DIAGNOSISANDMANAGEMENTOFHCV-RELATEDGN
CCSzeto DepartmentofMedicine&Therapeutics TheChineseUniversityofHongKong
KDIGO
DISCLOSURES
• GileadSciencesInc:consultancy
• AstraZeneca:conferencesupport
• Pfizer:speakerandconferencesupport
• BaxterHealthcare:speaker,researchgrantandconsultancy
• FreseniusMedicalCare:researchgrant
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HCVINFECTIONISASYSTEMICDISEASE
Stanislas Pol. Nat Rev Nephrol 2019; 15: 73.
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HCVANDRENALDISEASE
• glomerulonephritisandrenalfailureareimportantextrahepaticcomplicationsofHCVinfection
• liverdiseasemaybemildorclinicallyabsent
• autopsystudies• inpatientswithHCVcirrhosis,60%hadevidenceofGN • inpatientswithoutcirrhosis,33%hadrenalinvolvement
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HISTOLOGICALPATTERNS
• membranoproliferativeglomerulonephritis• alsocalledmesangiocapillaryGN • mostcommonform
lesscommon• membranousnephropathy• IgAnephropathy• focalsegmentalglomerulosclerosis• polyarteritisnodosa• fibrillarglomerulonephritis• immunotactoidglomerulopathy
Diagnosis: renal biopsy is necessary! KDIG
O
MECHANISMOFKIDNEYINJURY
Stanislas Pol. Nat Rev Nephrol 2019; 15: 73.
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PATHOGENESISOFHCV-RELATEDGN
• typeIImixedessentialcryoglobulinaemia• systemicvasculiticsyndrome • mostcommoncauseischronicHCV(>80%cases) • happenin~10%ofHCVinfectedpatients
‒ GNin60%ofthesepatients ‒ MCGNisthemostcommonform ‒ glomerulardepositionofHCVproteins
• MCGNwithoutcryoglobulinaemiaalsopossible
• allpatientswithHCV-associatedGNhavedetectableHCVRNAinserum
Meyers CM, et al. Am J Kidney Dis. 2003;42:631–657.
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VS.CRYOGLOBULINEMICGLOMERULOPATHY
Brouet’sclassification• TypeI:Isolatedmonoclonalimmunoglobulin(IgG,IgM)-Multiplemyeloma;
Waldenstrommacroglobulinemia• TypeII:Polyclonalimmunoglobulin(IgG)inassociationwithmonoclonal
immunoglobulin(usu.IgMκchain)withRFactivity-HepatitisCvirus;HIV• TypeIII:PolyclonalantiglobulinbindtopolyclonalIgG-Rheumaticdiseases,hepatitis
CvirusNB.• typeIIandIIIare“mixed”cryoglobulinemia;rheumatoidfactorpositive• cryoglobulinemicglomerulopathymostcommonintypeII
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CRYOGLOBULINEMICGN:PATHOLOGY
https://www.uninet.edu/cin2001-old/conf/ferrario/ferrario.html.
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HISTOLOGICALDDX
LM IF EM
HCV with cryoglobulinemic GN
MPGN pattern with “wire loop” lesions or hyaline thrombi
IgM and IgG with both κ and λ light chain
mesangial and subendothelial ED deposits; type II may have microtubular structure (20-30 nm)
HCV with MPGN MPGN pattern without “wire loop” lesions or hyaline thrombi
polyclonal igG and IgM
mesangial and subendothelial ED deposits; duplication of GBM
type 1 cryoglobulinemic GN
MPGN pattern with “wire loop” lesions or hyaline thrombi
monoclonal IgG or IgM
mesangial and subendothelial crystalline / paracrystalline deposits
lupus nephritis endocapillary proliferation or “wire loop” lesions or hyaline thrombi
polyclonal IgG; full house pattern
mesangial, subendothelial, or subepithelial ED deposits
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ASSESSMENTOFHISTOLOGICALACTIVITY
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ASSESSMENTOFHISTOLOGICALCHRONICITY
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PROGNOSIS
• 1/3remission,oftenspontaneous• 1/3gradualprogessiontoend
stage• 1/5intermittentexacerbation
• overall10-yearsurvival~80%• age,baselineserumcreatinine,and
proteinuriaareindependentpredictorsofdialysis-dependentrenalfailure
Roccatello D, et al. Am J Kidney Dis 2007; 49: 69-82.
