From myeloma-related kidney disease [22].
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6617",leadTitle:null,fullTitle:"Immunoregulatory Aspects of Immunotherapy",title:"Immunoregulatory Aspects of Immunotherapy",subtitle:null,reviewType:"peer-reviewed",abstract:"Immunotherapy is an innovative, leading and valuable approach to the treatment and control of many diseases. It can solve many problems of public health worldwide. Many people in numerous countries are suffering from a wide range of diseases (communicable and non-communicable) that can be cured or controlled by the immune system and immunotherapy. Some immunological diseases (i.e. allergic reactions and asthma, autoimmune disease, immunodeficiency disease, hypersensitivity reactions, etc.) have immune response pathophysiology and by controlling immune system mechanisms, these diseases can be controlled and cured. Immunoregulatory Aspects of Immunotherapy focuses on immune system mechanism, diagnosis, treatment and other related problems. The chapters have applicable and scientific data in immunotherapeutic approaches based on medical sciences, and would be of benefit to all researchers in immunology, allergy and asthma fields. The book discusses the prevention, diagnosis, treatment and follow-up of patients who have dangerous diseases. We hope this book will be a new approach to the immunotherapy of diseases and will improve public health and wellbeing.",isbn:"978-1-78923-509-8",printIsbn:"978-1-78923-508-1",pdfIsbn:"978-1-83881-592-9",doi:"10.5772/intechopen.71636",price:119,priceEur:129,priceUsd:155,slug:"immunoregulatory-aspects-of-immunotherapy",numberOfPages:240,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"a2f42aa78dd846d4a1679066e72a7285",bookSignature:"Seyyed Shamsadin Athari",publishedDate:"August 1st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6617.jpg",numberOfDownloads:11764,numberOfWosCitations:7,numberOfCrossrefCitations:10,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:19,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:36,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 19th 2017",dateEndSecondStepPublish:"November 9th 2017",dateEndThirdStepPublish:"January 8th 2018",dateEndFourthStepPublish:"March 29th 2018",dateEndFifthStepPublish:"May 28th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",middleName:null,surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari",profilePictureURL:"https://mts.intechopen.com/storage/users/139889/images/system/139889.jpeg",biography:"Dr. Seyyed Shamsadin Athari is an assistant professor of immunology at the Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. He has an allergy and asthma toxicology postdoctoral degree and asthma management and controlling network fellowship. He has published more than 90 manuscripts in international journals on immunology, allergy, and asthma and more than 28 books. He is also on the editorial board of more than 65 international journals in medical sciences and has more than 12 inventions in medical sciences and has recorded 12 gene sequences in the gene bank. Dr. Athari has been invited as a top speaker for more than 40 international congresses and symposiums and has received several scientific awards from different scientific societies as a young top researcher and young scientist.",institutionString:"Zanjan University of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Zanjan University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"150",title:"Pure Immunology",slug:"pure-immunology"}],chapters:[{id:"60540",title:"Immune System Disorders: Hypersensitivity and Autoimmunity",doi:"10.5772/intechopen.75794",slug:"immune-system-disorders-hypersensitivity-and-autoimmunity",totalDownloads:2451,totalCrossrefCites:3,totalDimensionsCites:8,hasAltmetrics:1,abstract:"The immune response is known as a physiological mechanism to protect the body, providing defense to different systems that compose it and allowing its proper functioning. The ability to keep the organism free from foreign agents depends on the mechanisms of natural resistance or innate immunity, as well as the resistance that can develop over time through adaptive immunity. However, when these defense mechanisms fail, it can trigger injuries and diseases in the tissues, such as hypersensitivity, which is characterized as an excessive and undesirable reaction, produced by the immune system; as well as autoimmunity, which refers to the failure of the mechanisms of immunological tolerance, causing the reaction of the immune system against the body itself.",signatures:"José Luis Muñoz-Carrillo, Flor Pamela Castro-García, Francisca\nChávez-Rubalcaba, Isabel Chávez-Rubalcaba, José Luis Martínez-\nRodríguez and Marcela Elizabeth Hernández-Ruiz",downloadPdfUrl:"/chapter/pdf-download/60540",previewPdfUrl:"/chapter/pdf-preview/60540",authors:[null],corrections:null},{id:"60755",title:"Immune Checkpoint Blockade and Immune Monitoring",doi:"10.5772/intechopen.74688",slug:"immune-checkpoint-blockade-and-immune-monitoring",totalDownloads:1411,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The concept of immunological surveillance, a monitoring process in which the immune system detects and destroys by several effector mechanisms, virally infected and neoplastic transformed cells in the body, was developed more than 50 years ago. Based on current research, it is clear that the immune system can recognize and eliminate transformed cells. An increasing number of studies has investigated the immune system in cancer patients and how it is prone to immunosuppression, due in part to the decrease of lymphocyte proliferation and cytotoxic activity. Such weakened immune system is then unable to fully accomplish its role in immunological surveillance, allowing nascent transformed cells to escape the selective pressure of the immune system. The main goal of cancer immunotherapy has been to reawaken the immune system from a suppressive slumber to enable it to attack cancer cells once again. As the results from the last 10 years attest, cancer immunotherapy is the best strategy to restore the activity of the immune system and unleash its potential to destroy cancer cells in cancer patients. This chapter aims to discuss the recent findings on immune monitoring studies and the use of immune checkpoint inhibition in cancer immunotherapy.",signatures:"Jorge Augusto Borin Scutti, Luiz R. Travassos and Luiz M. Vence",downloadPdfUrl:"/chapter/pdf-download/60755",previewPdfUrl:"/chapter/pdf-preview/60755",authors:[null],corrections:null},{id:"59743",title:"New Strategies to Improve Therapeutic Vaccines",doi:"10.5772/intechopen.74900",slug:"new-strategies-to-improve-therapeutic-vaccines",totalDownloads:1234,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Vaccination represents a viable and attractive strategy for therapeutic treatment of cancers by the power of a patient’s own immune system. Major advances in cellular and molecular immunology have led to the approval of the first therapeutic cancer vaccine by FDA. However, the development of cancer vaccines remains infant. Maximizing the therapeutic efficacy while minimizing side effects of the therapeutic cancer vaccine remains key challenges to this field. In this review, we summarized the recently developed strategies to induce anti-tumor responses in vivo to improve the outcomes of cancer vaccines, with an emphasis on the guiding principles that are critical for rational design of effective and safe vaccines against cancers.",signatures:"Chunsong Yu and Haipeng Liu",downloadPdfUrl:"/chapter/pdf-download/59743",previewPdfUrl:"/chapter/pdf-preview/59743",authors:[null],corrections:null},{id:"61330",title:"Therapeutic Potentials of IL-10 versus IL-12",doi:"10.5772/intechopen.76914",slug:"therapeutic-potentials-of-il-10-versus-il-12",totalDownloads:1090,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Cytokines are low molecular weight proteins having roles in essential biological processes, particularly for the immune system. As they have a key role to play, an abnormality in their function can lead to wide variety of diseases (clinical consequences). Thus using the cytokines as therapeutic targets has been an area of active research. Of the entire family, we would like to shed light on two major ones IL-10 and IL-12 having an array of roles in cellular response to infection and autoimmunity. IL-12 is a pro-inflammatory cytokine that has been shown to enhance IFN-γ producing T cell responses and has been widely tested as a vaccine adjuvant. Many studies have shown that IL-12 acts as a link between innate and adaptive immunity by inducing IFN-γ production and polarizing naive CD4 T cells to become Th1 cells. It also has roles in CD8 T cell differentiation. On the other hand, IL-10 is an anti-inflammatory cytokine and has role in maturation of memory CD8 T-cell. It also plays a critical role in preventing autoimmunity and also limits tissue injury by interfering with the intensity and duration of immune response. We would thus like to discuss in details about the therapeutic use of these cytokines for infections as well as diseases such as cancer, autoimmune disorders etc.",signatures:"Vishakha Bhurani and Sarat Kumar Dalai",downloadPdfUrl:"/chapter/pdf-download/61330",previewPdfUrl:"/chapter/pdf-preview/61330",authors:[null],corrections:null},{id:"60355",title:"Immune System Modulation Produced by Ultraviolet Radiation",doi:"10.5772/intechopen.75450",slug:"immune-system-modulation-produced-by-ultraviolet-radiation",totalDownloads:1114,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Exposure to ultraviolet radiation (UVr) contained in sunlight is a major cause of skin illness such as sunburn, aging and cancer. UVr triggers local effects on the skin, which involve local inflammation, tissue remodeling, regulatory cytokines release and migration of dendritic cells (DCs). However, these localized effects on the exposed area are not the only ones that take place after sun or UVr exposure. A less known effect of UVr is the modulation of systemic immunity, through the generation of specific regulatory cells. These cells are induced, at least in part, by skin-migrating tolerogenic DCs. Moreover, bone marrow cell precursors can also be biased to a tolerogenic or suppressor phenotype. The sunlight- or UVr-induced immune system modulation can cause skin disorders like skin cancer and cutaneous photosensitivity in Lupus, but it also may be useful to treat cutaneous pathologies such as psoriasis and vitiligo. Moreover, the systemic immunosuppressor effect of UVr exposure may also be useful to treat autoimmunity of internal organs. Finally, as an inducer of cutaneous inflammatory response, UV phototherapy may also be useful in the treatment of cutaneous infections. Overall, UVr has profound immunomodulatory capacity that can be beneficial or deleterious for human health.",signatures:"Eliana M. Cela, Mariela L. Paz, Juliana Leoni and Daniel H. González\nMaglio",downloadPdfUrl:"/chapter/pdf-download/60355",previewPdfUrl:"/chapter/pdf-preview/60355",authors:[null],corrections:null},{id:"61006",title:"Toll-Like Receptors: The Key of Immunotherapy in MSCs",doi:"10.5772/intechopen.76644",slug:"toll-like-receptors-the-key-of-immunotherapy-in-mscs",totalDownloads:1073,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Human mesenchymal stem cells (MSCs) are potential candidates for various applications in the fields of immunotherapy. Their multilineage differentiation capability and immune modulatory features allow their prospective application for the management of different immunological circumstances. However, the local microenvironment, in addition to the source of the MSCs can control diverse biological features of the cells. Indeed, throughout their therapeutic application, MSCs may interact with their microenvironment through their expressed toll-like-receptors (TLRs), producing immune modulating reactions. Stimulation of MSCs before or within the potential treatment procedures with distinct TLR ligands may assist as an effective step controlling the biological function of the MSCs as needed in different therapeutic stages of the disease.",signatures:"Mohamed K. Mekhemar, Christof E. Dörfer and Karim M. Fawzy El-\nSayed",downloadPdfUrl:"/chapter/pdf-download/61006",previewPdfUrl:"/chapter/pdf-preview/61006",authors:[null],corrections:null},{id:"60000",title:"Immunotherapeutic Approaches of Rheumatoid Arthritis and the Implication on Novel Interventions for Refractoriness",doi:"10.5772/intechopen.75553",slug:"immunotherapeutic-approaches-of-rheumatoid-arthritis-and-the-implication-on-novel-interventions-for-",totalDownloads:1173,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Rheumatoid arthritis is an autoimmune disorder involving the chronic inflammation of affected joints which lead to the distortion and eventually destruction of the articular tissues. Clinically, many therapeutic methods are being used for RA treatment. Non-steroidal anti-inflammatory drugs (NSAIDs), steroid, and disease-modifying anti-rheumatic drugs (DMARDs) are the three main categories of intervention approaches. Among which DMARDs, targeting mainly the release of pro-inflammatory cytokines, demonstrated high efficacy because of its direct drug action that alter the underlying disease mechanisms rather than simply to mediate symptoms relieve. However, the use of DMARDs also accompanying some unwanted