Publications by authors named "Maurizio Salvadori"

70 Publications

Microbiota, renal disease and renal transplantation.

World J Transplant 2021 Mar;11(3):16-36

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

Aim of this frontier review has been to highlight the role of microbiota in healthy subjects and in patients affected by renal diseases with particular reference to renal transplantation. The microbiota has a relevant role in conditioning the healthy status and the diseases. In particular gut microbiota is essential in the metabolism of food and has a relevant role for its relationship with the immune system. The indigenous microbiota in patients with chronic renal failure is completely different than that of the healthy subjects and pathobionts appear. This abnormality in microbiota composition is called dysbiosis and may cause a rapid deterioration of the renal function both for activating the immune system and producing large quantity of uremic toxins. Similarly, after renal trans-plantation the microbiota changes with the appearance of pathobionts, principally in the first period because of the assumption of immunosuppressive drugs and antibiotics. These changes may deeply interfere with the graft outcome causing acute rejection, renal infections, diarrhea, and renal interstitial fibrosis. In addition, change in the microbiota may modify the metabolism of immuno-suppressive drugs causing in some patients the need of modifying the immunosuppressant dosing. The restoration of the indigenous microbiota after transplantation is important, either to avoiding the complications that impair the normal renal graft, and because recent studies have documented the role of an indigenous microbiota in inducing tolerance towards the graft. The use of prebiotics, probiotics, smart bacteria and diet modification may restore the indigenous microbiota, but these studies are just at their beginning and more data are needed to draw definitive conclusions.
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http://dx.doi.org/10.5500/wjt.v11.i3.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009061PMC
March 2021

New Year's greeting and overview of in 2021.

World J Transplant 2021 Feb;11(2):7-15

Department of Transplantation Renal Unit, Careggi University Hospital, Florence 50139, Italy.

() was launched in December 2011. While we are celebrating 's 10-year anniversary, we are very proud to share with you that since its first issue, has published 312 articles, which have been cited 2786 times (average cites per article of 9.0). Together with an excellent team effort by our authors, Editorial Board members, independent expert referees, and staff of the Editorial Office, advanced in 2020. In this editorial, we summarize the journal's bibliometrics, including its citation report, published articles in 2020, peer review rate and manuscript invitation metrics, as well as its Editorial Board members and existing problems of . The overall aim of this editorial is to promote the development of in 2021. We appreciate the continuous support and submissions from authors and the dedicated efforts and expertise by our invited reviewers. This collective support will allow us to be even more productive in 2021. In addition, we commit to working with you all to raise the academic influence of over the upcoming year. Finally, on behalf of , we wish you and your families the best for the New Year.
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http://dx.doi.org/10.5500/wjt.v11.i2.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896244PMC
February 2021

Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy.

World J Transplant 2020 May;10(5):90-103

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.
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http://dx.doi.org/10.5500/wjt.v10.i5.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428791PMC
May 2020

Current protocols and outcomes of ABO-incompatible kidney transplantation.

World J Transplant 2020 Jul;10(7):191-205

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

One of the principal obstacles in transplantation from living donors is that approximately 30% are immunologically incompatible because of the presence in the recipient of antibodies directed against the human leukocyte antigen system of the donor or because of the incompatibility of the ABO system. The aim of this review is to describe the more recent data from the literature on the different protocols used and the clinical outcomes of ABO-incompatible kidney transplantation. Two different strategies are used to overcome these barriers: desensitization of the recipient to remove the antibodies and to prevent their rebound after transplantation and the exchange of organs between two or more pairs. The largest part of this review is dedicated to describing the techniques of desensitization. Even if the first reports of successful renal transplantation between ABO-incompatible pairs have been published by 1980, the number of ABO-incompatible transplants increased substantially in this century because of our improved knowledge of the immune system and the availability of new drugs. Rituximab has substantially replaced splenectomy. The technique of apheresis has improved and more recently a tailored desensitization proved to be the more efficient strategy avoiding an excess of immunosuppression with the related side effects. Recent reports document outcomes for such transplantation similar to the outcomes of standard transplantation.
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http://dx.doi.org/10.5500/wjt.v10.i7.191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416363PMC
July 2020

Therapeutic apheresis in kidney transplantation: An updated review.

