Irmgard Neumann - Systemerkrankungen mit Nierenbeteiligung

Systemerkrankungen mit 

Nierenbeteiligung 

ÖGN Fuschl 2013 

Irmgard Neumann 

Wilhelminenspital Wien

• ANCA-Vaskulitis 

• Standardtherapie 

• MPO and PR3 ANCA - 2 Catagories 

• Follow up – Patients at risk 

• Remissionserhaltung 

• Lupus Nephritis 

• Standardtherapie 

• Hydroxychloroquine 

• Rolle von Rituximab

Induktions-Therapie 

Erhaltungs-Therapie 

3x0,5-1g Methylprodnisolon 

à 1mg/kg Aprednislon 

àtaper 

plus 

Cyclophosphamid (i.v./p.o.) 

oder 

Rituximab (bevorzugt bei Relapse !) 

OCS 

Azathioprin (2mg/kg) 

MTX (25mg/wk) Cave renal !! 

MMF 

Rituximab 

Dialysepflichtig 

+ Plasmaseparation

30 years ANCA - where are we today 

• ANCA sind ein Schlüsselbefund in der Diagnostik der SVV 

• Nur cANCA/PR3-ANCA und pANCA/MPO-ANCA klinisch relevant 

• Der diagnostische Wert von ANCAs bei „nicht-vaskulitischen“ 

entzündlichen Erkrankungen schlecht untersucht 

• Die klinische Bedeutung von ANCAs für das Monitoring der SVV ist 

nach wie vor Gegenstand vieler Diskussionen 

• Experimentelle in vivo Studien unterstützen die pathogenetische Rolle 

von MPO-ANCA, es gibt jedoch kein Tiermodel für PR3-ANCA

The spectrum of ANCA-associated vasculitis syndromes 

Falk RJ & Jennette JC. J ASN 2010

PR3 vs MPO-ANCA (regardless of clinical diagnosis) 

PR3 

MPO 

Age Younger Older 

Airway involvement +++ + 

Renal limited disease + ++ 

Inters88al lung disease -‐ ++ 

Granulomas ++ -‐ 

Relapses +++ + 

Cardiovascular events + ++

Frequency of PR3 ANCA and MPO ANCA specificities 

by a variety of clinical phenotypes 

n=502 (97% renal) 

Lionaki, Falk, A&R 2012

à ANCA specificity independently predicts Relapse in AAV with renal disease 


Relapse free survival 

MPO vs PR3 

MPO and PR3 ANCA 

within Chapel Hill Classif. 

MPA 

GPA 


Editorial 

Editorial 

Editorial 

ANCA vasculitis: to lump or split 

Why we should study MPA and GPA separately 

populations. Thus one could hypothesize that GPA is less 

doi:10.1093/rheum 

common in Japan because the genes, which play a key 

role in pathogenesis, occur much less frequently. 

ANCA antigen seems to have a central role in determining 

disease phenotype. Appropriate triggers (e.g. infection) 

in genetically predisposed people can produce 

PR3-associated disease, whereas other environmental 

factors (e.g. drugs or silica) result in MPO-associated 

disease. 

FIG. 1Relative frequency of GPA and MPA across the world. 

FIG. 1Relative frequency of GPA and MPA across the world. 

The three types of vasculitis associated Classification with ANCA and relapse diagnostic in GPA [4]. criteria Thesebeing findings developed support 

[ANCA-associated vasculitis (AAV)] are granulomatosis 

will need to include 

GPA, 

ANCA 

but not 

specificity 

MPA, is triggered 

as a discriminating 

by an infectio 

with polyangiitis (Wegener’s) (GPA), microscopic polyangiitis 

(MPA) and eosinophilic granulomatosis with polyan- 

ondary to exposure to propylthiouracil and hy 

In contrast, drug-induced vasculitis (most co 

feature [10]. This will help clarify the distinct clinical 

phenotypes of PR3-ANCA and MPO-ANCA–associated 

giitis (Churg–Strauss syndrome) (EGPA). They have been typically associated with induction of a vascu 

classified together in the majority of classification vasculitis systems and permit MPA with studies MPO-ANCA. into aetiopathogenesis Environmental expo to 

published since the introduction of ANCA, use including better-characterized the has beenand associated classified with patients. renal vasculitis, Futurea 

most recent 2012 Chapel Hill classification clinical system studies [1]. should these patients be powered also to have study MPA-type GPA and va 