adverse side effects, in particular, the development of refractoriness, which hampers the successful rate of treatment. In this chapter, the conventional RA drugs will be reviewed, focusing on the currently used and latest development of DMARDs. Novel methods that could improve RA pathogenesis will also be introduced. Because of the critical role of refractory RA, the progress of the disease to develop resistance to standard drug treatment will also be described. Finally, innovative RA therapeutic methods inspired by researches concerning the pathogenesis and contemporary treatments of RA will be discussed.",signatures:"Simon Wing-Fai Mok, Betty Yuen-Kwan Law, Vincent Kam-Wai\nWong and Liang Liu",downloadPdfUrl:"/chapter/pdf-download/60000",previewPdfUrl:"/chapter/pdf-preview/60000",authors:[null],corrections:null},{id:"60479",title:"Present and Future Therapies for Alzheimer’s Disease",doi:"10.5772/intechopen.75449",slug:"present-and-future-therapies-for-alzheimer-s-disease",totalDownloads:1062,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder and the most common type of dementia. Although four kinds of drugs are currently available for AD, these are symptomatic treatments and do not halt disease progression. Therefore, there is an urgent need for development of curative drugs for AD. Amyloid plaques are the main disease hallmark observed in AD brains. As amyloid-β (Aβ) is a major constituent of amyloid plaques, Aβ has been supposed to be pathogenic for AD (amyloid hypothesis). Thus, current, mainstream AD drug development is based around this hypothesis. In particular, both active and passive immunotherapies are aggressively employed. However, most clinical trials based on this hypothesis, including immunotherapies, failed to improve cognitive impairment in AD. Therefore, it is likely that AD onset is caused by factors besides Aβ. We have previously demonstrated that the intracellular domain of amyloid precursor protein (AICD) induces dynamic changes in gene expression and neuron-specific apoptosis, probably related to AD pathogenesis. Therefore, AICD may be a favorable target for AD therapies. In this chapter, current trials for AD therapies, especially immunotherapies targeting Aβ, are summarized. In addition, therapies targeting tau, another possible pathogenic molecule, are also described. Furthermore, we discuss the possibility of AICD as a novel therapeutic target for AD.",signatures:"Hisashi Nagase and Kohzo Nakayama",downloadPdfUrl:"/chapter/pdf-download/60479",previewPdfUrl:"/chapter/pdf-preview/60479",authors:[{id:"88080",title:"Dr.",name:"Kohzo",surname:"Nakayama",slug:"kohzo-nakayama",fullName:"Kohzo Nakayama"},{id:"124609",title:"Dr.",name:"Hisashi",surname:"Nagase",slug:"hisashi-nagase",fullName:"Hisashi Nagase"}],corrections:null},{id:"60496",title:"Serological Biomarkers for the Prediction and Detection of Human Papillomavirus Associated Cancers",doi:"10.5772/intechopen.75143",slug:"serological-biomarkers-for-the-prediction-and-detection-of-human-papillomavirus-associated-cancers",totalDownloads:1158,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"High-risk human papillomavirus (HPV) types are not only associated to uterine cervical cancer, but also to a fraction of cancers of the vulva, vagina, penis, anus, head and neck. An HPV infection generates a protective humoral immune response against the capsid proteins L1 and L2; however, an immune response against other HPV early proteins is also generated. This latter is not a protective response, but those antibodies can be useful as biomarkers of the status of the infection and/or the stage of the cancer lesion. Until now, there are no conclusive results regarding the use of anti-HPV antibodies as biomarkers in diagnosis. In this review, we hereby summarized the actual panorama of the humoral immune response against different HPV early proteins during the development of the disease as possible biomarkers for the prediction and detection of HPV-associated cancers.",signatures:"Lourdes Gutierrez-Xicotencatl, Azucena Salazar-Piña, Lilia Chihu-\nAmparan and Adolfo Pedroza-Saavedra",downloadPdfUrl:"/chapter/pdf-download/60496",previewPdfUrl:"/chapter/pdf-preview/60496",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"5776",title:"Allergen",subtitle:null,isOpenForSubmission:!1,hash:"20e406e7a94419ea2beba834a8030a79",slug:"allergen",bookSignature:"Seyyed Shamsadin Athari",coverURL:"https://cdn.intechopen.com/books/images_new/5776.jpg",editedByType:"Edited by",editors:[{id:"139889",title:"Dr.",name:"Seyyed Shamsadin",surname:"Athari",slug:"seyyed-shamsadin-athari",fullName:"Seyyed Shamsadin Athari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6963",title:"Immune Response Activation and Immunomodulation",subtitle:null,isOpenForSubmission:!1,hash:"ac7ce04a130a57849a8d3adb55d688ed",slug:"immune-response-activation-and-immunomodulation",bookSignature:"Rajeev K. 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Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"33329",title:"Prof.",name:"guifu",middleName:null,surname:"Ding",fullName:"guifu Ding",slug:"guifu-ding",email:"gfding@sjtu.edu.cn",position:null,institution:{name:"Shanghai Jiao Tong University",institutionURL:null,country:{name:"China"}}},{id:"244624",title:"Associate Prof.",name:"Congchun",middleName:null,surname:"Zhang",fullName:"Congchun Zhang",slug:"congchun-zhang",email:"zhcc@sjtu.edu.cn",position:null,institution:null},{id:"255541",title:"Mr.",name:"Jianze",middleName:null,surname:"Huang",fullName:"Jianze Huang",slug:"jianze-huang",email:"huangjz420@sjtu.edu.cn",position:null,institution:null},{id:"255547",title:"Mr.",name:"Chunsheng",middleName:null,surname:"Yang",fullName:"Chunsheng Yang",slug:"chunsheng-yang",email:"csyang@sjtu.edu.cn",position:null,institution:null}]}},chapter:{id:"62285",slug:"textured-bst-thin-film-on-silicon-substrate-preparation-and-its-applications-for-high-frequency-tuna",signatures:"Congchun Zhang, Jianze Huang, Chunsheng Yang and Guifu Ding",dateSubmitted:"February 7th 2018",dateReviewed:"June 3rd 2018",datePrePublished:"November 5th 2018",datePublished:"January 3rd 2019",book:{id:"7253",title:"Coatings and Thin-Film Technologies",subtitle:null,fullTitle:"Coatings and Thin-Film Technologies",slug:"coatings-and-thin-film-technologies",publishedDate:"January 3rd 2019",bookSignature:"Jaime Andres Perez-Taborda and Alba G. Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"33329",title:"Prof.",name:"guifu",middleName:null,surname:"Ding",fullName:"guifu Ding",slug:"guifu-ding",email:"gfding@sjtu.edu.cn",position:null,institution:{name:"Shanghai Jiao Tong University",institutionURL:null,country:{name:"China"}}},{id:"244624",title:"Associate Prof.",name:"Congchun",middleName:null,surname:"Zhang",fullName:"Congchun Zhang",slug:"congchun-zhang",email:"zhcc@sjtu.edu.cn",position:null,institution:null},{id:"255541",title:"Mr.",name:"Jianze",middleName:null,surname:"Huang",fullName:"Jianze Huang",slug:"jianze-huang",email:"huangjz420@sjtu.edu.cn",position:null,institution:null},{id:"255547",title:"Mr.",name:"Chunsheng",middleName:null,surname:"Yang",fullName:"Chunsheng Yang",slug:"chunsheng-yang",email:"csyang@sjtu.edu.cn",position:null,institution:null}]},book:{id:"7253",title:"Coatings and Thin-Film Technologies",subtitle:null,fullTitle:"Coatings and Thin-Film Technologies",slug:"coatings-and-thin-film-technologies",publishedDate:"January 3rd 2019",bookSignature:"Jaime Andres Perez-Taborda and Alba G. Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11444",leadTitle:null,title:"Happiness - Biopsychosocial and Anthropological Perspectives",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tToday, in the fields of psychology, medicine, biology, sociology, and anthropology, there is a great deal of research on the factors that are related to happiness and the effects of happiness on people's mental and physical health.
\r\n\r\n\tThis book aims to provide a comprehensive overview of this topic by exploring research, theories, biopsychosocial perspectives, and cross-cultural studies about happiness. The objectives of the project are: to analyze in-depth updates from research and clinic on how specific biological, psychological, and social factors are related to happiness, and how they develop in different contemporary cultural and anthropological contexts to further analyze their associations with mental health and, to investigate the interaction of demographic variables along different psychological and social trajectories, and thus obtain detailed information on the factors that influence the development of happiness.
\r\n\r\n\tFinally, this book aims to provide an overview to promote happiness and psychological well-being in the general population.
",isbn:"978-1-80355-592-8",printIsbn:"978-1-80355-591-1",pdfIsbn:"978-1-80355-593-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"fa84e7fc3611e5428e070239dcf5a93f",bookSignature:"Dr. Floriana Irtelli and Prof. Fabio Gabrielli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11444.jpg",keywords:"Psychotherapy, Mental Health, Relational Studies, Cultural Differences, Social Effects, Quality of Life, Anthropology, Psychophysiology, Well-Being, Measurement, Related Factors, Correlations",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 4th 2022",dateEndSecondStepPublish:"May 13th 2022",dateEndThirdStepPublish:"July 12th 2022",dateEndFourthStepPublish:"September 30th 2022",dateEndFifthStepPublish:"November 29th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Floriana Irtelli, psychoanalyst and psychotherapist, is a member of the International Association for Relational Psychoanalysis and Psychotherapy. She has worked at Fatebenefratelli Hospital in Milan performing research and clinical activities, in addition to authoring the books Illuminarsi di Benessere, Familiar-mente, and Contemporary Perspectives on Relational Wellness.",coeditorOneBiosketch:"Dr. Fabio Gabrielli, a philosopher, is a Professor of Philosophy of the Relationship at the School of Management (Milan campus), University Jean Monnet, Bari, Italy. He is a scientific member of QPP-Quantum Paradigms of Psychopathology and the 2015 Nobel Nominee.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"174641",title:"Dr.",name:"Floriana",middleName:null,surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli",profilePictureURL:"https://mts.intechopen.com/storage/users/174641/images/system/174641.jpeg",biography:"Floriana Irtelli is a psychoanalyst/psychotherapist and member of the International Association for Relational Psychoanalysis and Psychotherapy (IARPP) who has been lecturing for several years at the Catholic University of the Sacred Heart, Milan, Italy. She has worked at Fatebenefratelli Hospital in Milan performing research and clinical activities. She is among the authors of several books, including A Fresh Look at Anxiety Disorders and Psychopathy - New Updates on an Old Phenomenon, and has published articles for the Journal of Affective Disorders, Research in Psychotherapy, and the Journal for Psychiatric and Mental Health Nursing. She has participated in numerous conferences, seminars, and congresses. Dr. Irtelli is the sole author of the books Illuminarsi di Ben-essere, Familiar-mente, and Contemporary Perspectives on Relational Wellness.",institutionString:"Catholic University of the Sacred Heart",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Catholic University of the Sacred Heart",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:{id:"259407",title:"Prof.",name:"Fabio",middleName:null,surname:"Gabrielli",slug:"fabio-gabrielli",fullName:"Fabio Gabrielli",profilePictureURL:"https://mts.intechopen.com/storage/users/259407/images/system/259407.jpg",biography:"Dr. Fabio Gabrielli (2015 Nobel Prize nominee) has been Full\nProfessor of Philosophical Anthropology at Ludes University of\nLugano, Switzerland. Currently, he is also working as Professor\nof Philosophy of the Relationship at the School of Management,\nUniversity Jean Monnet, Bari, Italy. He is also a visiting professor, PWSTE, at the University of Jaroslaw, Poland. Dr. Gabrielli\nis a member of the International Scientific Committee of the\nQuantum Paradigms of Psychopathology (QPP) - European section, and a member\nof the Scientific Board of the Aracne Publishing House in Rome for the Neo-existential Anthropology Series. He is the honorary-national president of CCSVI in\nMultiple Sclerosis – ONLUS. 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For the last four decades, tax compliance has been a subject matter of considerable interest to many researchers from a variety of academic disciplines including accounting, economics, history, law, psychology, political science, and sociology [1]. A great deal of studies has already contributed to the tax literature discovering factors that shape taxpayer compliance behavior. However, most of them focus on taxpayer’s behavioral responses to the tax system and fiscal policy.
Taxation is a highly structured process of institutionalized entities like taxpayers, tax practitioners, tax administration, and up to government and tax lawmakers [2]. Besides, tax compliance is a complex phenomenon in the actors in the field, and their interactions have a great impact on individual taxpayers’ behavior [3]. Hence, lack of research on important entities can undermine our understanding of tax compliance behavior that is intimately intertwined [4].