World J Transplant 2019 Oct;9(6):103-122

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

Therapeutic apheresis is a cornerstone of therapy for several conditions in transplantation medicine and is available in different technical variants. In the setting of kidney transplantation, immunological barriers such as ABO blood group incompatibility and preformed donor-specific antibodies can complicate the outcome of deceased- or living- donor transplantation. Postoperatively, additional problems such as antibody-mediated rejection and a recurrence of primary focal segmental glomerulosclerosis can limit therapeutic success and decrease graft survival. Therapeutic apheresis techniques find application in these issues by separating and selectively removing exchanging or modifying pathogenic material from the patient by an extracorporeal aphaeresis system. The purpose of this review is to describe the available techniques of therapeutic aphaeresis with their specific advantages and disadvantages and examine the evidence supporting the application of therapeutic aphaeresis as an adjunctive therapeutic option to immunosuppressive agents in protocols before and after kidney transplantation.
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http://dx.doi.org/10.5500/wjt.v9.i6.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851502PMC
October 2019

Histological and clinical evaluation of marginal donor kidneys before transplantation: Which is best?

World J Transplant 2019 Aug;9(4):62-80

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Via Cesare Battisti, Pescia (PT) 2-51017, Italy.

Organ shortage represents one of the major limitations to the development of kidney transplantation. To increase the donor pool and to answer the ever increasing kidney request, physicians are recurring to marginal kidneys as kidneys from older donors, from hypertensive or diabetic donors and from non-heart beating donors. These kidneys are known to have frequently a worse outcome in the recipients. To date major problem is to evaluate such kidneys in order to use or to discard them before transplantation. The use of such kidneys create other relevant question as whether to use them as single or dual transplant and to allocate them fairly according transplant programs. The pre-transplant histological evaluation, the clinical evaluation of the donor or both the criteria joined has been used and according the time each criterion prevailed over the others. Aim of this review has been to examine the advantages and the drawbacks of any criterion and how they have changed with time. To date any criterion has several limitations and several authors have argued for the development of new guidelines in the field of the kidney evaluation for transplantation. Several authors argue that the use of omic technologies should improve the organ evaluation and studies are ongoing to evaluate these technologies either in the donor urine or in the biopsies taken before transplantation.
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http://dx.doi.org/10.5500/wjt.v9.i4.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715576PMC
August 2019

Hepatitis C and renal transplantation in era of new antiviral agents.

World J Transplant 2018 Aug;8(4):84-96

Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

Data from World Health Organization estimates that the hepatitis C virus (HCV) prevalence is 3% and approximately 71 million persons are infected worldwide. HCV infection is particularly frequent among patients affected by renal diseases and among those in dialysis treatment. In addition to produce a higher rate of any cause of death, HCV in renal patients and in renal transplanted patients produce a deterioration of liver disease and is a recognized cause of transplant glomerulopathy, new onset diabetes mellitus and lymphoproliferative disorders. Treatment of HCV infection with interferon alpha and/or ribavirin had a poor efficacy. The treatment was toxic, expensive and with limited efficacy. In the post-transplant period was also cause of severe humoral rejection. In this review we have highlighted the new direct antiviral agents that have revolutionized the treatment of HCV both in the general population and in the renal patients. Patients on dialysis or with low glomerular filtration rate were particularly resistant to the old therapies, while the direct antiviral agents allowed achieving a sustained viral response in 90%-100% of patients with a short period of treatment. This fact to date allows HCV patients to enter the waiting list for transplantation easier than before. These new agents may be also used in renal transplant patients HCV-positive without relevant clinical risks and achieving a sustained viral response in almost all patients. New drug appears in the pipeline with increased profile of efficacy and safety. These drugs are now the object of several phases II, III clinical trials.
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http://dx.doi.org/10.5500/wjt.v8.i4.84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107518PMC
August 2018

Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: Open challenges in the remission induction therapy.