GPA and MPA have been considered together MPAinindependently. clinical MPO-ANCA This poses [5]. significant difficulties for 

and treatment studies because they sharestudies many clinical under way in There which areGPA significant and MPA differences are combined 

outco 

features: for example, renal involvement together, is identical and in GPA previous and MPA. studies Walsh et will al. [6], need in a study to be of 

both diseases with a pauci immune focal re-evaluated segmentalwithtors thisfor inrelapse mind. inMany 535 patients studieswith areeither underpowered 

GP 

necrotizing glomerulonephritis. Granulomatous involvement, 

particularly of the upper respiratory tract, is a char- 

reported that PR3-ANCA positivity was asso 

to permit 

four 

this 

European 

analysis. 

studies 

Studies 

followed 

of MPA 

up for 

will 

1804 

consequently 

be much harder in Caucasian populations, 

acteristic feature of GPA, but not of MPA; eosinophilia, much higher risk of relapse than MPA [HR 1 

where MPA is relatively uncommon. The epidemiology, 

asthma and atopy typically occur in EGPA. More than 1.39, 1.89)], confirming previous reports of r 

90% of GPA and MPA patients are ANCA clinical positive. features, In trigger associated factors, with outcome PR3-ANCAand positivity genetic or fac- 

specificity stronglyofsuggest Thethat recently GPA and completed MPA should Genome-Wide be con- 

GPA 

most European studies, the ANCA antigentors 

GPA is predominantly proteinase 3 (PR3), sidered and in MPA as separate is Study diseases. in AAV has provided further evidenc 

predominantly myeloperoxidase (MPO). Only 50% of and MPA should be viewed as separate 

Funding: No funding was received. 

EGPA patients are ANCA positive, mostly MPO. GPA The patients studied were from the UK a 

and MPA are traditionally treated in the same way with Europe, where the link between disease (G 

Richard A. Watts 1 and David G. I. Scott 2 

populations. Thus glucocorticoids one could hypothesize and immunosuppressive that GPA is less Accepted drugs. 13 July 2012 and ANCA specificity is closest. The genetic 

common in Japan Recent because epidemiological, the genes, which play genetic, a key outcome Correspondence 1 Department and trial to: of Richard Rheumatology, were A. Watts, studied Department Ipswich for ANCA of Hospital specificity NHS(PR3 Trust, an 

role in pathogenesis, data suggest occur much thatless considering frequently. GPA and MPA 

Rheumatology, Ipswich as a and single 

Ipswich 2 Norwich Hospital 

clinical Medical NHSphenotype. Trust, School, Ipswich IP4 

PR3-ANCA University ofwas Eastasso 

5PD, UK. 

ANCA antigen entity seems fortothe havepurposes a central role ofinclinical determin- studiesAnglia, E-mail: 

and 

Richard.watts@ipswichhospital.nhs.uk 

trials Norwich, is UK. HLA-DP, Rheumatology SERPINA1 and2012 

PRTN3, whereas 

Downloaded from http://rheumatology.oxfordjournals.org/ at

Unterschiede zwischen PR3-and MPO-ANCA-subsets 

• PR3-und MPO-ANCA subsets sind genetisch verschieden 

Genome-wide association study: 2687 European (GPA and MPA) , 7650 matched controls 

HLA-DP, SERPINA 1, PRTN3 for PR3 ANCA, 

HLA-DQ for MPO-ANCA (NEJM 2012) 

• Geographische Unterschiede in der Prävalenz von PR3-ANCA 

und MPO-ANCA 

• Extra-renale Manifestationen, Granulome und Relapse sind bei 

PR3-ANCA +ven Patienten häufiger 

• Nierenhistologie: Aktive und chronische Läsionen häufiger bei 

MPO-ANCA+ven Patienten 

• Kein Tiermodel für PR3 disease 

Unterschiede in der Pathogenese, Ätiologie.. 