In the real world, professional tax practices are highly relevant to determine taxpayer compliance. Tax practitioner can exert considerable influence on taxpayers in the tax compliance process by either helping them to enforce or exploit the tax law [5]. Many taxpayers, being helpless of overwhelming volumes and mysterious jargons in the tax laws, resort to the assistance from tax professionals who are well-informed of the complex tax rules. Moreover, having limited resources to run their business, taxpayers often defer to tax practitioners for the important decisions about their own tax matters. Therefore, it is essential to understand what makes the practitioners compliant and how they achieve compliance in taxpayer compliance process. However, scientific studies on tax practice in relation to taxpayer compliance are scarce. Furthermore, there is not a widely accepted definition of tax practitioner compliance.
The main objective of the chapter is to provide tax scholars, tax practitioners, and tax authorities with a better understanding of tax practitioner compliance in connection with taxpayers’ choice of their tax position. Toward this end, I glean useful knowledge from research findings and synthesize them in order to clarify the meaning of tax compliance in relation to taxpayer and tax practitioner and their interactions. Herein, I refer to tax practitioners as private sector tax professionals who help taxpayers to prepare their tax returns and/or provide advice on tax matters including accountants, paid preparers, lawyers, etc.
Tax practitioner behavior is of great concern to taxpayers, as well as tax authorities. Shafer and Simmons [6] maintain tax advisors have abandoned concern for the public interests in favor of commercialism. The dilemma mainly arises from their dual role as a client advocate and gatekeeper safeguarding the fairness of the tax system. In other words, an aspect of tax practitioner compliance relates to the conflict of client advocacy and professional responsibilities [7]. Mason and Garrett Levy [8], p. 127, defines client advocacy as “a state of mind in which one feels one’s primary loyalty belongs to the taxpayer. It is exhibited by a desire to represent the taxpayer zealously within the bounds of the law and by a desire to be a fighter on behalf of the taxpayer.”
For example, a noncompliant practitioner is willing to accept overly aggressive or, in its extreme, a fraudulent tax reporting if the probability of detection and punishment is perceived to be relatively low. However, an important question still remains unresolved. Should tax practitioner aggressiveness in terms of recommending tax treatment be deemed noncompliant without any consideration whatsoever? Is tax practitioner compliance achieved if the practitioner takes too conservative a tax position in favor of the government which, arguably, represents public interests?
This chapter attempts to discover the key to understand the puzzling concept of tax practitioner compliance by illuminating the role of tax practitioners in the self-assessment system (“SAS”) in regard to income tax return reporting positions. Since most of prior studies predominantly investigate tax compliance in the frame of individual taxpayers’ evasion decision under detection risk, the term tax compliance and taxpayer compliance are often used interchangeably. For the purpose of the article, however, tax compliance should be carefully distinguished from taxpayer compliance. I presume that the tax compliance refers to
Taxpayer noncompliance refers to any failure to meet tax obligations, and it does not necessarily require intention to pay less tax than the law demands. It may result from deliberate underreporting, inadvertent misreporting, or nonfiling of tax return. The tax gap, which is a popular measure of noncompliance in an aggregate level, is defined as the difference between actual tax collected and the potential tax collection under full compliance [10]. It consists of nonfiling, underreporting, and underpayment of tax [11], which represent filing noncompliance, reporting noncompliance, and payment noncompliance, respectively.
Tax evasion and tax avoidance consist in deliberate act of noncompliance. While tax evasion refers to intentional underpayment of taxes by deliberate nondisclosure of taxable resources [12], tax avoidance is widely considered a legal way of reducing tax dues. Tax avoidance, however, is often against the spirit of the laws, thereby has a chance to be challenged by tax authorities, which eventually falls under the category of noncompliance.
The majority of scientific studies on tax compliance address the problem of individuals’ tax evasion decision in the form of underreporting taxable income or overclaiming unwarranted deductions. In particular, most of them are concerned with SAS, in which taxpayers are given opportunities to underreport, and their initial tax liabilities are determined by self-declaration, while the true income will not be observable by tax authorities unless a tax audit is conducted. Thus, tax noncompliance, in the narrowest sense, refers to taxpayers’ dishonesty in their tax reporting.
However, it should be noted that, from the viewpoint of taxpayers, noncompliance problem lies not only in undercompliance but also in overcompliance: noncompliance can result not only from underreporting or underpayment but also from overreporting or overpayment. Inadvertent noncompliance may result from the errors and mistakes of taxpayers or tax practitioners. Nevertheless, the researchers and policymakers have paid little attention to the problem of overcompliance. It may be that taxpayers are assumed to be rational enough to deal with tax matters, and thus, discovering of underreporting should be deemed the consequence of their intentional misconduct. On the basis of rationality assumptions, any mistakes may be seen as not due to incompetence but to a lack of commitment to declare a correct tax return [13].
Tax laws are increasingly voluminous, and the law provisions are sometimes terribly complicated to be fully understood. It takes a lot of time and effort to meet the tax obligations, and even if they pay much attention enough to avoid inadvertent errors and mistakes, tax liabilities are often subject to uncertainty from varying interpretations of ambiguous tax situations. For a further understanding, the following section discusses the issues of tax law complexity and ambiguity.
In practice, many taxpayers are faced with the complexity of tax laws and the uncertainty of enforcement. In most developed countries, tax law is complex, and it requires a very high reading age to be correctly understood [14]. Taxation cost (taxes and compliance cost) is perceived to be much more painful loss for small business taxpayers because they lack sufficient resources to manage their business [15].
If tax laws are vague and complicated, it may be difficult to fully comply with the law even with no intention to evade. Owing to the complex nature, ordinary taxpayers cannot cope well with tax requirements. Sakurai and Braithwaite [16] showed that the most important reason that their survey respondents gave for using tax service was that the desire to avoid the risk of potential tax penalties resulting from inaccurate tax returns. The professional tax knowledge that prevents the taxpayer from unintentional overpayment as well as underpayment can be purchased from the tax practitioners. Thus, an aspect of tax practitioner compliance can be better construed in connection with professional competence that ensures correct tax reporting.
McKerchar [17] maintains that tax complexity is a double edge sword for practitioners: on one side, it induces taxpayers into the arms of practitioners facilitating the market for tax service; but sometimes, it is too much a burden even for them to juggle. Although compliance duties can be addressed more correctly by the tax practitioner, the assistance of the tax practitioner cannot eliminate the risk of inadvertent noncompliance due to the complexity inherent in the law.
Carnes and Cuccia [18] argue that complexity is a source of unintentional noncompliance, and it may represent opportunities for intentional noncompliance as well. More often, tax practitioners can only reduce the uncertainty by assessing the likelihood a tax treatment will be sustained on its merits [19]. That said, inadvertent noncompliance is in part attributable to tax law ambiguity. A tax situation is ambiguous if its proper tax treatment is not
Studies on tax practitioner behavior attempt to discover the conditions in which tax advisors would recommend more aggressive reporting position [21]. A number of studies have been conducted investigating factors that impact tax practitioners’ willingness to accept aggressive reporting positions; among them are attitude toward risk [22], the threat of penalties [23], and client’s risk preference [24]. In particular, Prospect theory [25] may also serve as a theoretical basis to explain tax practitioner’s behavior. According to the Prospect theory, people exhibit risk seeking tendency in a loss situation, while being risk averse in a gain situation. Newberry et al. [26] found that CAPs were more likely to sign a tax return containing a large and ambiguous deduction to retain an existing client than to gain new one.
However, tax practitioner studies tend to avoid compliance or noncompliance, directly focusing instead on aggressiveness [27]. Phillips and Sansing [28] underline that conservative and aggressive are
There are a variety of motives in hiring tax practitioners. As it is, the role of tax practitioners in tax compliance process can be best understood considering the multifaceted aspects of tax service. Frecknall-Hughes and Moizer [29] argue that the work of tax practitioners in its broadest way can be divided into two kinds: tax compliance and tax planning/avoidance advice; the formal relates to resolve uncertainty in which tax position can be correctly settled, and the latter is associated with ambiguous tax situations in which legitimate tax position is not deterministic. Stephenson [30] discovered four separate constructs underlying the demands for tax practice: legal compliance, time savings, money savings, and protection from the tax authority.
Many taxpayers tend to claim accuracy as their main objective in tax preparation [31]. In that case, the quality of tax service is to ensure the tax returns do not contain inadvertent errors or omissions. It is somewhat evident that taxpayers hire tax practitioners to save time and effort required to achieve compliance. They will delegate tax return preparation to the practitioner, if the opportunity cost of self-reporting exceeds the service fee. Tax practitioners are also expected by their clients to reduce the chances of audit and penalty, thereby lowering monetary and psychic costs associated with audits that would otherwise have occurred [32]. Tax practitioners may provide professional assurance of compliance by verifying and assessing acceptable tax positions in the SAS [33].
Every tax legislation, however, contains “gray” areas that produce ambiguous tax situations. Tax practitioners cannot get rid of entire uncertainty, but they can only gauge the likelihood the position not being upheld by the tax court. The tax position is subject to some uncertainty and hence may step into a process of negotiation with the tax authorities [29]. Indeed, Frecknall-Hughes and Kirchler [34] came up with negotiation theory as a conceptual framework for understanding the nature of tax practice. They argue that the tax advisor/preparer and the tax inspector (who are the employee of revenue authority) are negotiators who act respectively on behalf of a client and the tax authority. While laypersons may see the task of trials and tax audits as revealing the truth about the matter, many practitioners approach their job as being able to negotiate the best settlement for their clients [35].
Some tax practitioners promote unacceptable tax minimization arrangements, assisting their clients in devising strategies to exploit legal ambiguities [36]. They are inclined to view testing the outer limits of the tax law as a natural and acceptable feature [37]. In recent decades, their role has become more complicated and sophisticated with the special tax knowledge required to facilitate tax avoidance [38]. For example, Sikka and Hampton [39] criticize that accountancy firms have sold tax avoidance schemes to corporations and wealthy individuals, which they refer to as tax solutions or tax strategies.
Nevertheless, it is important to distinguish legally permissible tax planning from potentially unacceptable tax scheme. Adapting motivational postures theory [40], Kang [41] coined two terms indicating differentiated features of tax avoidance: deferential avoidance and defiant avoidance, while deferential avoiders stand firm within the boundaries of the law, defiant avoiders try to push the boundaries of the law’s intent by self-serving in terms of law interpretation.
The role of tax practitioners has been viewed as representative of both taxpayers and the government [42]. One might argue that they have to act as advocates for their clients and to serve as intermediaries in the tax system. Tax practitioners should be concerned not only with their client’s interest but also with general publics in conducting their practices. Indeed, OECD [43] published a report highlighting the importance of trilateral relationships among tax authorities, taxpayers, and tax intermediaries in promoting taxpayer compliance. In a nutshell, tax practitioners have a legitimate and efficient function as intermediaries or “knowledge brokers” between taxpayers and revenue authorities [44]. They can provide a useful line of communication between tax inspectors and taxpayers. Furthermore, tax professionals can provide a check-and-balance function that prevents tax authorities’ possible extortion or tax inspectors’ harassment on the part of taxpayers, thereby safeguarding the equity of a tax system [7].
There are a variety of expectations for tax practitioner work, and sometimes an “expectation gap” arises from the misperception of each other’s expectation. Expectations gap refers to the difference between client expectations and the professional’s perceptions of those expectations and vice versa [20]. Christensen [45] argues that tax preparers’ perceptions of what clients expect from tax service differ significantly from clients’ expectations. Tax preparers may rationalize it is their clients who demand aggressive tax reporting. Schisler [24] maintains that many taxpayers insist on aggressive tax advice. In contrast, according to Tan [46], taxpayers favor conservative tax advice if the taxpayers’ main objective is filing an accurate tax return. This issue is worthwhile to be explored in more depth in the following section.