World J Nephrol 2018 May;7(3):71-83

Department of Nephrology and Dialysis, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

Renal involvement with rapidly progressive glomerulonephritis is a common manifestation of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, which is characterized by end-stage renal disease and high mortality rates in untreated and/or late referral patients. The long-term renal survival has improved dramatically since the addition of cyclophosphamide (CYC) and recently of rituximab (RTX) in association with corticosteroids in the remission induction therapeutic regimens. However, renal prognosis remains unfavorable for many patients and the mortality rate is still significantly high. In this review, we analyze the open challenges to be addressed to optimize the induction remission therapy, principally in patients with advanced kidney failure. This concern the first-line therapy (CYC or RTX) based on different parameters (estimated glomerular filtration rate at baseline, new or relapsed disease, ANCA specificity, tissue injury, safety), the role of plasma exchange and the role of new therapies. Indeed, we discuss future perspectives in induction remission therapy by reporting recent advances in new targeted therapies with particular reference to avacopan, an orally administered selective C5a receptor inhibitor.
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http://dx.doi.org/10.5527/wjn.v7.i3.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937030PMC
May 2018

Immunoglobulin G4-related kidney diseases: An updated review.

World J Nephrol 2018 Jan;7(1):29-40

Division of Nephrology, Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy.

This review will encompass definition, pathogenesis, renal clinical manifestations and treatment of immunoglobulin G4-related diseases (IgG4-RDs). IgG4-RD is a recently recognized clinical entity that often involves multiple organs and is characterized by high levels of serum immunoglobulins G4, dense infiltration of IgG4 cells and storiform fibrosis. Cellular immunity, particularly T-cell mediated immunity, has been implicated in the pathogenesis of IgG4-RDs. The most frequent renal manifestations of IgG4-RD are IgG4-related tubulointerstitial nephritis, membranous glomerulopathy and obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis. IgG4-RD diagnosis should be based on specific histopathological findings, confirmed by tissue immunostaining, typical radiological findings and an appropriate clinical context. The first line treatment is the steroids with two warnings: Steroid resistance and relapse after discontinuation. In the case of steroid resistance, B cell depleting agents as rituximab represent the second-line treatment. In the case of relapse after discontinuation, steroid treatment may be associated with steroid sparing agents. Since the disease has been only recently identified, more prospective, long-term studies are needed to an improved understanding and a more correct and safe treatment.
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http://dx.doi.org/10.5527/wjn.v7.i1.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760510PMC
January 2018

Biomarkers in renal transplantation: An updated review.

World J Transplant 2017 Jun;7(3):161-178

Maurizio Salvadori, Renal Unit, Department of Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Genomics, proteomics and molecular biology lead to tremendous advances in all fields of medical sciences. Among these the finding of biomarkers as non invasive indicators of biologic processes represents a useful tool in the field of transplantation. In addition to define the principal characteristics of the biomarkers, this review will examine the biomarker usefulness in the different clinical phases following renal transplantation. Biomarkers of ischemia-reperfusion injury and of delayed graft function are extremely important for an early diagnosis of these complications and for optimizing the treatment. Biomarkers predicting or diagnosing acute rejection either cell-mediated or antibody-mediated allow a risk stratification of the recipient, a prompt diagnosis in an early phase when the histology is still unremarkable. The kidney solid organ response test detects renal transplant recipients at high risk for acute rejection with a very high sensitivity and is also able to make diagnosis of subclinical acute rejection. Other biomarkers are able to detect chronic allograft dysfunction in an early phase and to differentiate the true chronic rejection from other forms of chronic allograft nephropathies no immune related. Finally biomarkers recently discovered identify patients tolerant or almost tolerant. This fact allows to safely reduce or withdrawn the immunosuppressive therapy.
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http://dx.doi.org/10.5500/wjt.v7.i3.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487307PMC
June 2017

Complement related kidney diseases: Recurrence after transplantation.

World J Transplant 2016 Dec;6(4):632-645

Maurizio Salvadori, Elisabetta Bertoni, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement. These abnormalities often remain after transplantation because they are constitutional and poorly influenced by the immunosuppression. This fact justifies the high recurrence rate of these diseases. Early diagnosis of recurrence is essential for an optimal therapeutically approach, whenever possible. Patients affected by end stage renal disease due to C3 glomerulopathies or to atypical HUS, may be transplanted with extreme caution. Living donor donation from relatives is not recommended because members of the same family may be affected by the same gene mutation. Different therapeutically approaches have been attempted either for recurrence prevention and treatment. The most promising approach is represented by complement inhibitors. Eculizumab, a monoclonal antibody against C5 convertase is the most promising drug, even if to date is not known how long the therapy should be continued and which are the best dosing. These facts face the high costs of the treatment. Eculizumab resistant patients have been described. They could benefit by a C3 convertase inhibitor, but this class of drugs is by now the object of randomized controlled trials.
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http://dx.doi.org/10.5500/wjt.v6.i4.632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175220PMC
December 2016

Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN.