… Therapeutische Implikationen

Renale Prognose: Relapse – active renal disease 

Schlüsselbefund = Hämaturie !!! dysmorphe Erys, Zylinder, ev Proteinurie 

Renal survival according to the histologic categories 

Pictures I. Bajema 

A Berden, JASN 2010

Maintenance Therapy - IMPROVE 

Time to First Relapse and First Major Relapse 

Hiemstra, JAMA 2010

CYCLOPS – long term follow-up 

Data of 148 patients 

Median follow-up 4.3 years 

P=0.029 

Harper, Ann Rheum Dis 2012

CYCLOPS – long term follow-up 

Pulse daily oral (DO) 

Deaths 13 12 

Relapse rate patient –year 0.18 0.08 p

GPA and Relapse 

Disease-free interval and carrier status. 

57 patients with GPA grouped according 

to Staphylococcus aureus; p

Risikofaktoren für Relapse 

Relapse – Risiko ist variabel 

• GPA oder PR3-ANCA (vs. MPA) 

• ANCA positiv in Remission 

• Steigende ANCA-Titer 

• HNO 

• Lungenbeteiligung 

• GPA: Staph aureus carrier 

• SKrea 2 bis 3,0 mg/dl am Ende der Induktions-Therapie 

• Weniger CYC zur Induktion (CYCOPS, MYCYC)

Rituximab - Remissions -Erhaltung 

- Zeitintervall zum Relapse ist variabel 

- Risiko bei 6 Monaten↑ 

- B Zell Re-Population ~10 Monat, aber variabel 

à mehr Relapse nach B-cell return 

• Relapse nicht mit ANCA -Anstieg assoziiert 

• Einige Relapse auch ohne B-Zellen 

- „Add on“ RIT zu anderen IS-à Infektionen unverändert

RITUXIMAB – Maintenance for refractory AAV 

Protocolized versus non-protocolized TX 

% 56 ENT, 34 lung, 27 joint, 16 renal, 12 eye, 12 skin, 7 PNP, 7 CNS 

RITUXIMAB 

Group A (n=28) 

Group B (n= 45) 

Group C (n=19) 

1g x 2 or 375mg/m2 x 4; repeated at relapse 

1g x 2 à 1x1g every 6 mo for 2 years (6g total) 

relapsers from Group A->followed by Scheme B 

A B C 

Response 26/28 (93%) 43/45 (95%) 18/19 (95%) 

Relapses at 2 years 19/26 (73%) 5/43 (12%)** 2/18 (11%)** 

Relapses at last f-up 22/26 (85%) 11/43 (26%)** 10/18 (56%)** 

(median 44 mo) 

SAEs 16 in 19 pts 32% 45 in 21pts 47% 20 in 7pts 37% 

Infections 10 30* 14 

*13 in 2 pts 

** p

n=19 

n=19 

n=28 

2g 6g relapsers 

àwait 

from A 

à 6g 

Smith R,Jayne A&R, 2012

Ausschnitt 

• All (n=8) Remission by 6 months 

• Mean follow-up 12 mo (6-30), no deaths, no further severe infections 

à RTX can be considered for gen AAV and concomitant severe infection

Lupus Nephritis 

Standardtherapie 

-Hydroxychloroquine 

Rolle von Rituximab

Downloaded from ard.bmj.com on September 10, 2012 - Published by group.bmj.com 

ARD Online First, published on July 31, 2012 as 10.1136/annrheumdis-2012-201940 

Recommendation 

Joint European League Against Rheumatism and 

European Renal Association–European Dialysis and 

Transplant Association (EULAR/ERA-EDTA) 

recommendations for the management of adult and 

paediatric lupus nephritis 

George K Bertsias, 1 Maria Tektonidou, 2 Zahir Amoura, 3 Martin Aringer, 4 

Ingeborg Bajema, 5 Jo H M Berden, 6 John Boletis, 7 Ricard Cervera, 8 Thomas Dörner, 9 

Andrea Doria, 10 Franco Ferrario, 11 Jürgen Floege, 12 Frederic A Houssiau, 13 

John P A Ioannidis, 14 David A Isenberg, 15 Cees G M Kallenberg, 16 Liz Lightstone, 17 

