Pathogenesis and Treatment in IgA Nephropathy: An International Comparison

342 Pages·2016·7.333 MB·English

by  Yasuhiko Tomino (eds.)

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
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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
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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
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