Research on the interaction between taxpayers and tax practitioners exists much less than is required, providing the immense amount of time and money spent on tax compliance [20]. Kaplan et al. [5] emphasize the role of tax practitioners in tax compliance by demonstrating that if a tax practitioner provides aggressive tax advice, the taxpayer is likely to take the aggressive tax position that might not be upheld in a tax audit. On the contrary, Hite and McGill [47] argue that taxpayers tended to disagree with aggressive advice and to agree instead with conservative advice. Or, there is also evidence that conservative taxpayers defer to the opinion of aggressive tax practitioners [48]. Not surprisingly, there are taxpayers who will still accept whatever types of advice their practitioners recommend.
For the tax practitioner, clients’ risk preferences could influence the willingness of practitioners to recommend aggressive positions [49]. Cloyd [50], Cuccia et al. [51], and Schisler [24] indicate tax practitioners’ tendency to recommend more aggressive positions when taxpayers are more aggressive (risk seeking). Notably, Duncan et al. [52] found the opposite evidence showing the more risk-averse the taxpayer, the more aggressive the tax practitioner, and the more aggressive the taxpayer, the more conservative tax position recommended by the practitioner. Furthermore, Bobek et al. [53] examined how the role of client advocacy influenced tax professionals’ decision processes and outcomes and provided empirical results revealing that client characteristics influence tax professionals’ advocacy attitudes. These findings suggest that taxpayers and tax practitioners’ decisions are interdependent, and studies on their interaction dynamics could be a promising approach to find new insights into tax compliance.
Wurth and Braithwaite [54] underline that practitioners are responsive to influences from many sources—clients, tax authorities, professional associations, governments, international bodies, and the organizations and cultures. For example, Doyle et al. [55] investigated the moral reasoning of tax practitioners in social contexts and in tax contexts, and they found tax practitioners’ significantly lower level moral reasoning than nonpractitioners in tax contexts. The study implies that client advocacy may deter tax practitioners’ moral reasoning. Reckers et al. [23] pointed out that less important taxpayers are more likely to receive more conservative advice from the tax practitioners. On the contrary, Bandy et al. [56] asserted that economic importance of the taxpayer had little effect on tax practitioners’ willingness to be aggressive in terms of providing advice or signing aggressive tax return. Spilker et al. [57] provide evidence that tax practitioners interpret ambiguity in the tax law differently in planning than in compliance stage because they are more vulnerable to problematic tax advice that might result in litigations and reputational loss.
In connection with taxpayer compliance, Practitioner-Client role model developed by Tan [58] recognizes two parties’ expectations, and behavioral dynamics can emphasize that how taxpayers and tax practitioners interact with each others are likely to affect each other’s tax decisions. Similarly, The Wheel of Social Alignments put forth by Braithwaite and Wenzel [59] synthesizes the drivers of tax compliance regarding tax practitioners as alternative authorities to tax officials.
Some taxpayers exhibit their preference of conservative advice over aggressive one. However, Sakurai and Braithwaite [60] show that some taxpayers prefer “no risk no fuss” type. As with their diverse motivational postures [40], it is natural of taxpayers to exhibit diversity in their preference over tax advice as well as tax position. It is therefore in communicating with their clients, tax practitioners should educate, persuade, and encourage taxpayers to acknowledge the responsibility for their decisions in order to reduce expectation gap [61]. In many cases, ineffective communication is attributable to the failure to achieve compliance procedures accompanied by unintended consequences. The absence of clear communication and the failure to make reasonable enquiries when information or documentation provided by a client appears to be inaccurate or incomplete [62] tend to engender the disappointment in their tax service experienced.
Tax practitioner self-seeking behavior together with compliance cost can afford unique opportunities to explore taxpayer decision. Tax law complexity increases the cost of compliance, and compliance costs are widely regarded as high. For the part of taxpayers, it may seem unfair to hire a tax professional in order to understand the laws. Taxpayers may expect their compliance cost to be offset by the tax service. If they deem the service fee as a mere expense accompanied by no additional benefit, they will be likely to be more aggressive in order to restore equitable condition. For instance, Jackson et al. [63] well demonstrated how taxpayers and tax practitioners decisions are interrelated. Drawing on mental accounting theory, they postulate mental aggregation of preparation cost with taxes, and tax professionals may place their clients in positive prepayment positions. The concept of mental accounting derived from research on prospect theory describes the set of cognitive operations used by individuals to organize, evaluate, and keep track of financial activities [64]. Then, they provide evidence that tax return preparation fees are larger for taxpayers who receive tax refunds than for taxpayers who owe additional taxes. It is argued that compliance costs paid to the tax preparer and the expected tax refund occur in the same mental account. Thus, taxpayers who have a favorable mental representation of tax return preparation fees may be willing to pay for higher costs incurred by tax practitioners.
In this chapter, I attempt to distinguish tax practitioner compliance from taxpayer compliance for a better understanding of tax compliance process. And I maintain that tax practitioner behavior can be assessed in the light of tax compliance, bringing about new perspective on tax compliance literature. As the extent and nature of tax practice are highly relevant to tax compliance, it is worthwhile to investigate the meaning of tax compliance in relation to tax practitioner compliance behavior.
As in taxpayer compliance, tax practitioner compliance can be either inadvertent or intentional. Tax practitioner noncompliance results the lack of professional competence and objectivity. Nevertheless, it is somehow inevitable for them to make mistakes due in part to the inherent uncertainty and ambiguity of the tax legislation. In order for them to ensure compliance, the tax practitioners continue to develop their professional skills; they must stay knowledgeable about current tax issues that have impact, positively or negatively, on their clients. Furthermore, the tax practitioner should be responsive to the environment in terms of both what clients want as well as what tax laws allow. However, their ethical judgment based on professional proficiency should not be affected by client pressure.
In return for their prestige, professions have certain obligations to their clients, colleagues, and the society [65]. For the meaning of tax compliance must include both compliance with the letter of the law and a respectful attitude toward the spirit of the law and fiscal policy [66], tax practitioner compliance may as well be construed in their decisions as well as underlying attitudes toward clients, colleagues, and the tax system. As a service provider, the tax practitioner must strive to reduce inconsistencies between expectations and experiences. As a member of the professions, the tax practitioner refrains from abusive tax schemes that can stimulate institutional corruptions. As a professional, the tax practitioner should safeguard the integrity of the tax system. In short, the tax practitioners should be carefully place themselves between tax authority and their clients as watch dogs to maintain the integrity of the tax system.
Tax practitioners’ noncompliance, in its extreme, occurs when they ignore clients’ legitimate right to reduce tax dues, but in its other extreme, tax practitioner noncompliance ensues from their acceptance or collusion of tax evasion. It is therefore necessary for tax authorities to acknowledge that tax practitioners play a role of effective interventions to improve taxpayer compliance. Above all, the practitioners are the ones to prevent taxpayers from taking overly aggressive or/and illegal tax positions. Furthermore, business taxpayers and their tax practitioners can be highly interdependent for tax practitioners can become business confidants [67].
There are many areas of research that have been understudied. Among them lies the conflict of interest between taxpayers and tax practitioner. Although the tax practitioner is hired by the taxpayer, they may act in accordance to their own interest rather than to the benefit of clients. This type of problem mostly arises from the information asymmetry between the taxpayer and the tax practitioner. Some practitioners may take advantage of private information to their own merit. The conflict of interest between taxpayers and tax practitioners that is worthwhile to be explored to establish a complete body of tax compliance literature.
Multiple myeloma (MM) is a malignant plasma cell neoplasia with an incidence of about 11 cases per 100,000 patients/year [1]. The clinical manifestations of this tumor are characterized by the presence of one or more signs gathered by the acronym CRAB: Calcium elevated, Renal impairment, Anemia, Bone lesions [2].
The renal failure, as end-stage organ damage related to MM, is defined as a value of serum creatinine of 177 microml/L (>2 mg/dL) or creatinine clearance <40 mL/min/1.73 m2, according with a recent review of diagnostic criteria for the plasma cell dyscrasia [3]. Renal impairment is a frequent complication of MM, that accounts for roughly 40% of newly diagnosis patients (10% requiring dialysis). Notably, this rate increases in the relapsed/refractory population. There is a strong association between the outcome of patients and entity of kidney injury in terms of overall survival and risk of early mortality [4, 5, 6]. The MM kidney involvement is mainly due to the toxic activity of monoclonal free light chains (FLCs), which can affect every structure of the nephron, from basement membranes of the glomeruli to renal tubules. The most common cause of acute kidney disease (AKI) is represented by light chain cast nephropathy (LCCN). Less frequent lesions associated with MM are immunoglobulin light chain (AL) amyloidosis, light chain deposition disease (LCDD), and other rarest pathologic entities [7, 8, 9]. The diagnosis of the causes of renal impairment is based on blood and urine tests, bone marrow aspirate, and biopsy. The kidney biopsy should be performed only if the cause is not clear and particularly for figuring out lesions different from LCCN as AL amyloidosis, LCDD, or kidney disease not related to MM (i.e. diabetes mellitus or arterial hypertension) [4, 10].
The AKI associated with LCCN is an emergency that can lead rapidly to an end stage renal disease (ESRD) with lifelong dialysis needs. For that reason, it is mandatory on one hand to act on the precipitating factors in order to prevent the onset of AKI, and on the other hand starting an immediate specific therapy with novel agent to achieve a quick reduction of FLCs productions, avoiding the interaction of the toxic proteins with the nephron. Besides the Proteasome Inhibitors, Immunomodulatory Drugs and Steroids, the new Monoclonal Antibodies are becoming an interesting option of therapy for these patients. In the fit population, the autologous hematopoietic stem cells transplantation is feasible, also in presence of dialytic need. The association of mechanical removal of the serum FLCs with the systemic therapy could be useful but is to date under investigation [4, 10, 11]. In this chapter, it is discussed the management of renal impairment associated with symptomatic multiple myeloma a malignant neoplasia. The kidney diseases associated with nonmalignant or premalignant monoclonal gammopathies, defined monoclonal gammopathies of renal significance (MGRS) are not covered here.
Renal impairment is one of the most frequent MM complications and its frequency varies according with the definition used for this condition. Overall, roughly 50% of patients with MM experience acute kidney injury (AKI) or chronic kidney disease (CKD) at some time during the course of their disease. Particularly, between 20 and 50% of newly diagnosed patients experience AKI or CKD during the disease course and a median rate of 1–3% (up to 12%) have a severe acute or chronic renal failure requiring dialysis [12, 13, 14, 15, 16, 17, 18]. According to estimated glomerular filtration rate (eGFR), the reported prevalence of AKI was 17% using the current International Myeloma Working Group criterion (<40 mL/min/1.73 m2) [4, 19, 20]. Using the RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) criteria, a clinical study showed that the 35% of patients with MM presented AKI [21]. Different kidney pathology lesions were described in patients with MM but only LCCN must be considered a myeloma defining event, because almost always occurs in presence a serum monoclonal (M) spike of >3 g/dL or clonal plasma cells of >10% in bone marrow and others myeloma features [3]. Less frequent myeloma-related renal pathologies are represented by AL amyloidosis. LCDD, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, thrombotic microangiopathy, fibrillary glomerulonephritis, cryoglobulinemia, pyelonephritis, focal segmental glomerulosclerosis, plasma cell infiltration, renal extramedullary hematopoiesis and crystal-line podocytopathy (Table 1) [22].
MM | LC preference | MGRS | Other hematologic diseases | |
---|---|---|---|---|
MCN | ∼100% | None | No | CLL, WM |
AL amyloidosis | 5–15% | Lambda | Yes | WM, CLL |
MIDD | 59–65% | Kappa | Yes | WM, CLL |
LCFN | 31–50% | Kappa | Yes | WM, CLL |
MG-related MPGN | <20% | None | Yes | CLL, WM |
ITG | 12.5% | None | Yes | CLL |
From myeloma-related kidney disease [22].
Abbreviations: AL, immunoglobulin light chain; CLL, chronic lymphocytic leukemia; ITG, immunotactoid glomerulonephritis; LCFN, light-chain Fanconi syndrome; MCN, myeloma cast nephropathy; MG, monoclonal gammopathy; MIDD, monoclonal immunoglobulin deposition disease; MM, multiple myeloma; MPGN, membranoproliferative glomerulonephritis; WM, Waldenström’s macroglobulinemia.
