Pathogenesis and Treatment in IgA Nephropathy An International Comparison Yasuhiko Tomino Editor 123 Pathogenesis and Treatment in IgA Nephropathy ThiSisaFMBlankPage Yasuhiko Tomino Editor Pathogenesis and Treatment in IgA Nephropathy An International Comparison Editor YasuhikoTomino MedicalCorporationSHOWAKAI Tokyo Japan ISBN978-4-431-55587-2 ISBN978-4-431-55588-9 (eBook) DOI10.1007/978-4-431-55588-9 LibraryofCongressControlNumber:2016933030 ©SpringerJapan2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexempt fromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthis book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained hereinorforanyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerJapanKK Preface Ihave studied IgAnephropathyfor morethan 40yearsandhave obtainedseveral findings in the fields of pathology, immunology, molecular biology, and experi- mental pathology—all of which have shed much light on the mechanisms of initiation, development, and progression of this disease. I have also undertaken new treatments for patients and developed animal models for IgA nephropathy. This book discusses the latest findings on the pathogeneses and treatment of IgA nephropathy.Itparticularlyfocusesonrecentlyrecognizedinitiationandprogres- sion factors and varying treatmentstrategiesindifferentregionssuch asAsia, the EU,andtheU.S. Nearly 50 years have passed since Dr. Jean Berger first described primary IgA nephropathy (“Nephropathy with mesangial IgA-IgG deposits”) as a new disease entity. Immunohistopathologically, IgA nephropathy is characterized by the gran- ulardepositionofIgA(polymericIgA1)andC3inglomerularmesangialareaswith mesangialcellproliferationandtheexpansionofmesangialmatrices.Itisclearthat IgAnephropathyisoneofthemostcommontypesofchronicglomerulonephritisin the world. This disease may lead to end-stage kidney disease (ESKD), with its enormouseconomicimpactonhealthcareeverywhere.Effortsbymanyinvestiga- tors around the world have gradually clarified various aspects of the pathogenesis andtreatmentofIgAnephropathy. Itshouldbenotedhowever,thattherearemanycontroversialstrategiesforthe treatment of patients with IgA nephropathy throughout the world, and there are several limitations for treatment in each country. At present, the most important therapeutics goal for patients with IgA nephropathy is the decrease of urinary protein excretion. For example, it has been assumed that the removal of palatine tonsillar tissues might reduce the production of polymeric IgA1 and decrease the frequency of renal parenchymal injury resulting from episodes of macroscopic hematuria and proteinuria. This volume provides nephrologists everywhere with an overview and comparison of both global and regional findings in basic and clinical fields in IgA nephropathy. It covers genetic variation, aberrant IgA1 v vi Preface production,andclassification,etiology,guidelines,andtreatmentgoals,witheach chapterwrittenbytopinternationalresearchers. Many thanks go to Professor Emeritus Toshikazu Shirai, Juntendo University, Tokyo, Japan, who introduced me to the field of IgA nephropathy and first suggested ways in which it could be studied in the laboratory; to many other physicians who have continuously sustained me in my efforts over the years; to the technicians, dieticians, and nurses who have performed somanyof the exper- iments or clinical tests; and to my many patients whose diseases have always providedthemostimportantofinsights. Finally,Iwishtothankalloftheauthorsfor theircontributions tothisvolume and my family for the many hours of relaxation they provided when I was away frommywork. OverlookingtheTokyoMetropolitanBuilding YasuhikoTomino Tokyo,Japan August2015 Overview YasuhikoTomino DivisionofNephropathy,DepartmentofInternalMedicine,FacultyofMedicine, JuntendoUniversity,Tokyo,Japan,(PresentAddress:MedicalCorporation SHOWAKAI,Tokyo,Japan) Pathogenesis of IgA Nephropathy IgA nephropathy is generally considered to be an immune-complex-mediated or galactose-deficient polymerized IgA (Gd IgA1)-mediated glomerulonephritis. Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy. It has been hypothesized that susceptibility genes for IgA nephropathy can be detected by a genome-wide scan using a spontaneous animal model, i.e., the ddY mouse strain. The peak marker D10MIT 86 on chromosome 10 is located on a region syntenic to human 6q22-23 with IGAN1, which is responsible for familiar IgA nephropathy. Thus, it is important to determine the pathogenesis of Gd IgA1 production and the occurrence of sporadic IgA nephropathy. There are several developmental and/or exacerbating factors in this disease. Factors previously reported to be associated with disease progression include the male sex, age, prolonged duration, nephrotic range