Stephen D Marks, 18 Alberto Martini, 19 Gabriela Moroni, 20 Irmgard Neumann, 21 

Manuel Praga, 22 Matthias Schneider, 23 Argyre Starra, 24 Vladimir Tesar, 25 

Carlos Vasconcelos, 26 Ronald F van Vollenhoven, 27 Helena Zakharova, 28 

Marion Haubitz, 29 Caroline Gordon, 30 David Jayne, 31 Dimitrios T Boumpas 1 

ditional data are 

shed online only. To view 

files please visit the 

al online (http://ard.bmj. 

umbered affiliations see 

f article. 

espondence to 

imitrios T Boumpas, 

ABSTRACT 

Objectives To develop recommendations for 

the management of adult and paediatric lupus nephritis 

(LN). 

Methods The available evidence was systematically 

reviewed using the PubMed database. A modified Delphi 

method was used to compile questions, elicit expert 

opinions and reach consensus. 

Results Immunosuppressive treatment should be 

INTRODUCTION 

Approximately 50% of patients with systemic 

Ann Rheum Dis 2012 

lupus erythematosus (SLE) will develop lupus 

nephritis (LN), which increases the risks for renal 

failure, cardiovascular disease and death. In 2008, 

we published the first European League Against 

Rheumatism (EULAR) recommendations on the 

management of SLE. 1 Since then, several controlled 

trials have been published upon which updated

EULAR/ERA-EDTA Recommendations 

for the management of lupus nephritis 2012 

Indikation zur Nierenbiopsie bei SLE 

Jeder Hinweis auf eine Nierenbeteiligung 

- reproduzierbare Proteinurie ≥0.5 g/24h 

- insbesonere + glomerulärer Hämaturie 

In Erwägung zu ziehen bei: 

- isolierter glomerulärer Hämaturie 

- isolierter Leukurie (nach Ausschluß einer Infektion) 

- ungeklärter Niereninsuffzienz bei unauffälligem Harnsediment 

(insbesondere bei aPL-AK) 

Klinische, serologische oder andere Laborparameter 

korrellieren nicht (ausreichend) mit der Nierenhistologie !



Beurteilung der Nierenbiopsie 

à ISN/RPS 2003 classification system (àglomeruläre Veränderungen) 

à UND - Activity und Chronicity Indices 

- Tubulointerstitielle Läsionen 

- Vasculäre Veränderungen (insbes. bei APL - Antikörpern) 

• ) Adäquates Sample für Lichtmikroskopie (≥8 glomeruli) 

4 Färbungen (H&E, PAS, trichrome silver) 

• ) Immunohistologie (IgG, IgA, IgM, C3, C1q, κ and λ light chains) 

insbesondere bei LN V 

• ) ELMI hilfreich in einzelnen Fällen

Therapie -Konzept 

• Immunsuppressive Therapie 

à immunologische Remission 

- renal 

- extrarenal 

- serologisch 

Induktionstherapie à Erhaltungstherapie 

• Nicht-immunsuppressive Therapie 

• ACE-I +/- ARB bei Proteinurie (>0.5 g/24-‐hr) Hypertonie 

• RR-Therapie 

• Statine (LDL < 100 mg/dL) KHK-Risiko 5–8 x erhöht ! 

• Hydroxychloroquin 

• Vit D 

• Antikoagulation - Nephrotisches Syndrom, SAlb

Lupus nephritis Initial treatment 



Class IIIA or IIIA/C (±V) 

Class IVA or IVA/C (±V) 

MMF (3 g / day) 

oder 

Low-dose i.v. CYC 

(3g, Euro Lupus) 

+ Glucocorticoide: Initial: 3 x IV Methylprednisolon 500-750 mg 

à oral Prednisolone 0.5 mg/kg/d für 4 Wochen, 

reduzieren bis ≤10 mg/d mit Monat 4 bis 6 

Ungünstige prognostische Faktoren (rascher Abfall der GFR, Histologie) 