According with autopsy and kidney biopsy series the LCCN was reported in approximately 30% of patients followed by LCDD and AL amyloidosis between 10 and 20% and 20% respectively [23, 24].
Kidney is a major target for monoclonal immunoglobulins (MIg) produced by MM malignant plasma cells because of its peculiar characteristics:
manages the 25% of cardiac output;
filters and reabsorbs light chains;
presents immunological and immunogenic properties that make it a specific target for immunoglobulins;
shows special physiochemical conditions (high concentrations of various solutes, pH, salts concentrations) that allow and facilitate the toxic action of MIg;
it is characterized by the presence of specific receptors for immunoglobulins in tubular cells.
The kidney lesions in MM patients are caused mainly by the production of monoclonal immunoglobulins or their fragments (light or heavy chains) by clonal plasma cells that carry out toxic effects on different nephron’s structures.
Rarely the kidney injuries are not related to MIg activity. Following the most frequent:
Expansion of bladder or ureteral extramedullary plasmocytoma with obstruction of the urinary tract and renal parenchymal plasma cell infiltration, that are uncommon and rarely represent the unique cause of renal failure [25, 26, 27];
Hypercalcemia, that represents a complication of symptomatic MM with a prevalence is 2- to 3-fold higher (25–45%) in patients with high levels of serum creatinine. Hypercalcemia may cause prerenal AKI because of dehydration and vasoconstriction, and it could act as precipitating factor of LCCN [28, 29, 30].
Infections, often associated with AKI [31].
Dehydration and nephrotoxic agent administration, such nonsteroidal anti-inflammatory drugs, diuretics, and renin-angiotensin-aldosterone system blockers, that may be involved in the development of prerenal AKI and the formation of light chains (LC) casts.
Specific treatments of MM, frequently associated to development of AKI [32, 33, 34]:
Bisphosphonates, especially Zoledronic Acid, are widely used to treat hypercalcemia and MM bone disease and have been involved in the development of acute tubular necrosis [35];
Renal thrombotic microangiopathy is a rare cause of myeloma-associated renal injury and could be a potential complication of proteasome inhibitors, particularly Carfilzomib [36, 37];
Lenalidomide has been described as a cause of acute reversible non-LC–related Fanconi syndrome [38, 39];
Tumor lysis syndrome, very unusual in the past, is increasingly described at the start of chemotherapy because of the high efficacy of the novel agents, particularly in patients with altered kidney function treated with Proteasome Inhibitor–based regimens [40].
The main mechanism of kidney injury related to MIg is deposition or precipitation of the complete MIg or their fragment, usually the serum monoclonal FLCs. Physicochemical characteristics of MIg, particularly of the variable domain, define the localization and pattern of kidney lesions [41]. Two-thirds of AL amyloidosis are due to lambda light chains (LC), while nearly three-quarters of LCDD and light chain proximal tubulopathy is caused by a monoclonal kappa LC [42, 43, 44, 45]. Specific lambda or kappa subtypes underlie for a large proportion of these kidney diseases: for example, lambda VI accounts for more than 40% of AL amyloidosis, while kappa I and IV are specific for LCDD [46, 47].
In presence of high tumor mass, with a production of a huge quantity of FLCs, the characteristic kidney lesions are represented by the LCCN (Figure 1). As mentioned above, the MIg related renal complications not associated with the tumor mass are more frequently diagnosed in patients with MGRS and rarely cause a severe AKI. The LCCN occurs when a large amount of FLCs are produced by monoclonal plasm cells (rarely by B clonal lymphoid cells as in course of Waldenström Disease or Chronic Lymphoid Leukemia). Physiologically our organism produces roughly 500 mg of polyclonal free light chains, that circulate as monomers of 22 kDa but, particularly the lambda, they may assemble as dimers of 45 kDa, with a intravascular distribution of 15%. After glomerular filtration, the serum FLCs are reabsorbed by proximal tubular cells through a mechanism of endocytosis associated to tandem receptors cubilin and megalin and degraded in the cellular lysosomes. For this reason, a low amount only of FLCs are detected in the final urine (<30 mg/day) [48, 49, 50, 51, 52]. In case of a massive production of FLCs, the resorption capacity can be exceeded, with a consequent high concentration of protein into the lumen of the loop of Henle. Moreover, the increased reabsorption can damage proximal tubular cells causing the reduction of their catabolic capacities. FLCs reach the distal part of loop of Henle precipitate in the tubules as a result of binding with a protein named uromodulin (formerly called Tamm-Horsfall mucoprotein, or THMP), normally secreted by cells of the thick ascending limb of the loop of Henle. The uromodulin constitutes the matrix of all urinary casts. This interaction occurs between LC CDR3 hypervariable region that binds to a 9-amino acid sequence of uromodulin [53, 54, 55, 56]. Another factor that can favor the uromodulin binding and the predisposition to light chain cast nephropathy may be the isoelectric point (pI) of the involved FLCs. Their pI >5.1 (that is above the tubular fluid pH in the distal nephron) will have a positive charge, which may promote binding via charge interaction to anionic uromodulin (THMP; pI = 3.2) [57, 58, 59]. The binding and precipitation as co-aggregates lead to the formation of obstructing, dense, intratubular casts in the distal and collecting tubules (rarely in proximal tubules and glomerulus). Consequently, it starts a process characterized by a giant cell reaction and interstitial inflammation and fibrosis. The obstructive activity of casts causes decreasing of glomerular filtration rate, tubular rupture, extravasation of monoclonal light chain into the interstitium, further promoting the interstitial inflammatory process. The inflammation could in turn develop an irreversible fibrosis in absence of immediate therapeutic intervention [56, 60, 61]. It is under investigation the role of crystalline organization of LC cast in triggering distal tubulointerstitial inflammation through NOD-like receptor family receptor, pyrin domain containing 3 (NLRP3) inflammasome and interleukin-1beta production [62].
Images of LCCN: upper right and left Hematossilin-Eosin staining; lower right k stain (left picture) and lambda stain (right picture); lower left PAS stain.
Different factors may facilitate and promote intratubular cast formation:
volume depletion [63], by slowing flow within the tubules, that can promote the formation of large aggregates;
metabolic acidosis, because of low urinary pH, loop diuretics, by increasing luminal sodium chloride;
increased urinary calcium and hypercalcemia, mainly because of consequent volume depletion and renal vasoconstriction;
radiocontrast media (particularly high-osmolar agents), which may interact with LC;
nonsteroidal anti-inflammatory drugs (NSAIDs), which may precipitate acute kidney injury in 7–30% of MM patients, particularly in case of LCCN [58, 59, 64, 65, 66].
Furthermore, the excessive endocytosis of monoclonal FLCs in the proximal tubules leads to generation of hydrogen peroxide and redox signaling with activation of several pro-inflammatory pathways as mitogen-activated protein kinases ERK1/2, JNK, p38, and nuclear factor-kB. This process is in turn associated to the production of inflammatory cytokines such as interleukin-6 and monocyte chemoattractant protein-1 (MCP-1) and the upregulation of apoptotic pathways. Recently it is demonstrated that activation of signal transducer and activator of transcription 1 (STAT1) is the main pro- inflammatory mechanism caused by FLCs reabsorption, leading to the production of interleukin-1b and of the pro- fibrotic agent transforming growth factor b. These molecular processes develop as the consequence of the generation of hydrogen peroxide by the FLCs, which appears to depend on the molecular characteristics of the variable domain [67, 68, 69, 70]. This inflammatory process leads to an irreversible fibrotic reaction. Both affinity and concentration of the FLCs determine the pathogenesis of LCCN. In fact, the probability of cast formation presents a linear association with the serum level of the monoclonal FLCs and the amount of its urinary excretion. LCCN rarely occurs in presence of a serum concentration of <500 mg/l. The risk varies also with the molecular characteristics of each individual FLC. Notably, neither kappa or lambda isotype nor variability subgroups, which are independent of CDR3 molecular sequence, correlate with the risk of LCCN [71, 72].
A broad spectrum of clinical manifestations can characterize the MM renal complications, from dramatic cases of AKI to slower onset of CKD. These different clinical features can help to define the best diagnosis according with the hypothetical causes, avoiding potentially dangerous intervention as the kidney biopsy.
In case of AKI or subacute renal injury most of patients are likely to have a LCCN, although other causes can include hypercalcemia, nephrotoxic agents like NSAIDs, Bisphosphonates and antimyeloma agents (Lenalidomide and Carfilzomib) and, rarely, radiocontrast agents. The LCCN typically progresses rapidly, with an increase in creatinine that is observed over 1–3 months. For this reason, it should be suspected in all patients who are >40 years of age with an unexplained documented creatinine increase over a period of less than 6 months and a bland urine sediment. In fact, it is very uncommon that patients with untreated LCCN could show stable kidney function beyond 6 months.
Only in rare cases patients affected by MM develop a subacute or acute kidney disease due to tubulointerstitial nephritis, associated with LC deposition in the tubular basement membrane, plasma cell infiltration, thrombotic microangiopathy (associated to Carfilzomib or Bortezomib treatment), hyper-viscosity syndrome (more frequent in case of Waldenström Disease), through impairment of microcirculation and crystal-storing histiocytosis.
In case of gradual or progressive kidney impairment, with an increase of serum creatinine over 6 months or more, is unlikely that a LCCN could represent the underlying cause of renal impairment, unless the patients experienced different episodes of light chain cast nephropathy without a complete renal recovery leading to CKD. Many forms of kidney complications in MM patients can show, as clinical onset, the presence of some degree of proteinuria, frequently with a nephrotic syndrome, and albuminuria as principal feature. This presentation can help to differentiate the cause of renal complication because the LCCN presents, other that AKI, a proteinuria that is predominantly (90%) composed of monoclonal light chains (Bence Jones protein) and slight amount of albuminuria. The presence of albuminuria and a massive proteinuria is characteristic of an underlying AL amyloidosis and other MIg related glomerular disorders. The MIDD, particularly in case of LCDD, can show both albuminuria from glomerular damage and light chain excretion with associated cast nephropathy. Other diseases associated with a CKD and predominant albuminuria or nephrotic syndrome are immunotactoid glomerulopathy, monoclonal cryoglobulinemic glomerulonephritis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), or C3 glomerulopathy.
The diagnostic process in patients with a kidney disease and a malignant monoclonal gammopathy depends on clinical presentation through a multistep approach:
definition of the role of the monoclonal in the pathogenesis of the kidney disease in order to avoid inappropriate toxic treatment;
characterization of the pathologic lesions in order to define the more appropriate treatment strategy;
decision about the opportunity of performing the kidney biopsy.
First of all, it is important to underline that the renal failure as end-organ damage event for symptomatic MM is defined by a value of serum creatinine of 177 microml/L (>2 mg/dL) or creatinine clearance (CrCl) of <40 mL/min/1.73 m2, according with a recent review of diagnostic criteria for the plasma cells dyscrasia by the International Myeloma Working Group [3]. For evaluation of CrCl, eGFR, assessed by either the Modification of Diet in Renal Disease (MDRD) formula or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, seems to give accurate results in this MM population. However, CKD-EPI seems to more accurately reflect GFR than does MDRD, mostly in higher levels of GFR [73, 74, 75, 76]. Another method that can used to define the renal function is an equation on the basis of both serum creatinine and cystatin-C (CysC). This method is very accurate but it is not easily applicable in all the Centers. β2-microglobulin is another widely used marker that reflects both renal function and tumor burden in patients with MM and for this reason is included in the revised International Staging System [77, 78, 79]. Despite the above consideration, eGFR should be used only in patients with stable renal function. In cases of AKI, RIFLE (Risk, Injury, Failure, Loss and End-Stage Kidney Disease) criteria and AKIN (Acute Kidney Injury Network) classification would seem to be more sensitive for the determination and evaluation of this condition [80, 81].
