy against COVID-19 and are currently being tested in clinical trials.
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http://dx.doi.org/10.3389/fmed.2020.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385132PMC
July 2020

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Am J Transplant 2020 11 2;20(11):3149-3161. Epub 2020 Oct 2.

Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Whether kidney transplant recipients are capable of mounting an effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adaptive immune response despite chronic immunosuppression is unknown and has important implications for therapy. Herein, we analyzed peripheral blood cell surface and intracellular cytokine phenotyping by flow cytometry along with serum antibody testing in 18 kidney transplant recipients with active coronavirus disease 2019 (COVID-19) infection and 36 matched, transplanted controls without COVID-19. We observed significantly fewer total lymphocytes and fewer circulating memory CD4 and CD8 T cells in the COVID-19 subjects. We also showed fewer anergic and senescent CD8 T cells in COVID-19 individuals, but no differences in exhausted CD8 T cells, nor in any of these CD4 T cell subsets between groups. We also observed greater frequencies of activated B cells in the COVID-19 patients. Sixteen of 18 COVID-19 subjects tested for anti-SARS-CoV-2 serum antibodies showed positive immunoglobulin M or immunoglobulin G titers. Additional analyses showed no significant correlation among immune phenotypes and degrees of COVID-19 disease severity. Our findings indicate that immunosuppressed kidney transplant recipients admitted to the hospital with acute COVID-19 infection can mount SARS-CoV-2-reactive adaptive immune responses. The findings raise the possibility that empiric reductions in immunosuppressive therapy for all kidney transplant recipients with active COVID-19 may not be required.
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http://dx.doi.org/10.1111/ajt.16261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436882PMC
November 2020

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis.

J Exp Med 2020 09;217(9)

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets.
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http://dx.doi.org/10.1084/jem.20191699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478737PMC
September 2020

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium.

Am J Transplant 2020 11 4;20(11):3140-3148. Epub 2020 Aug 4.

Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID-19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID-19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID-19 during the 9-week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow-up period of 52 days (IQR: 16-66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin-6 levels. In sum, hospitalized kidney transplant recipients with COVID-19 have higher rates of acute kidney injury and mortality.
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http://dx.doi.org/10.1111/ajt.16185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405285PMC
November 2020

Digital pathology for second opinion consultation and donor assessment during organ procurement: Review of the literature and guidance for deployment in transplant practice.

Transplant Rev (Orlando) 2020 10 13;34(4):100562. Epub 2020 Jun 13.

Department of Pathology, UPMC Shadyside Hospital, University of Pittsburgh, Pittsburgh, PA, USA.

Telepathology has been an important application for second opinion consultation ever since the introduction of digital pathology. However, little is known regarding teleconsultation for second opinion in transplantation. There is also limited literature on telepathology during organ donor procurement, typically utilized when general pathologists on-call request back-up to help assess donor biopsies for organ suitability or to diagnose newly discovered tumors with urgent time constraints. In this review, we searched Pubmed/Embase and websites of transplant organizations to collect and analyze published evidence on teleconsultation for donor evaluation and organ procurement. Of 2725 records retrieved using the key terms 'telepathology', 'second opinion' and 'transplantation', 26 suitable studies were included. Most records were from North America and included validation studies of telepathology being used for remote frozen section interpretation of donor biopsies with whole slide imaging. The data from these published studies supports the transition towards digital teleconsultation in transplant settings where consultations among pathologists are still handled by pathologists being called on site, via telephone and/or email.
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http://dx.doi.org/10.1016/j.trre.2020.100562DOI Listing
October 2020

Editorial of Special Issue "Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy".

Int J Mol Sci 2020 Jun 14;21(12). Epub 2020 Jun 14.

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

In this Special Issue entitled "Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy", of the International Journal of Molecular Sciences, that includes original articles and reviews, authors have underlined the role of biomedical research in providing new insights into the pathologies of complex kidney diseases [...].
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http://dx.doi.org/10.3390/ijms21124244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353067PMC
June 2020

Donor-transmitted cancer in kidney transplant recipients: a systematic review.

J Nephrol 2020 Dec 13;33(6):1321-1332. Epub 2020 Jun 13.

