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

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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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