In order to define the best diagnostic strategy, it is mandatory to consider some critical points:
LCCN is still a frequent mode of discovery of a previously unknown MM. In case of AKI of unknown origin, particularly in the elderly in absence of MM features, it is crucial to consider LCCN. Initial diagnostic workup should include serum and urinary protein electrophoresis and measurement of FLC.s Nephelometric assays such as the Freelite® test (Binding Site, Birmingham, UK) represent a reliable and invaluable tool for the diagnosis and management of LCCN. The presence of a monoclonal spike or hypogammaglobulinemia, a urinary albumin/protein ratio of <10%, and/or a significantly increased level of one FLCs isotype with an abnormal kappa/lambda ratio should prompt to perform a bone marrow examination to define the diagnosis of MM through the evaluation of monoclonal plasma cells;
in patients with a known diagnosis of Multiple Myeloma, smoldering Multiple Myeloma, or high-risk monoclonal gammopathy of undetermined significance (MGUS) and a unexplained reduced kidney function, there are some mandatory tests as assessment of volume and acid-base status, urinalysis with sediment examination, measurement of serum calcium (corrected for serum albumin concentration), serum uric acid and serum phosphorus, serum protein electrophoresis and immunofixation, serum FLCs assay, 24-h urine electrophoresis with immunofixation, 24-h albuminuria, urinary albumin/total protein ratio < 10% and urinary albumin/creatinine <30 mg/mmol, kidney ultrasound. The urinary FLCs assays, should not be performed because are not helpful in the evaluation of acute or subacute kidney injury in MM patients. It is also important to rule out possible nephrotoxic agent exposure;
if the diagnostic approach reveals an obstructive uropathy as hydronephrosis, hypercalcemia, hypovolemia, or urate nephropathy, these conditions should be treated or corrected;
in patients without reversible cause ok AKI or in absence of correction of these disorders a diagnosis of LCCN is highly suspected in case of a serum FLCs concentration >500–1500 mg/l, a predominance of monoclonal light chains in 24-h protein electrophoresis with immunofixation, a bland urine sediment, low amount of urine albuminuria or urinary albumin/total protein ratio < 10% and urinary albumin/creatinine <30 mg/mmol. In this case, the kidney biopsy is not mandatory [4];
in case of abnormal urine sediment, a serum FLC level < 500 mg/L or a predominance of albumin by 24-h protein electrophoresis with immunofixation or urinary albumin/protein ratio of >10% (or urinary albumin/creatinine >30 mg/mmol) the kidney biopsy is mandatory to exclude a diagnosis of AL amyloidosis, MIDD or MIg related nephropathy. If AL amyloidosis is suspected, a subcutaneous fat aspirate in positive for Rosso Congo stain 70% of patients [82]; if the fat biopsy is negative, a renal biopsy is required. Indication for a kidney biopsy should take into account either renal and extrarenal features of monoclonal gammopathy, and also alternative or associated causes of renal disease such as diabetes or atherosclerosis [4]. In fact, in >15% of MM patients with renal impairment a renal biopsy indicated that kidney failure is not associated with the plasma cell dyscrasia: in particularly the main causes were arterio-nephrosclerosis (6%), diabetic glomerulosclerosis (5%), post-infectious glomerulonephritis (2%), or even smoking-related glomerulopathy (0.5%) [33].
Recently it is demonstrated that kidney biopsy may be helpful in the prognostication of LCCN. A retrospective study of patients with MM and LCCN (47% required dialysis at presentation) showed that the number of casts per millimeter square in the cortex and, to a lesser extent, the degree of interstitial fibrosis/tubular atrophy were independent prognostic factors of renal outcome. Another relevant data from the study is that the extent of cast formation could not be predicted by initial clinical data and particularly the level of the involved FLCs [56, 83].
Particular clinical cases are represented by the patients with electrolyte abnormalities as the onset of renal impairment, besides the frequent manifestations as hypercalcemia. Normoglycemic glycosuria, aminoaciduria, proximal renal tubular acidosis, hypouricemia, and phosphate wasting are signs of tubular dysfunction [84]. In these cases, light chain proximal tubulopathy could be a rare complication of MM with clinical manifestations of Fanconi syndrome [85].
Furthermore, pseudohyponatremia can occur in MM patients with a severe hyperprotidemia.
The AKI associated to MM is a medical emergency. The diagnosis must be performed as fast as possible. The supportive care and anti-myeloma treatment should be started immediately in order to recovery the renal function and, in case of dialysis, make the patients independent from that.
The first step in the management of renal failure is to set preventive measures, particularly in MM patients with high risk of LCCN (i.e., FLCs concentration > 1500 mg/L) through different actions:
avoiding of NSAIDS and radiological exams with radiocontrast media
a careful administration of bisphosphonates
prompt treatment of infections with non-nephrotoxic antibiotics.
The early therapeutic approach aims to correct the precipitating factors and stabilize hemodynamic conditions, decreasing the tubular precipitation of FLCs with uromodulin.
The treatment approach consists in the following procedures [11, 85, 86, 87]:
vigorous rehydration with saline fluids (24-h 4–5 L) in order to achieve a high urine flow. The hydration must be managed carefully in case of oliguric AKI or heart failure. It is necessary to limit the afflux of sodium and chloride in distal tubules using half normal saline fluid. In case of volume depletion, it should be used isotonic fluids for initial volume replacement. In the absence of volume depletion or following, one-half isotonic saline at an initial rate of 150 mL/h, adjusted to maintain the urine output at approximately 100–150 mL/h (approximately 3 L/day), should be administrated. There is no uniform agreement about the administration of isotonic sodium bicarbonate aiming to achieve a urine pH > 7, particularly in presence of acidic urine pH, that can facilitate cast formation. This approach must be avoided in patients with hypercalcemia because of the risk of calcium phosphate precipitation;
hypercalcemia must be treated with rehydration and intravenous administration of Bisphosphonate with a dosage and infusion adapted with the eGFR. Among bisphosphonate the Pamidronate is associated lower risk of renal complications than Zoledronic Acid. Considering the pharmacodynamics properties, the anti-receptor activator of nuclear-factor kappa B ligand monoclonal antibody Denosumab represents the best option that may be proposed because this drug does not need dose adjustment according with the eGFR [35, 88];
the loop diuretics should be used only in presence of severe fluid overload since there is some concern that they may facilitate cast formation;
treatment with renin-angiotensin-aldosterone system blockers and NSAIDs must be discontinued;
in case of infections a prompt and vigorous antibiotics therapy with nephrotoxic antibiotics must be started as quickly as possible;
hyperuricemia, if present, should be treated;
hyper-viscosity is a rare cause of AKI among MM patients and should be treated with plasmapheresis and appropriate chemotherapy;
conventional dialysis should be initiated for the usual indications (i.e. fluid overload, hyperkalemia, and uremia) and it is not useful for the removal of free light chains. In this MM populations, hemodialysis is the preferred modality and peritoneal dialysis is an option for patients who develop end-stage kidney disease (ESKD) and require chronic dialysis.
The goal of any therapy for MM patients with renal impairment will involve either reducing the exposure of the kidney to FLCs either inhibiting the interaction of FLCs with uromodulin. Different studies demonstrated that:
the recovery of renal function is associated to a reduction in serum FLCs concentration > 50% [89];
the relationship between the probability of renal recovery and the degree of an early FLCs reduction in myeloma kidney is linear [90];
besides the degree of reduction, also the speed at which the FLCs reduction occurs is important to reach a recovery of kidney function. It was described that patients who achieved a sustained reduction within 21 days were significantly more likely to recover renal function than those who did not achieve a reduction [90]. It is to date controversial if the FLCs assays can replace 24 h urine collections for monitoring of disease response.
To achieve a rapid reduction of the circulating concentrations of pathological FLCs in patients with LCCN, the production rate of monoclonal proteins by the plasma cell clone must first be quickly decreased for a sustained time. Antimyeloma therapy is the mainstay of treatment for patients with MM associated-AKI. The choice of optimal drug class and therapeutic associations must follow the following principles:
novel agents in association with Dexamethasone will obtain the fastest and deepest responses;
the drugs should show safety and efficacy in renal failure, including dialysis;
the medical therapy should not impair collection of peripheral hemopoietic stem cells if there is any possibility of a future autologous hemopoietic stem cells transplant (ASCT);
the ASCT should be considered a treatment option also in dialysis-dependent patients in transplant-eligible population.
To date, the MM treatment consists in different classes of drugs administrated in association with Steroids either in transplant-eligible either non-transplant eligible population [4]. The main classes used in clinical practice are represented by Proteasome-Inhibitors (Bortezomib, Carfilzomib, Ixazomib), Immunomodulatory Drugs (Thalidomide, Lenalidomide, Pomalidomide), Monoclonal Antibodies (Elotuzumab, Daratumumab, Isatuximab). The newest class of drugs are the Immunoconjugates anti-BCMA (Belantamab-mafodotin), Selective Inhibitor of Nuclear Export (SINE) (Selinexor) and Cellular Therapies as bi-specific antibodies and CAR-T cells (both used in trial), Melfuflen, Iberdomide, Venetoclax. Conventional chemotherapy drugs usually used in association with novel drugs in the treatment of MM or for hemopoietic stem cells mobilization and ASCT conditioning are represented by Cyclophosphamide and Melphalan.
Unfortunately, there are little evidences about the efficacy and safety of these new agents and their association in patients with acute kidney impairment included in the clinical trials because, the threshold of renal function for inclusion is generally an eGFR ≥60 ml/min. Another difficulty in the treatment of patients with Myeloma related-AKI is the need of a dose adjustment according with kidney function because of renal extraction and/or metabolism (Table 2).
High-dose Dexamethasone is a key component in the treatment of LCCN because of its potent cytotoxic and anti-inflammatory activity properties diagnosis of AKI and can represent a bridge therapy before starting the anti-myeloma treatment [91, 92].
Conventional anti-myeloma agents most used in treatment of MM are Cyclophosphamide and Melphalan. Cyclophosphamide is preferred to Melphalan, which is eliminated by the kidneys, because it does not need a dose adjustment according to eGFR and is frequently associated to novel agents and Steroids. Melphalan, in combination or as conditioning regimen, needs adequate dose reductions according with renal failure to avoid severe cytopenias and non-hematologic toxicities. The cardiac toxicity of Doxorubicin limits its indications in this setting of patients.
The Proteasome Inhibitors (PIs) are a class of drugs which primary mechanism of action is the inhibition of catalytically active subunits of proteasome, a large multi-catalytic protein complex that degrades many cellular proteins. Besides anti-apoptotic activity, PIs also act as immunosuppressants and inhibit bone resorption. Currently, three PIs, Bortezomib, Carfilzomib, and Ixazomib, are used for the MM treatment, mainly in association with other agents, either in MM newly diagnosed (NDMM) patients either in MM relapsed/refractory (RRMM) population.
Bortezomib is a reversible PI, administered in intravenous or subcutaneous way, licensed for NDMM and RRMM patients in association with novel agents and conventional chemotherapy. It represents the mainstay in the treatment of patients with MM-related nephropathy, particularly LCCN. The rationale for use of Bortezomib in this setting lies in:
the short time of a sustained response;
high overall and complete response in combination regimens;
good tolerability with a similar toxicity in patients with a renal impairment;
half-time life independent of renal clearance,
direct anti-inflammation activity in myeloma kidney disease.
Particularly the inhibition of nuclear factor κB (NFkB), which activation is involved in the development of irreversible tubulointerstitial fibrosis, is likely to contribute to improved renal outcomes through prevention of progressive inflammation and fibrosis. Reversal of renal impairment has been observed in several studies of patients with MM-related renal impairment, including some patients who became independent of dialysis after treatment with Bortezomib. Remarkably, renal responses in patients treated with Bortezomib-based schedules tend to occur rapidly, usually within the initial two to three cycles of treatment and this response is consistent and sustained. Bortezomib should be administered after the dialysis procedures, because they may reduce the drug concentrations [93, 94, 95, 96].
Carfilzomib is a tetrapeptide epoxyketone PI that irreversibly binds to the β5-proteasome subunit and the LMP7 (iβ5) subunit of the immunoproteasome with greater affinity than Bortezomib, characterized by an intravenous administration. It is indicated for the treatment of RRMM patients mainly in association with Lenalidomide and Dexamethasone or only Dexamethasone with different dosages. Based on the pharmacokinetic data, no adjustment of the initial dose is recommended for patients with mild, moderate, or severe baseline renal impairment, or in case of chronic dialysis therapy. Particularly, the data from real-word evaluations and clinical trials suggest that Kd56 (Carfilzomib 56 mg/2 plus Dexamethasone) has a favorable benefit-risk profile and should be considered an in patients with RRMM, regardless of kidney function. A warning is represented by its potential cardiac and some rare complications as thrombotic microangiopathy, that could preclude its use as a standard for LCCN [97, 98, 99, 100].