proteinuria, hypertension, glomerularsclerosis,andtubulointerstitialinjuryinpatientswithIgAnephropathy. Otherdevelopmentaland/orexacerbatingfactorsforpatientswithIgAnephropathy are:(1)complementactivation,(2)bloodcoagulationactivityand/oritsinhibition in plasma, (3) the activity of cytokines/growth factors, (4) the activity of reactive oxygen species (ROS), (5) the activation of adhesion molecules, (6) apoptosis, (7)podocyteloss(podocytopenia),and(8)theroleofmegalin.Itiswidelyassumed that glomerular mesangial cell proliferation and mesangial expansion represent majorpathologicalmechanismsinthisdiseaseusingtheanimalmodels. Treatment for IgA Nephropathy PreviousglobalapproachestodrugtherapyofIgAnephropathyhaveincludedanti- platelet drugs, anticoagulants, prednisolone (PSL), immunosuppressants, fish oil, renin angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhib- itors, angiotensin II receptor blockers), and/or tonsillectomy. At present, the most vii viii Overview important therapeutic goal in patients with IgA nephropathy is the control of hypertensionandthedecreaseofurinaryproteinexcretion. Blood pressureofless than 130/80 mmHg is the therapeutic target in patients with IgA nephropathy. Patients with more or less normal renal function, with or without proteinuria or hypertension,havebeenpreferablytreatedwithRASinhibitors.Severalinvestiga- torsreportedthatRASinhibitorsreducethelevelsofurinaryproteinexcretionand preserve renal function in patients with IgA nephropathy. Furthermore, RAS inhibitorsarerecommendedonthebasisoftheirbeneficialeffectsontheproduction ofcytokinesandextracellularmatrix(ECM)components,evenwhenhypertension is not present. RAS inhibitors are generally considered to have cardiac and renal protective actions, and they may improve glomerular hypertension due to the dilatationofefferentarteriolesinthekidneysandalsosuppressglomerularsclero- sis.Thenonspecifictherapeuticapproachinvolvesareductioninthedietaryintake of protein in patients with IgA nephropathy who have developed renal failure. Long-termdietaryrestrictionisgenerallyconsideredtoreducethelevelsofurinary proteinandameliorateglomerularinjuriesinpatientswithIgAnephropathy. ThecommitteesonIgAnephropathylocallyandinternationallyhavepublished several clinical guidelines, including the KDIGOand Japanese guidelines, for the diagnosisandtreatmentofpatientswiththisdisease.However,therearecontrover- siessurroundingthetreatmentofthisdiseaseinmanysocietiesofnephrology.One suchcontroversyistheuseoftonsillectomy,whichhasbeenappliedinpatientswith IgAnephropathyfortworeasons, especiallyinJapan.First,tonsillarlymphocytes from patients with IgA nephropathy have been found to produce more polymeric IgAthanhealthycontrols.Ithasbeenassumedthattheremovaloftonsillartissues mightreducetheproductionofpolymericGdIgA1.Second,tonsillitisisafrequent precipitating event leading to macroscopic hematuria and proteinuria, frequent glomerularcrescentformation,acutetubularinjury,and/orareductioninglomerular filtration rate (GFR). Therefore, tonsillectomy may reduce the frequency of renal parenchymal damage resulting from episodes of macroscopic hematuria and pro- teinuria.InJapan,itissuggestedthattonsillectomywithsteroidpulsetherapymay provide a rapid and good therapeutic outcome in IgA nephropathy patients who show high expression of TLR9 in tonsillar plasmacytoid dendritic cells. Because controversies continue to exist for the treatment of this disease, it is important to developnewtreatmentstrategiesforthisdisease,suchasbonemarrowtransplanta- tion(BMT),usingspontaneousanimalmodelsandthenapplyingittopatients. Because the treatmentof IgA nephropathy is still controversial internationally, several current topics of etiology and treatment amongst the various societies of nephrologywillbediscussedinthisbook. Contents PartI Pathogenesis 1 IsIgANephropathyaSingleDisease?. . . . . . . . . . . . . . . . . . . . . . . 3 CheeKayCheungandJonathanBarratt 2 AdvancesinGeneticsofImmunoglobulinANephropathy. . . . . . . 19 HongZhang,RiccardoMagistroni,andAliGharavi 3 IsIgANephropathy(IgAN)aFamilialorSporadicDisease?. . . . . 43 IchieiNarita,YoshikatsuKaneko,YumiItoh,YuichiSakamaki, SeitaroIguchi,SuguruYamamoto,MinakoWakasugi, JunichiroJ.Kazama,andShinGoto 4 HeterogeneityofAberrantO-GlycosylationofIgA1inIgA Nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 JanNovak,KazuoTakahashi,HitoshiSuzuki,ColinReily, TylerStewart,HiroyukiUeda,KoshiYamada,ZinaMoldoveanu, M.ColleenHastings,RobertJ.Wyatt,JiriMestecky,MilanRaska, BruceA.Julian,andMatthewB.Renfrow 5 DifferencesofHistologicalClassificationBetweentheJapanese HistologicalGradeClassificationandtheOxfordClassification. . . 69 KensukeJohandKeelyMayMcNamara 6 PodocyteInjuryandSignificanceofUrinaryPodocalyxinand Megalin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 KatsuhikoAsanuma 7 ComplementActivation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 IsaoOhsawa ix