lupus nephritis: an update on classifications schemes and ... · when to think of lupus nephritis...

43
Lupus nephritis: an update on classifications schemes and new insights into pathogenesis Kerstin Amann Dept. of Nephropathology Institute of Pathology, University of Erlangen-Nürnberg Krankenhausstr. 12 D-91054 Erlangen, [email protected]

Upload: tranhanh

Post on 20-Jun-2019

215 views

Category:

Documents


2 download

TRANSCRIPT

Page 1: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Lupus nephritis: an update on classifications schemes and new

insights into pathogenesis

Kerstin Amann Dept. of Nephropathology Institute of Pathology, University of Erlangen-Nürnberg Krankenhausstr. 12 D-91054 Erlangen, [email protected]

Page 2: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Lupusnephritis (LN) - the chameleon of renal pathology

proliferative Lupus-GN

SLE is a polygenic autoimmune disease….

Page 3: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

(Anders and Rovin 2016)

SLE… persistently active auto- reactive T- and B-cell clones

IF-alpha

in-situ formation of IC complement activation

Page 4: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

When to think of lupus nephritis (LN) ?

in up to 60% first manifestation of the disease

variable renal manifestation: Asymptomatic proteinuria / hematuria Nephrotic syndrom GN with rapid progressive course (RPGN) Interstitial nephritis

Serum-creatinine and -urea: normal or increased

Urine:

Proteinuria with/without hematuria Leucocytes and cylinders

Autoantibodies in serum: ANAs, anti-dsDNS, anti-phospholipid ab Serum - complement levels (C3, C4) often decreased

Page 5: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

How to diagnose LN ?

• First diagnosis of SLE : early phase, class II or V without typical serology, months to years before SLE-criteria are fullfilled

• Known SLE

• baseline biopsy - „silent“ GN • New onset of renal disease • „follow-up“biopsy: after 6 months or after therapy • Repeat biopsy when renal symptoms suddenly change

(Wilhelmus et al, NDT 2015)

Page 6: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

A typical case…..

Serum: Hb 9.2 g/dl, Thrombocytes 141 000/µl, Leucocytes 2 650/µl Urea 166 mg/dl, Crea 5.80 mg/dl C3c < 0.30 g/l, ASL titre, ANA, dsDNA not yet available Urine: Protein: 12516 mg/g Crea, leucocytes 270/µl, erythrocytes 3400/µl - dysmorphic, leucocytes and cylinders Ultrasound of kidneys: enlarged with increased echogenicity

→ Renal biopsy

Page 7: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Diffuse crescentiv GN cellular crescents in 15/18 glomeruli

Page 8: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:
Page 9: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

IgA IgG

C1q C3c

Page 10: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

IgA IgG

IgM C3c

Page 11: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Fall 1 - EM Ausgedehnte subendotheliale, mesangiale bzw. intrakapilläre feingranuläre Depositen.

Page 12: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Diffuse necrotizing and crescentic GN with cellular crescents in 15/18 glomeruli, interstitial edema and interstitial inflammation and so-called full-house pattern in immunofluorescence and immunohistology

Diagnosis

→ diffuse lupus nephritis (ISN/RPS IV-(A/G))

ANA 1:320, dsDNA antibody 1500 U/ml (normal range 0-7 U/ml),

Page 13: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Lupus nephritis (LN) (Hrick et al, NEJM 1998, 24: 888-899)

HE, X 320 IgG immunofluorescence microscopy, x 320

Page 14: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN - classifications - history

Page 15: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

2002 Consensus Meeting of working groups of ISN and the RPS

Preliminary suggestion of a novel, simplified and prognostically orientated classification of LN

(„The classification of glomerulonephritis in systemic lupus erythematosus revisited“, Weening et al., JASN 2004,15:241-50, KI 2004, 65:521-30)

basis: modified WHO classification of 1995 aim:

Better standardisation of definitions (>= 12 glomeruli) More clinical relevance Uniform and reproducible reporting system between various centers

Page 16: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN - classification ISN/RPS 2003

(Weening et al., Kidney Int. 2004)

Page 17: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Signs of activity and chronicity

(Weening et al., Kidney Int. 2004)

class III and IV => A and/or C

Page 18: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Signs of activity and chronicity

(Weening et al., Kidney Int. 2004)

class III and IV => A and/or C

Page 19: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Heptinstall´s Pathology of the Kidney, Seventh Edition

Activity- and chronicity score in LN (NIH- or Austin-Score)

(Austin et al. 1983)

Each criterion can be score 0-3; Fibrinoid necrosis, cellular cres-cents count twice Activity index: max. 24 Chronicity index: max. 12