Cr > 133 umol/l
Cr < 133 umol/l
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EXPERIENCEINTHEPAST
• patientswithmoderateproteinuriaandprogressiverenalfunctionworsening(butnotRPGN)• sustainedviralresponsewithIFN-α±ribavirin:15%to55% • buthasnoeffectonrenalfunctiondeterioration
• renalfunctionisbetterpreservedwithsteroidtherapytraditionalregimen:• pulsemethylprednisolone0.5-1.0g/dayfor3days • thenprednisolone0.5mg/kg/day • graduallytailto10mg/day • totaltreatmentfor6months
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ANTI-VIRALTHERAPYFORHCV-RELATEDGN:RATIONALE
i.e.patientswithmildproteinuriaandstablerenalfunction
• possibilityofspontaneousremission• substantialobservationaldatashowingthatremissionofhematuria,proteinuria,and
improvementofGFRinpatientswithHCV-associatedGNwhoobtainedsustainedHCVRNAclearancebyDAAs
othersupportivemeasures• ACEinhibitor/ARB• bloodpressurecontrol• diureticsforsymptomrelief
KDIGO Hepatitis C Work Group. Kidney Int Suppl. 2018;8:91–165.
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DAA:THEEVIDENCE
• 44consecutivepatientswithHCV-associatedmixedcryoglobulinemia• sofosbuvir-baseddirect-actingantiviraltherapy• SVR12andSVR24:100%
• BirminghamVasculitisActivityScore5.41±3.53atbaseline→2.35±2.25atweek4→1.39±1.48atweek12→1.27±1.68atweek24
Laura Gragnani, et al. Hepatology 2016; 64: 1473-1482.
• meancryocritvalue7.2±15.4%atbaseline→2.9±7.4%atwee12→1.8±5.1%atweek24KDIGO
CONCERNWITHANTI-VIRALTHERAPY
• limitedpublisheddata• inallpatientswithproteinuriareduction,HCVRNAclearancewasobservedatthe
endofantiviraltherapyconcern• uncertaineffectonlong-termrenaloutcome• clinicalbenefitinpatientswithSVRmaybetransient• dissociationbetweenviralandrenalresponsecouldhappenlater
i.e.relapseofvasculitispossibledespiteSVR
Fabrizi F, et al. Int J Artif Organs. 2007;30:212–219. Bonacci M, et al. Gastroenterology. 2018;155:311–315.
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SEVERECASES:TRADITIONALAPPROACH
• steroidtherapyasprevious,plus:
• cyclophosphamide:2mg/kg/dayfor8to16weeks
• plasmaexchange:3Lplasmathreetimes/weekfor2to3weeks
• rituximab:375mg/m2/weekfor4weeksKDIGO
ISTHISAPPROACHEFFECTIVE
• retrospectivestudyof105patientswithessentialmixedcryoglobulinemiavasculitisandrenalinvolvement,followedfor72months(85%HCVpositive)
• 80%hadoralorpulsesteroidsand/orcytotoxicagents• 67%hadplasmaexchange
• patientsurvivalat10yearswas49%• longtermrenalremissionin14%
Tarantino A, et al. Kidney Int 1995; 47: 618-623.
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RITUXIMABISBETTER
• 59patientswithcryoglobulinemicvasculitisandrelatedskinulcers,activeglomerulonephritis,orrefractoryperipheralneuropathy
• randomizedto• rituximab(2infusionsof1gmeach,withasecondcourseatrelapse) • conventionaltreatmentplussteroid;AZAorCP;orplasmapheresis
• survivalat12months:64.3%versus3.5%• BirminghamVasculitisActivityScoredecreasedonlyafterrituximab
11.9±5.4atbaseline→7.1±5.7atmonth2→4.4±4.6atmonth24
De Vita S, et al. Arthritis Rheum. 2012;64:843–853.
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ANOTHERRCTONRITUXIMAB
• 24patientswithcryoglobulinemicvasculitisinwhomantiviraltherapyhadfailedtoinduceremission
• randomizedto
• rituximab(375mg/m2/weekfor4weeks)• bestavailabletherapy(maintenanceorincreaseinimmunosuppressivetherapy)
• remissionat6months:83%versus8%
Sneller MC, et al. Arthritis Rheum. 2012;64:835–842.
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SUMMARYOFCURRENTRECOMMENDATIONS
presentation treatment
stable renal function; non-nephrotic proteinuria direct acting antiviral therapy
cryoglobulinemia flare, nephrotic syndrome, or RPGN
direct acting antiviral therapy + immunosuppressive treatment ± plasma exchange
active HCV-associated GN not responding to direct acting antiviral therapy
rituximab
KDIGO Hepatitis C Work Group. Kidney Int Suppl. 2018;8:91–165.
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