Renal Unit, University and Hospital Trust of Verona, Verona, Italy.

The transmission of cancer from a donor organ is a rare event but has important consequences. Aim of this systematic review was to summarize all the published evidence on cancer transmission in kidney recipients. We reviewed published case reports and series describing the outcome of recipients with donor-transmitted cancer until August 2019. A total of 128 papers were included, representing 234 recipients. The most common transmitted cancers were lymphoma (n = 48, 20.5%), renal cancer (42, 17.9%), melanoma (40, 17.1%), non-small cell lung cancer (n = 13, 5.6%), neuroendocrine cancers comprising small cell lung cancer (n = 11, 4.7%) and choriocarcinoma (n = 10, 4.3%). There was a relative lack of glioblastoma and gastrointestinal cancers with only 6 and 5 cases, respectively. Melanoma and lung cancer had the worst prognosis, with 5-years overall survival of 43% and 19%, respectively; while renal cell cancer and lymphomas had a favorable prognosis with 5-years overall survival of 93 and 63%, respectively. Metastasis of cancer outside the graft was the most important adverse prognostic factor. Overall reporting was good, but information on donors' cause of death and investigations at procurement was often lacking. Epidemiology of transmitted cancer has evolved, thanks to screening with imaging and blood tests, as choriocarcinoma transmission have almost abolished, while melanoma and lymphoma are still difficult to detect and prevent.
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http://dx.doi.org/10.1007/s40620-020-00775-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701067PMC
December 2020

Everolimus for BKV nephropathy in kidney transplant recipients: a prospective, controlled study.

J Nephrol 2021 Apr 12;34(2):531-538. Epub 2020 Jun 12.

Nephrology, Dialysis, and Transplantation, University of Genova, and Policlinico San Martino, Largo R. Benzi 10, 16132, Genoa, Italy.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m, 95% CI 10.5-40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.
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http://dx.doi.org/10.1007/s40620-020-00777-2DOI Listing
April 2021

COVID-19 and kidney transplantation: an Italian Survey and Consensus.

J Nephrol 2020 08 3;33(4):667-680. Epub 2020 Jun 3.

Division of General and Transplant Surgery, University of Pisa, Pisa, Italy.

Italy was the first Western country to face the COVID-19 pandemic. Here we report the results of a national survey on kidney transplantation activity in February and March 2020, and the results of a three-round Delphi consensus promoted by four scientific societies: the Italian Society of Organ Transplantation, the Italian Society of Nephrology, the Italian Society of Anesthesia and Intensive Care, and the Italian Group on Antimicrobial Stewardship. All 41 Italian transplant centers were invited to express their opinion in the Delphi rounds along with a group of seven experts. The survey revealed that, starting from March 2020, there was a decline in kidney transplantation activity in Italy, especially for living-related transplants. Overall, 60 recipients tested positive for SARS-CoV2 infection, 57 required hospitalization, 17 were admitted to the ICU, and 11 died. The online consensus had high response rates at each round (95.8%, 95.8%, and 89.5%, respectively). Eventually, 27 of 31 proposed statements were approved (87.1%), 12 at the first or second round (38.7%), and 3 at the third (9.7%). Based on the Italian experience, we discuss the reasons for the changes in kidney transplantation activity during the COVID-19 pandemic in Western countries. We also provide working recommendations for the organization and management of kidney transplantation under these conditions.
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http://dx.doi.org/10.1007/s40620-020-00755-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268183PMC
August 2020

SARS-CoV-2 pandemic and the need for transplant-oriented trials.

Transpl Int 2020 08 14;33(8):966-968. Epub 2020 May 14.

Department of Medicine, Icahn School of Medicine at Mount Sinai, Translational Transplant Research Center, New York, NY, USA.

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http://dx.doi.org/10.1111/tri.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267390PMC
August 2020

COVID-19 in kidney transplant recipients.

Am J Transplant 2020 Jul 12;20(7):1941-1943. Epub 2020 Apr 12.

Dipartimento di Medicina e Chirurgia, Università di Parma, UO Nefrologia, Azienda Ospedaliera-Universitaria Parma, Parma, Italy.

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http://dx.doi.org/10.1111/ajt.15891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228396PMC
July 2020
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