World J Nephrol 2016 Jul;5(4):308-20

Maurizio Salvadori, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

This review revises the reclassification of the membranoproliferative glomerulonephritis (MPGN) after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and pathogenesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized: The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecific treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in finding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.
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http://dx.doi.org/10.5527/wjn.v5.i4.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936338PMC
July 2016

Update on immunoglobulin a nephropathy. Part II: Clinical, diagnostic and therapeutical aspects.

World J Nephrol 2016 Jan;5(1):6-19

Maurizio Salvadori, Department of Renal Transplantation and Renal Diseases, Careggi University Hospital, 50139 Florence, Italy.

Immunoglobulin A nephropathy (IgAN) is characterized by different clinical manifestations and by long-term different outcomes. Major problem for the physicians is to understanding which patients are at risk of a disease evolution and to prescribe the right therapy to the right patients. Indeed, in addition to patients with a stable disease with no trend to evolution or even with a spontaneous recovery, patients with an active disease and patients with a rapidly evolving glomerulonephritis are described. Several histopathological, biological and clinical markers have been described and are currently used to a better understanding of patients at risk, to suggest the right therapy and to monitor the therapy effect and the IgAN evolution over time. The clinical markers are the most reliable and allow to divide the IgAN patients into three categories: The low risk patients, the intermediate risk patients and the high risk patients. Accordingly, the therapeutic measures range from no therapy with the only need of repeated controls, to supportive therapy eventually associated with low dose immunosuppression, to immunosuppressive treatment in the attempt to avoid the evolution to end stage renal disease. However the current evidence about the different therapies is still matter of discussion. New drugs are in the pipeline and are described. They are object of randomized controlled trials, but studies with a number of patients adequately powered and with a long follow up are needed to evaluate efficacy and safety of these new drugs.
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http://dx.doi.org/10.5527/wjn.v5.i1.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707169PMC
January 2016

Update on immunoglobulin A nephropathy, Part I: Pathophysiology.

World J Nephrol 2015 Sep;4(4):455-67

Maurizio Salvadori, Department of Transplantation and Renal Diseases, Careggi University Hospital, 50139 Florence, Italy.

Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identified even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 (IgA1) with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a "lanthanic" deposition remains to be clarified. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarified.
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http://dx.doi.org/10.5527/wjn.v4.i4.455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561843PMC
September 2015

Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment.

World J Transplant 2015 Jun;5(2):52-67

Maurizio Salvadori, Elisabetta Bertoni, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.
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http://dx.doi.org/10.5500/wjt.v5.i2.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478600PMC
June 2015

Complement involvement in kidney diseases: From physiopathology to therapeutical targeting.

World J Nephrol 2015 May;4(2):169-84

Maurizio Salvadori, Elisabetta Bertoni, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Complement cascade is involved in several renal diseases and in renal transplantation. The different components of the complement cascade might represent an optimal target for innovative therapies. In the first section of the paper the authors review the physiopathology of complement involvement in renal diseases and transplantation. In some cases this led to a reclassification of renal diseases moving from a histopathological to a physiopathological classification. The principal issues afforded are: renal diseases with complement over activation, renal diseases with complement dysregulation, progression of renal diseases and renal transplantation. In the second section the authors discuss the several complement components that could represent a therapeutic target. Even if only the anti C5 monoclonal antibody is on the market, many targets as C1, C3, C5a and C5aR are the object of national or international trials. In addition, many molecules proved to be effective in vitro or in preclinical trials and are waiting to move to human trials in the future.
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http://dx.doi.org/10.5527/wjn.v4.i2.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419127PMC
May 2015

What's new in clinical solid organ transplantation by 2013.

World J Transplant 2014 Dec;4(4):243-66

Maurizio Salvadori, Elisabetta Bertoni, Department of Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.
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http://dx.doi.org/10.5500/wjt.v4.i4.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274595PMC
December 2014

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.

Nat Genet 2014 Nov 12;46(11):1187-96. Epub 2014 Oct 12.

Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
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http://dx.doi.org/10.1038/ng.3118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213311PMC
November 2014

European Renal Best Practice Guideline on kidney donor and recipient evaluation and perioperative care.

Nephrol Dial Transplant 2015 Nov 9;30(11):1790-7. Epub 2014 Jul 9.

Renal Division, University Hospital Ghent, Ghent, Belgium.

The European Best Practice Guideline group (EBPG) issued guidelines on the evaluation and selection of kidney donor and kidney transplant candidates, as well as post-transplant recipient care, in the year 2000 and 2002. The new European Renal Best Practice board decided in 2009 that these guidelines needed updating. In order to avoid duplication of efforts with kidney disease improving global outcomes, which published in 2009 clinical practice guidelines on the post-transplant care of kidney transplant recipients, we did not address these issues in the present guidelines.The guideline was developed following a rigorous methodological approach: (i) identification of clinical questions, (ii) prioritization of questions, (iii) systematic literature review and critical appraisal of available evidence and (iv) formulation of recommendations and grading according to Grades of Recommendation Assessment, Development, and Evaluation (GRADE). The strength of each recommendation is rated 1 or 2, with 1 being a 'We recommend' statement, and 2 being a 'We suggest' statement. In addition, each statement is assigned an overall grade for the quality of evidence: A (high), B (moderate), C (low) or D (very low). The guideline makes recommendations for the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and perioperative recipient care.All together, the work group issued 112 statements. There were 51 (45%) recommendations graded '1', 18 (16%) were graded '2' and 43 (38%) statements were not graded. There were 0 (0%) recommendations graded '1A', 15 (13%) were '1B', 19 (17%) '1C' and 17 (15%) '1D'. None (0%) were graded '2A', 1 (0.9%) was '2B', 8 (7%) were '2C' and 9 (8%) '2D'. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.We present here the complete recommendations about the evaluation of the kidney transplant candidate as well as the potential deceased and living donor, the immunological work-up of kidney donors and recipients and the perioperative recipient care. We hope that this document will help caregivers to improve the quality of care they deliver to patients. The full version with methods, rationale and references is published in Nephrol Dial Transplant (2013) 28: i1-i71; doi: 10.1093/ndt/gft218 and can be downloaded freely from http://www.oxfordjournals.org/our_journals/ndt/era_edta.html.
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http://dx.doi.org/10.1093/ndt/gfu216DOI Listing
November 2015

European renal best practice guideline on the management and evaluation of the kidney donor and recipient.

Nefrologia 2014 May 10;34(3):293-301. Epub 2014 Mar 10.

The purpose of this Clinical Practice Guideline is to provide guidance on evaluation of the kidney donor and transplant recipient as well as on the management of the recipient in the perioperative period. It is designed to provide information and aid decision-making. It is not intended to define a standard of care, and should neither be construed as one nor should it be interpreted as prescribing an exclusive course of management. The original version of this guideline was published in Nephrology, Dialysis and Transplantation and this current version is a reduced article aiming to disseminate the guideline into Spanish-speaking countries and transplant communities.
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http://dx.doi.org/10.3265/Nefrologia.pre2014.Feb.12490DOI Listing
May 2014

[Italian adaptation of the European Renal Best Practice (ERBP) guideline on kidney donor and recipient evaluation and perioperative care].

G Ital Nefrol 2014 Mar-Apr;31(2)

Recently, the ERBP (European Renal Best Practice) guideline on kidney donor and recipient evaluation and perioperative care has been published and disseminated to the international nephrology community. This guideline aims at providing evidence-based recommendations on the evaluation of the kidney transplant candidate. They evaluate the immunologic workup of kidney donors and recipients, they recommend the evaluation, selection and preparation of deceased and living kidney donors and the perioperative care of the kidney transplant recipient. We report here the Italian adaptation of these guidelines, with a focus on the main statements elaborated for each single clinical question.
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August 2015

Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy.

World J Transplant 2014 Mar;4(1):1-17

Maurizio Salvadori, Elisabetta Bertoni, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty.
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http://dx.doi.org/10.5500/wjt.v4.i1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964192PMC
March 2014

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations.

World J Nephrol 2013 Aug;2(3):56-76

Maurizio Salvadori, Elisabetta Bertoni, Renal Unit, Careggi Hospital, Careggi University, Florence 50139, Italy.