Ixazomib is an oral, highly selective, and reversible PI that binds and inhibits the chymotrypsin-like activity of the β5-subunit of 20S proteasome, which leads to the disruption of cellular regulatory mechanisms, which in turn inhibits cell growth and survival pathways leading to the induction of apoptosis. According to the pharmacokinetics and safety results, a reduced Ixazomib dose of 3 mg (on days 1, 8, and 15 of the 28-day cycles) is recommended in MM patients with severe renal insufficiency or ESRD requiring hemodialysis, compared to the recommended standard 4 mg dose for patients with normal renal function or mild or moderate RI. The drug can be administered regardless of the time of dialysis in patients requiring hemodialysis with ESRD [101, 102].
The Immunomodulatory Drugs (IMiDs) are oral agents approved for the treatment of NDMM and RRMM populations in association with other novel drugs or only with Dexamethasone. IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory: Recently the recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided greater insight about their mechanism of action. To date, the three IMiDs used for the treatment of MM patients include Thalidomide, Lenalidomide and Pomalidomide. Iberdomide is a novel, orally administered and highly effective cereblon-modulator, currently under investigation as promising novel agent for the treatment of heavily pretreated RRMM patients.
Thalidomide is not excreted by the kidneys and can be used even in patients requiring chronic dialysis without dose adjustment. However, some toxic effects, such as unexplained hyperkalemia, con lead to a careful use in patients receiving dialysis. Other warning is represented by the thrombogenic properties, with the need of prophylactic anti-coagulation, and poor tolerability, because of neurotoxicity, particularly in elderly patients. Besides these side effects, Thalidomide has shown a significant improvement of renal function in a high proportion of patients with MM presenting renal insufficiency and can represent an option in association with Bortezomib, Dexamethasone, and Daratumumab for the NDMM patients transplant-eligible as induction and consolidation therapy [103, 104, 105].
Lenalidomide is a second-generation IMiD that represents the backbone in different associations for the treatment of NDMM, either eligible and non-eligible transplant patients, and RRMM populations. Because of primary excretion by the kidney, a dose-adjusted treatment according to renal function is mandatory for patients with MM and renal impairment. The main toxicities observed in patients with renal impairment is represented by thrombocytopenia. The data from clinical trials and real-word experiences demonstrated the efficacy of this drugs in achieving a renal recovery but only if dose modification is provided [106, 107, 108].
Pomalidomide is the third generation IMiD, indicated for the treatment in different combinations for RRMM population. Before its excretion, Pomalidomide is largely metabolized by CYP450 in the liver, and only 2% of the drug that has not been metabolized is excreted in urine. This agent does not need a dose modification according to renal function and this property makes Pomalidomide is highly attractive for the therapy of population with MM-related nephropathy. Data from clinical trials, in association with Dexamethasone or with other agents (i.e. Isatuximab, Bortezomib), showed benefit from a therapy with Pomalidomide with an acceptable safety profile also in population with severe kidney impairment [109, 110].
Monoclonal antibodies (MoAbs) currently used for the treatment of MM patients are represented by anti-CD38 MoAbs Daratumumab and Isatuximab and anti-CS1 MoAb Elotuzumab.
Daratumumab is a human IgG1κ MoAb that binds to a unique CD38 epitope leading to a killing of Myeloma cells shortly through a variety of mechanisms, including complement-mediated cytotoxicity, antibody-dependent cytotoxicity, and antibody-dependent phagocytosis. An immunomodulatory action has been demonstrated as well.
It represents an important agent in combination for the treatment of NDMM and RRMM. Recently, besides the intravenous administration, a subcutaneous formulation has been approved for the MM therapy. The data from different studies demonstrated a rapid hematological response as well as a strong renal response also in patients with a severe renal impairment and dialysis need. The safety profile was acceptable in this population. No dose modification is needed according to renal function [111, 112, 113, 114].
The first immunoconjugate used outside clinical trials is the Belantamab mafodotin, first-in-class anti-BCMA immunoconjugate with a humanized IgG1 anti-BCMA monoclonal antibody conjugated by a protease-resistant maleimidocaproyl linker to a microtubule-disrupting agent, monomethyl auristatin F (MMAF). In patients with mild or moderate renal impairment (eGFR >30 mL/min) no dose adjustment is necessary. Currently, insufficient data are available for patients with severe renal impairment to support any dose recommendation. Clinal trials including patients with various degrees of renal impairment are ongoing to address this issue [118, 119].
No data are available about dose modifications of promising and effective treatment as CAR-T cells [122, 123, 124] therapy, bi-specific antibodies [125, 126, 127], and other agents as Venetoclax [128, 129, 130], Melfuflen [131, 132, 133], and Iberdomide [134, 135] in case of renal impairment, and particularly dialysis-dependence.
Cr clearance | > 60 ml/min | 30–59 ml/min | 15–29 ml/min | < 15 mil/min | On dialisys | |
---|---|---|---|---|---|---|
Melphalan | Yes | 200 mg/m2 | 160–200 mg/m2 | 140–200 mg/m2 | 140–200 mg/m2 | 140 mg/m2 |
Bortezomib | No | 1.3 mg/m2 | No modification | No modification | No modification | No modification |
Talidomide | No | 100–200 mg/die | No modification | No modification | No modification | No modification |
Lenalidomide | Yes | 25 mg/die | 10 mg/die | 15 mg once every other day | 5 mg/die | 5 mg/die |
Pomalidomide | No | 4 mg/die | No modification | No modification | No modification | No modification |
Carfilzomib | No | 20–27 mg/m2 56 mg/m2 | No modification | No modification | No modification | No modification |
Ixazomib | No | 4 mg/die | No modification | 3 mg/die | 3 mg/die | 3 mg/die |
Elotuzumab | No | 10 mg/kg 20 mg/m2 | No modification | No modification | No modification | No modification |
Daratumumab | No | 16 mg/kg 1800 mg s.c. | No modification | No modification | No modification | No modification |
Isatuximab | No | 10 mg/kg | No Modification | No Modification | No Modification | No Modification |
Belantamab mafodotin | No | 2.5 mg/kg | No Modification | No data | No data | No data |
Selinexor | No | 160 mg | No Modification | No Modification | No Modification | No data |
Dose-adjustment of anti-myeloma drugs according with creatinine clearance.
According to the clinical data and the international guidelines for the management in patients with MM-related kidney impairment, and particularly in presence of LCCN, Bortezomib-based treatment is the gold standard in term of efficacy in hematologic and renal response and safety profile. The best agents to be associated to Bortezomib and high-dose of Dexamethasone is still under debate, because of lack of clinical trial. Cyclophosphamide and Thalidomide can be optimal options for efficacy, safety, pharmacokinetic characteristics without impact on peripheral stem cells collection for the transplant-eligible patients. In this setting, the introduction of Daratumumab could increase the efficacy in terms of hematological and renal responses without increased toxicity. The NDMM non-transplant eligible population can benefit from the association of Daratumumab with Bortezomib-Melphalan and Prednisone. Lenalidomide could be used in transplant-eligible and non-transplant eligible populations but is more difficult to manage because the need of dose adjustment on renal function and its myelotoxicity.
Different regimens can be exploited in the treatment of RRMM patients. It is mandatory to consider not only the efficacy but also the need of adjustment of dosage according to renal failure in order to achieve the best results with an acceptable safety profile. This is more and more important in the heavily pretreated patients, where the comorbidities and side effects remarkably impact on the outcomes and quality of life. Furthermore, the RRMM patients present a higher risk of renal impairment with a lower probability of recovery. Monoclonal Antibodies, Pomalidomide, and Carfilzomib (with a careful assessment for cardiologic side effects) represent the best options in different associations.
Despite the availability and the efficacy of novel agents, high-dose therapy with hemopoietic peripheral stem cells transplantation (ASCT) represents currently the standard of care for NDMM defined transplant-eligible for age (<70 years) and fitness, according to comorbidity and performance status [136, 137, 138]. In recent years, several reports have shown that the use of ASCT is safe and effective in MM patients with renal impairment However, there still have some considerable variabilities in reported survival outcomes and renal recovery from the limited literature because the available studies (cohort studies, retrospective studies, and case report) are characterized by different priorities in clinical and renal response. The cohort analysis seemed to take more attention to the clinical response. On the other side, the retrospective studies were more interested to renal function change [139]. One of major issue has been represented by the dosage of Melphalan as conditioning: it is demonstrated a large interpatient variability in melphalan exposure for the patients undergoing ASCT [136]. However, the use of higher dosage of Melphalan has been shown to improve survival with an increased but acceptable transplant-related toxicities [136, 140]. According to the reports of meta-analysis and the data from the literature it is possible to conclude that:
renal impairment and dialysis should not be considered an exclusion criterion for the eligibility to ASCT;
ASCT could be a feasible therapy and can lead to similar remission outcomes to those without advanced renal failure;
patients with MM-related kidney disease after ASCT have a good overall results and improvement of renal function but present a low survival rate (rate of mortality from 4% to 29%) [4];
renal impairment does not affect the quality of stem cell collection or engraftment [4];
the clinical responses of the conditioning Melphalan therapy in patients with renal failure remains controversial as well as the best dosage in this population (140–200 mg/m2) [139];
In this population, it is advisable to reduce the dose of Melphalan by 25% in case of creatinine clearance between 10 and 45 ml/min and by 15% in patients with a creatinine clearance between 46 and 60 ml/min: particularly full Melphalan dose of 200 mg/m2 is safe and effective in case of creatinine clearance between 30 and 60 ml/min [141, 142];
ASCT can lead to dialysis-independence (up to 29% of patients) [143]. This population needs careful evaluation prior to ASCT by a multidisciplinary team and dose adjustment for all drugs in order to avoid serious toxicities should be taken into consideration [144].
Following are reported some practice recommendations for management of transplant-eligible patients with MM-related kidney disease:
an induction Bortezomib-based (in association with Cyclophosphamide or Thalidomide and, if possible, Daratumumab) is preferable for short time of response and absence of myelotoxicity and no need of dose adjustment on renal function. In case of a combination with Lenalidomide is mandatory to reduce the dosage according with renal function;
PBSC collection should be accomplished using either Cyclophosphamide combined with G-CSF, or, if in stringent complete remission/complete remission G-CSF, 15–30 mg/kg daily for 5 days associated with Plerixafor;
The doses of Cyclophosphamide in stem cell mobilization prior to ASCT are Low dose (LD-Cy) from 1 to 1,5 g/m2 intravenously, Intermediate dose (MD-Cy) from 3 to 4 g/m2 intravenously, High dose (HD-Cy) from 5 to 7 g/m2 intravenously: the first option is the most preferred in the practical use and clinical trial to avoid long-term cytopenias and extra-hematological toxicities [145, 146, 147];
The doses of G-CSF in stem cell mobilization prior to ASCT are 5 mcg/kg twice daily (i.e. 10 mcg/kg/day) subcutaneously twice daily for 4–5 days [148];
The dose of Plerixafor is 0,24 mg/kg subcutaneously, one dose to be given the night before stem cell collection: this agent is used in case of MM poor mobilizer patients [149, 150];
avoid dialysis on the day of Melphalan, administered over 30 min in 1 or 2 days;
stem cell reinfusion should be performed after 24 h over 1 or 2 days, post dialysis;
double ASCT could be considered in fit patients according to the results and safety of first ASCT;
consider consolidation and maintenance therapy in order to improve the overall response and outcome of patients.
The medical therapy is finalized to a rapid and sustained suppression of malignant plasma cells clone but it could be not enough fast and effective to translate into an immediate reduction of monoclonal FLCs, leading to prolonged renal exposure to these pathologic proteins. For this reason, it has been considered the possibility of using of complementary mechanical strategies, dedicated to remove the monoclonal light chains from the circulation.
The mechanical approach should avoid the prolonged exposition of nephron to elevated serum concentration of monoclonal LC.