àCYC 1x/Monat in höheren Dosen (0.75-1g/m2) für 6 Monate 

Non-responders unter MMF od CYC 

à switch von MMF auf CYC bzw. CYC auf MMF 

à Rituximab 

IVIG, PLEX, IA

Lupus nephritis Initial treatment 



Class V LN 

MMF (3 g/day) 

+ oral Prednisolon (0.5 mg/kg/day) 

Non-responders: CYC 

Calcineurin inhibitors (Cyclosporin A, Tacrolimus) 

Rituximab 

Class II LN mit Proteinurie > 1 g/day (unter ACEI/ARB): 

Corticosteroide (0.25-0.5mg/kg/d) 

+/- Azathioprin (1-2 mg/kg/d)

Lupus nephritis Subsequent Treatment 



MMF (2 g/day) 

oder AZA (2 mg/kg/day) mindestens 3 Jahre 

+ low dose prednisone 

(5-7.5 mg/day) 

Calcineurin inhibitors diskutiert bei LN V 

Generell: 

- Ausschleichen der Substanzen, Gucocorticoide zuerst 

- Bei initial gutem Ansprechen auf MMF gut à MMF belassen 

- Schwangerschaft geplant àswitch auf AZA

Maintenance Therapy - For how long 

risk factors for progression to CKD: 

• African, Hispanic ethnicity 

• young age, 

• BX: crescents 

• lack of complete remission 

• persistently elevated Screatinine or sign proteinuria 

• persistently elevated APL-AB 

• persistently low levels of C3 

• frequent relapses 

Risk factors for renal flare 

• Young age at onset of SLE (

Severe LN – Induction MMF versus CYC 

Systematic review – pooled results 

Definition: 

• Class IV >15% cresc and/or glomerular capillary necrosis (often Screa↑) 

• Relapsing disease despite CYC (often Screa↑) 

• Proliferative LN (III or IV) with impaired renal function 

-> studies & personal communication: n= 382 

à MMF and CYC equally effective in inducing remission 

à Relapse rate, risk of ESRD higher in MMF 

Rovin B, CJASN 2013

HCQ - Clinical Benefits 

SLE : Less flares (HCQ-discontinuation à 6x greater rate of flares) 

Lower prednisone doses Canadian HCQ Study Group (NEJM 1991) 

LN: Multiple cohort studies (29 and 1480 SLE patients) 

Lower incidence and prevalence of renal disease wilth HCQ 

(A& Rheum 2005; A& Rheum 2010) 

Less nephritic flares 

random withdrawl study, 3yrs f-up, n=47 

-> 74% reduction risk of nephritic flares with HCQ (4% vs 14%) 

(Tsakones,Lupus 98) 

Reduced risk of developing renal disease (n=203) 

lower frequ.of CLASS IV LN 

lower GC doses 

lower SLE activity (LUNIMA, 2009) 

Improvement of renal outcomes in LN III+/-V, IV+/- V at 12 months 

(Hopkins lupus Cohort 2006, 

Lupus 2006, 2008, A&Rheum 2009)

HCQ - Clinical Benefits 

Lipids: Tgl↓ LDL↓ HDL↑ 

Improves glucose profiles (↑binding of insulin to ist receptor) 

à metabolic syndrome ↓ 

Reduces risk of malignancy 

Thromboprotective

B- Zell Depletion bei Lupus Nephritis 

Background 

SLE: 5-6 fach erhöhtes Risiko für KHK 

(chronische Entzündung, Immunosuppression) 

LN: 

Response auf CYC oder MMF: 30-60% < 6 Monaten 

55-80% 50% erhalten noch 10 Jahre nach Diagnose eine IS

Rituximab bei Lupus Nephritis 

Review: 300 Patienten, 21 Studien 

Häufigste Indikation für Rituximab: Refraktäre oder Relapsierende LN 

Follow-up 3-36 Monate; nur 11/21 Studien: follow-up >12 Monate 

Follow-up period >12 months 

Response rate (CR+PR) 50-100% 

(median 80%) 

No benefit for combining other immunosuppressive agents with Rituximab 

J W. Gregersen, D. R. W. Jayne Nat. Rev. Nephrol. 2012

Irmgard Neumann - Systemerkrankungen mit Nierenbeteiligung

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