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidney-liver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases I and II. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.
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http://dx.doi.org/10.5527/wjn.v2.i3.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832913PMC
August 2013

Is it time to give up with calcineurin inhibitors in kidney transplantation?

World J Transplant 2013 Jun;3(2):7-25

Maurizio Salvadori, Elisabetta Bertoni, Department of Renal Transplantation, Careggi University Hospital, 50139 Florence, Italy.

Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti-human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.
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http://dx.doi.org/10.5500/wjt.v3.i2.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782241PMC
June 2013

Antineoplastic effects of mammalian target of rapamycine inhibitors.

World J Transplant 2012 Oct;2(5):74-83

Maurizio Salvadori, Renal Unit, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Italy.

Cancer after transplantation is the third cause of death and one of the more relevant comorbidities. Aim of this review is to verify the role of different pathogenetic mechanisms in cancer development in transplant patients and in general population as well. In particular has been outlined the different role exerted by two different families of drug as calcineurin inhibitor and mammalian target of rapamycin (mTOR) inhibitor. The role of mTOR pathways in cell homeostasis is complex but enough clear. As a consequence the mTOR pathway deregulation is involved in the genesis of several cancers. Hence the relevant role of mTOR inhibitors. The authors review the complex mechanism of action of mTOR inhibitors, not only for what concerns the immune system but also other cells as endothelial, smooth muscle and epithelial cells. The mechanism of action is still now not completely defined and understood. It implies the inhibition of mTOR pathway at different levels, but mainly at level of the phosphorylation of several intracellular kinases that contribute to activate mTOR complex. Many prospective and retrospective studies in transplant patients document the antineoplastic role of mTOR inhibition. More recently mTOR inhibitors proven to be effective in the treatment of some cancers also in general population. Kidney cancers, neuroendocrine tumors and liver cancers seem to be the most sensitive to these drugs. Best results are obtained with a combination treatment, targeting the mTOR pathway at different levels.
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http://dx.doi.org/10.5500/wjt.v2.i5.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782237PMC
October 2012

Renal transplant allocation criteria, desensitization strategies and immunosuppressive therapy in retransplant renal patients.

J Nephrol 2012 Nov-Dec;25(6):890-9

Department of Nephrology, University of Florence, Florence, Italy.

This review covers the issue of kidney retransplantation. Patients waiting for a second transplant are increasing in number, and it is more and more difficult to find a suitable kidney. The main reasons are both clinical and immunological. Immunological problems are the most difficult to overcome. New techniques allow the identification of anti-HLA antibodies previously not easy to find. As a consequence, patients waiting for a new transplant are often hyperimmunized, and the cross-match is often positive. The authors discuss several immunosuppressive approaches for such patients and new allocation criteria to allow an easier retransplant. New allocation programs such as acceptable mismatch programs and paired kidney exchange programs are being implemented, and new drugs are now emerging allowing new desensitization criteria. Some of them are not yet on the market, but preliminary clinical studies show such drugs to be promising in a short time.
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http://dx.doi.org/10.5301/jn.5000207DOI Listing
May 2013

Enteric-coated mycophenolate sodium immunosuppression in renal transplant patients: efficacy and dosing.

Transplant Rev (Orlando) 2012 Oct 3;26(4):233-40. Epub 2012 Aug 3.

Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA.

Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) formulation, has improved both short- and long-term outcomes following renal transplantation, but is often associated with gastrointestinal (GI) complications that can lead to dose reduction or discontinuation, potentially jeopardizing patient outcomes. Enteric-coated mycophenolate sodium (EC-MPS) delivers equivalent MPA exposure to MMF and offers the potential to reduce GI burden (while maintaining patient safety). Here we review the efficacy of EC-MPS compared with MMF in renal transplant patients in terms of biopsy-proven acute rejection and graft loss, and examine the use of EC-MPS in newer regimens such as intensified dosing and calcineurin inhibitor minimization.
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http://dx.doi.org/10.1016/j.trre.2012.02.001DOI Listing
October 2012

Relationship among endothelial response to hyperemia, bone marrow-derived progenitor cells, and parathyroid hormone in renal transplantation.