The κ and λ FLCs are middle molecules that are physiologically present in the serum as monomers and dimers, with molecular weights of 22.5 kDa and 45 kDa, respectively. However, in MM patient monoclonal LC are frequently present as polymers of various sizes. In healthy individuals, the monomers and dimers are filtered freely at the glomerulus with serum half-lives of between 3 h and 6 h, and FLCs represent an early marker of myeloma response to chemotherapy when renal function is normal [151, 152]. In presence of severe renal failure, the serum half-lives of FLCs are prolonged with a consequent increasing of absolute serum concentrations. Therefore, in this context, serum half-lives are about 2–3 days and the reticuloendothelial system becomes the most important mechanism of clearance. The serum concentrations can remain elevated for long periods because of reduced renal clearance, even if an effective chemotherapy is promptly started with a reduction of FLCs production [153, 154, 155]. This prolonged kidney exposure to high FLCs levels could explain why it is reported a significantly lower rate of renal recovery in dialysis-dependent at disease presentation than in those with moderate renal impairment treated with Bortezomib-based therapy (approximately from 30% to 60%) [156]. These observations led to consider that the strategies to remove FLCs directly from the serum could have a particularly high effective role in the population with a significantly reduced FLCs clearance.
Rapid FLCs depuration may be achieved either through plasmapheresis or intensive hemodialysis using new-generation “high-cutoff” (HCO) protein–leaking dialyzers with very high permeability to proteins.
Before choosing the best approach for these patients with a severe renal impairment due to a LCCN is mandatory to subline preliminary considerations:
these therapies are pointless if used without efficient associated chemotherapy;
the renal effect of their combination with anti-plasma cell regimens is still debated;
FLCs, because of their molecular weight, re-equilibrate freely between intravascular and extravascular compartments and approximately 80% of FLCs are extravascular at any one time. Direct removal of FLCs from the serum could have an affective benefit therefore only if the whole body is cleared of monoclonal light chains to achieve a sustained reduction in serum FLC concentrations.
Plasma exchange would seem to be a logical treatment for LCCN because of technical characteristics. However, despite the effective FLCs plasma removal provided, the short duration of each session (typically 2 h or less) results in a limited clearance of the extra-vascular compartment. Furthermore, in case of increasing the dose of plasma exchange, there is the disadvantage of the non-targeted removal of FLCs. Plasma exchange also removes many essential proteins including intact immunoglobulins and clotting factors. About clinical efficacy, randomized trials, performed before the era of novel anti-myeloma agents and with a limitation of the absence of pathological demonstration of LCCN, failed to show a benefit of plasmapheresis. A more recent retrospective data evaluation in patients with biopsy-proven LCCN treated with the combination of plasmapheresis with high-dose Dexamethasone and Bortezomib or Thalidomide reported renal response rates of up to 75% [89, 157, 158].
For the MM LCCN patients requiring dialysis, another promising tool is represented by hemodialysis using conventional high-flux dialyzers, with a protein cutoff of 15–20 kDa. It provides only limited clearance of FLCs.
HCO dialyzers in reverse allow the removal of proteins up to 65 kDa and produce highly efficient clearing of both kappa and lambda LC with acceptable albumin loss. Because of the uppermost extravascular distribution of FLCs, prolonged HCO hemodialysis sessions are needed to achieve a removal of high quantities of LCs, with the risk of post-dialysis intravascular rebound. The first experiences with the association of intensive HCO hemodialysis and chemotherapy with novel agents showed hemodialysis independence rates of nearly 60% [90, 159, 160, 161, 162], in comparation with 30% rate reported in patients receiving conventional hemodialysis1 [36, 163].
Other techniques of FLCs removal consist in hemodialysis using adsorptive polymethylmetacrylate dialyzers, supra-hemodiafiltration with endogenous reinfusion after FLC adsorption hemodiafiltration using high-flux or very high flux membranes, or continuous veno-venous hemofiltration with HCO filters. Their efficacy on FLCs removal as compared to HCO hemodialysis remains to be assessed and little data are available in patients with MM and AKI.
Two randomized trial, MYRE [26] and EuLite [164], evaluated HCO hemodialysis in comparison with standard high-flux hemodialysis. Their clinical designs (Table 3) presented noticeable differences in terms of randomization, hemodialysis and chemotherapy schedule and expertise of centers. Notably, also the results were discordant: both studies demonstrated dialysis independence rates at 6 months of 60% but, in contrast, data differed in control groups, being significantly lower rate in MYRE trial (35%). At primary end point (3 months), in MYRE study the hemodialysis withdrawal rates were not significantly different. In a hand, the HCO group of EuLite experienced a high rate of serious adverse events (frequent severe infections), which resulted in frequent treatment interruptions, in the other hand tolerance of HCO hemodialysis was good in MYRE. Overall survival was similar in the 2 groups of the MYRE study, whereas mortality rate was higher in the HCO group of EuLite. Regarding the light chain isotype, no difference was observed in both studies in terms of HCO dialyzers. Despite the non-concordant data from these trials, the combination of HCO hemodialysis with an effective chemotherapy can be considered a therapeutic option for LCCN patients. Additional data are required for define the role of anti-CD38 MoAbs in this mechanical/chemotherapy approach.
Variable | MYRE | EuLite |
---|---|---|
Number of randomized patients | 98 | 90 |
Randomization | After a preinclusion period of 4–15 d, including symptomatic measures and high-dose steroids (dexamethasone 40 mg/d orally, 4 d) | Upfront |
Chemotherapy regimens | Bortezomib dexamethasone (and/or cyclophosphamide in patients without hematological response after 3 cycles) | Bortezomib-dexamethasone-doxorubicin |
Hemodialysys schedule | Identical in the HCO and control groups 8 sessions of 5 h over the first 10 d and then thrice weekly | Intensive HD in the HCO group Daily sessions of 8 h over the first 10 d, then 8-h sessions thrice weekly from day 12 to day 21, and finally 6-h sessions thrice weekly Standard HD in the control group 4-h sessions thrice weekly |
HCO dialyzers | Single HCO Theralite dialyzer (Gambro Dialysatoren GmbH, Hechingen, Germany) of 2.1 m2 in surface | 2 1.1 m2 HCO dialyzers in series |
Premature treatment discontinuation | 4 (8.7%) in the HCO groupa 2 (4.2%) in the control group | 9 (20.9%) in the HCO group 2 (4.2%) in the control group |
Dialysis independence | ||
At 3 mo | 41% (HCO) vs. 33% (control) P = 40.42 | 56% (HCO) vs. 51% (control) P = 40.81 |
At 6 mo | 56.5% (HCO) vs. 35% (control) P = 40.04 | 58% (HCO) vs. 66% (control) P = 40.76 |
At 12 mo | 61% (HCO) vs. 37.5% (control) P1/40.02 | 58% (HCO) vs. 66% (control) P = 40.76 |
MYRE and EuLite trials.
HCO, high cutoff; HD, hemodialysis.
The main problem in the treatment of LCCN is the dependence on fast and sustained FLCs reduction. Because no therapy is 100% effective against LCCN and it remains to be determined if mechanical devices can reduce FLCs in association with chemotherapy, new therapeutic approaches are needed to face this issue.
Recently a competitive inhibitor peptide (AHXCLSADSSGSYLYVCKK) capable of interrupting the binding between FLC and uromodulin, preventing obstruction, was described as effective in animal models. Earlier another agent, a polypeptide pituitary adenylate cyclase–activating poly-peptide with 38 residues (PACAP38), has demonstrated high activity at blocking cellular damage from FLCs in an in vitro setting [165]. Despite additional data regarding the clinical efficacy and the potential role in this setting are warranted, therapeutic approaches that can target the monoclonal protein rather than the plasma cell are extremely attractive, avoiding the use of toxic chemotherapy, in patients with AL amyloidosis who may be too frail to be treated with medical therapy.
Early assessment of hematologic response through serial FLCs assessment is crucial for the management of MM-related kidney diseases, particularly in case of LCCN. The absence of rapid and deep hematologic response can lead to the need to reinforce the previous regimen either by introducing an Immunomodulatory Drug or an anti-CD38 Monoclonal Antibody because:
in case of persisting AKI, hematologic response is the main predicting factor of renal survival, particularly for patients requiring dialysis, in whom the achievement of involved FLCs level below 500 mg/l after the first cycle of chemotherapy is an independent factor of renal recovery [26].
without indication for dialysis, a reduction of >90% monoclonal FLCs concentration is also associated with a high probability of renal response [27].
Besides the early and sustained FLCs reduction, another prognostic factor for renal recovery is represented by the severity of renal impairment. It was demonstrated the AKIN 3 stage is an independent predictor of poor renal outcome [27]. In this population the kidney biopsy may help predict renal prognosis and potentially guide therapeutic decisions (i.e. the reinforcement of chemotherapy with extracorporeal FLC removal) though two key predictive histologic features (Table 4) [56]:
Degree of interstitial fibrosis and/or tubular atrophy
Highest number of cortex cast for millimeter square
Variable | Definition | Score |
---|---|---|
Highest number of light chain casts per millimeter square in the cortex (Ca) | Highest number of light chain casts in one 20 field divided by the area of one 20 field in millimeter square | Ca1: <5 casts/mm2 Ca2: 5–10 casts/mm2 Ca3: >10 casts/mm2 |
Interstitial fibrosis/tubular atrophy (T) | Thickened tubular basement membranes with flattened epithelial cells, expanded interstitium with fibrosis, whichever is the highest | T0: <10% T1: 10–24% T2: 25–50% T3: >50% |
From [56].
Although life expectancy of patients with ESRD caused by LCCN has increased over the last decade, it remains inferior to 2 years in those requiring chronic hemodialysis [166]. Moreover, it has been shown that renal recovery can lead to improved survival in patients with MM but the life expectancy of patients with reversal of renal impairment remains inferior to patients with normal renal function at diagnosis. The International Myeloma Working Group defined criteria for renal response, defining complete, partial, and minor responses, but their clinical relevance remains to be evaluated (Table 5) [4]. In the clinical practice improvement in renal function, defined by a stable eGFR value ≥40 ml/min/1.73 m2, is represents desirable goal, particularly in fit eligible for ASCT.
Renal response | Baseline eGFR, mL/min/1.73 m2* | Best CrCl response |
---|---|---|
Complete response | <50 | ≥60 mL/min |
Partial response | <15 | 20–59 mL/min |
Minor response | <15 15–29 | 15–29 mL/min 30–59 ml/min |
Criteria for the definition of renal response to antimyeloma therapy.
eGFR is based on the Modification of Diet in Renal Disease formula, or the Chronic Kidney Disease Epidemiology Collaboration equation.
Abbreviations: CrCl, creatinine clearance; eGFR, estimate glomerular filtration rate.
Renal diseases associated to MM represent frequent complications of this malignant disease. The diagnosis could be challenging and it is mandatory to define the effective role of underlying MM in the renal pathology development and rule other cause as, for example, MGRS. Particularly, the LCCN is a dramatic renal complication of MM that need a prompt and fast diagnosis and therapy to avoid dialysis-dependence and improve the outcome of this population of patients. Despite the recent advances in the management of MM-related AKI further progress is required:
prevention and early diagnosis should be eagerly improved;
definition of the best therapeutic regimen, and likely the introduction of newest agent as anti-CD38 MoAbs, is mandatory to optimize the efficacy and reduction of toxicity of treatment and to enhance renal recovery that affects morbidity and mortality;
in patients requiring dialysis, further studies are needed to set the optimal modalities of the combination of HCO hemodialysis with chemotherapy;
therapeutic decisions, like change or enhancing therapy, should be guided by improved prediction of renal outcomes through pathology data from a wider use of the kidney biopsy in patients with severe LCCN AKI. For example, the chemotherapy in association with HCO hemodialysis could effective in patients with high risk of ESRD according with assessment of renal prognosis with kidney biopsy (high number of pathologic cast);
a more extensive multidisciplinary approach is mandatory to improve the management of these complications, particularly LCCN.
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All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
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He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. 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She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. 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Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. 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She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"1177",title:"Prof.",name:"Antonio",middleName:"J. 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