Page 20: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN immunhistochemy – Fullhouse Pattern

C3c

IgA IgG

IgM

C1q

7-15-5418

Page 21: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Immunofluorescence / Immunhistochemy – Fullhouse Pattern

Cave: Fullhouse-Pattern is not specific for LN ( i.e. infectious GN in endocarditis)

Page 22: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Electron microscopy

Heptinstall´s Pathology of the Kidney, Seventh Edition

Page 23: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Electron microscopy subendothelial osmiophilic depots

7-16-809 7-15-7768

Page 24: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Electron microscopy subepithelial osmiophilic depots

7-16-809

Page 25: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Electron microscopy Fingerprints

7-16-809

Page 26: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – Electron microscopy Tubuloreticular structures

7-15-271

Page 27: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

2002 ISN/RPS Consensus Conference on the classification of LN – the simple look

I. Minimal mesangial LN

II. Mesangioproliferative LN

III. Focal LN

IV. Diffuse segmental (IV-S) or global (IV-G) LN

V. Membranous LN

VI. Sclerotic LN

Page 28: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

II. Mesangioproliferative LN

LM: Hypercellularity or mesangial matrix expansion

IF /EM:

Immune deposits within the mesangium and/or few subepi-thelial and/or subendothelial

Page 29: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

III. Focal LN

Active or inactive focal, segmental and / or global endo- and/or extra-capillary proliferative GN A Active focal proliferative GN A/C Active and sclerotic focal proliferative GN C Inactive sclerotic focal proliferative GN

<50% of glomeruli !

Page 30: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

IV. Diffuse segmental (IV-S) or global (IV-G) LN

Active or inactive diffuse (>50%), segmental or global endo-/extracapillary proliferative GN A Active diffuse segmental or global proliferative GN A/C Active and sclerosing diffuse segmental or global proliferative GN C Diffuse segmental or global sclerosing GN

Page 31: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Wire loops LN III or IV

subendothelial immunecomplex deposits = wire loops

Page 32: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Differences between class IV-G and IV-S

Heptinstall´s Pathology of the Kidney, Seventh Edition

Page 33: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

ANCA positivity in LN ?

(Turner-Stokes KI 2017)

Page 34: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

V. Membranous LN

Gobal or segmental subepithelial immune deposits (>= 50% of capillary tuft) or mor-phological consequences in LM and / or IF and / or EM with / without mesangial alte-rations (cells, matrix) (>= 50% of glome-ruli).

combination with classes III and IV

V + III A or V + IV-S A / IV-G A

PLAR2- and THSD7A-negative

Page 35: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

VI. Sclerotic LN

>= 90% sclerosed glomeruli

(usually not seen in a renal biopsy!)

Page 36: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Distributions of classes according ISN/RPS 2003

Heptinstall´s Pathology of the Kidney, Seventh Edition

Page 37: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Switch of LN classes

Heptinstall´s Pathology of the Kidney, Seventh Edition

Page 38: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

And now back to our case…

diffuse lupus nephritis (ISN/RPS IV-(A/G))

Very high activity index (24/24) No signs of chronicity (0/12)

aggressive therapy necessary! prognosis ?

Page 39: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Serum creatinine

0

1

2

3

4

5

6

7

0 50 100 150 200 250

Cyclophosphamide

Mycophenolat mofetil (MMF)

Cre

atin

ine

mg/

dl

Tage

end of hemodialysis

last dsDNA-ab negative

Page 40: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

LN – differential diagnose

DD: nearly all other immunecomplex-mediated GNs !

Systemic disease ?

SLE-serology (ANA-, anti-DNS antibodies) ?

Histology: „wire loops“ and hyaline thrombi ( anti-phospholipid syndrom?) „full house“ immuneglobulin deposition (IgG, IgM, IgA+C1q,C3c) (cave: clinically not all SLE criteria may be fullfilled) Electron microscopy:

Deposits in all 3 compartments (mesangial, subendothelial and subepithelial) +- „fingerprint“ or tubuloreticular structures

Page 41: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

Vascular manifestationen of SLE – anti-phospholipid syndrome

7-16-2032 TMA

Page 42: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

New insights into pathogenesis - standard and pipeline drug intervention for LN

Anders and Rovin 2016

autovaccination

non-specific and specific suppression of autoan- tigen presentation

Page 43: Lupus nephritis: an update on classifications schemes and ... · When to think of lupus nephritis (LN) ? in up to 60% first manifestation of the disease variable renal manifestation:

New insights into pathogenesis - standard and pipeline drug intervention for LN

Anders and Rovin 2016

NF-kappa B

Several unmet medical needs in LN genetic and molecular profiling may help to individualise risk assessment and management