Transplantation 2012 Apr;93(8):835-41

Department of Medical and Surgical Critical Care, Thrombosis Center, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.

Background: Endothelial dysfunction may contribute to modulate cardiovascular complications in renal transplant recipients (RTRs), and a relationship between endothelial dysfunction and parathyroid hormone (PTH) levels in RTRs has been demonstrated. We evaluated the relationship between endothelial response to hyperemia and circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) PTH, and genetic parameters in RTRs.

Methods: In 120 RTRs and in healthy subjects without (n=107, group A) and with cardiovascular risk factors (n=109, group B), we evaluated endothelial response to hyperemia through digital tonometry (peripheral arterial tonometry) detected by reactive hyperemia index (RHI) and EPCs and CPCs by flow cytometry.

Results: In RTRs, RHI median value was lower than in group A (P=0.05). EPC number was significantly lower in RTRs than in groups A and B (P<0.0001), whereas PTH median value was significantly higher (P<0.0001). In RTRs, RHI values were significantly lower according to the presence of three or more risk factors (P=0.04) and positively correlated with EPCs (P=0.04) but not with PTH (P=0.2). In patients who underwent dialysis for more than 5 years, lower RHI values (P=0.08), EPC number (P=0.5), and higher PTH concentrations (P=0.09) than in patients with less than 1 year dialysis time were observed. No relationship between eNOS gene -786T>C, 894G>T, and 4a/4b polymorphisms and RHI, EPC, and CPC number was found.

Conclusions: This study shows an altered endothelial response, associated with reduced EPCs, and increased PTH in RTRs; the evaluation of endothelial status in RTRs may contribute to better assess the risk profile of these patients.
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http://dx.doi.org/10.1097/TP.0b013e318247a75dDOI Listing
April 2012

What is the purpose of launching the World Journal of Transplantation?

World J Transplant 2011 Dec;1(1):1-3

Maurizio Salvadori, Renal Unit, Department of Renal Transplantation, Careggi University Hospital, viale Pieraccini 18, 50139 Florence, Italy.

Congratulations to the publisher, members of the editorial board of the journal, all the authors and readers for launching the World Journal of Transplantation (WJT) as a new member of the World series journal family. Transplantations are rapidly evolving and share knowledge with a number of basic and clinical sciences: molecular biology, stem cell investigators, immune system, pharmacology, biotechnology, surgery and physicians of different organs such as the kidneys, liver, heart, lung, bone marrow and so on. The WJT is a peer reviewed open access journal centered on the different fields involved in transplant activity. If you want to share your experiences and new findings in the field of transplantation with your peers you will find the WJT a good media to publish your papers.
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http://dx.doi.org/10.5500/wjt.v1.i1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782228PMC
December 2011

The kidney, a victim and culprit of autoimmune and alloimmune responses.

Nephron Clin Pract 2011 11;119(3):c200-4. Epub 2011 Aug 11.

Nephrology and Dialysis, Istituto Scientifico Humanitas, Rozzano, Italy.

The Working Group of the European Renal Association-European Nephrology and Dialysis Association (ERA-EDTA) dedicated to immune system involvement in renal disease (Immunonephrology Working Group) was established in 2009 to facilitate exchanges of ideas on basic science research and new treatment protocols among European nephrologists. A section of the ERA-EDTA website describes activities and is open for new applications and proposals. In 2010, the first meeting of this Working Group focused on aspects of immune-mediated renal damage shared by kidney during glomerulonephritides or after kidney transplantation. From the large series of data reported, a previously disregarded presence of pathogenetic and therapeutic aspects common to glomerular diseases and transplanted kidneys was highlighted. Although the antigens involved in transplant rejection and in glomerulonephritis are different, a number of factors involved in the effector response are similar, mainly those based on the interaction between innate and adaptive immune mechanisms and on the strict cooperation between T and B cells. Moreover, the common target for the allo- and autoimmune attacks is represented by the endothelial cells, of which the kidney is particularly rich. These similarities may explain why immunomodulating treatments used in alloimmunity may also be useful in autoimmune diseases and vice versa. Considering renal damage from a holistic point of view may favour exchange of news for two formerly considered non-communicant areas, i.e. glomerular disease and renal transplantation nephrology sections.
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http://dx.doi.org/10.1159/000328913DOI Listing
April 2012