lupus nephritis: an update on classifications schemes and ... · when to think of lupus nephritis...
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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]
Lupusnephritis (LN) - the chameleon of renal pathology
proliferative Lupus-GN
SLE is a polygenic autoimmune disease….
(Anders and Rovin 2016)
SLE… persistently active auto- reactive T- and B-cell clones
IF-alpha
in-situ formation of IC complement activation
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
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)
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
Diffuse crescentiv GN cellular crescents in 15/18 glomeruli
IgA IgG
C1q C3c
IgA IgG
IgM C3c
Fall 1 - EM Ausgedehnte subendotheliale, mesangiale bzw. intrakapilläre feingranuläre Depositen.
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),
Lupus nephritis (LN) (Hrick et al, NEJM 1998, 24: 888-899)
HE, X 320 IgG immunofluorescence microscopy, x 320
LN - classifications - history
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
LN - classification ISN/RPS 2003
(Weening et al., Kidney Int. 2004)
LN – Signs of activity and chronicity
(Weening et al., Kidney Int. 2004)
class III and IV => A and/or C
LN – Signs of activity and chronicity
(Weening et al., Kidney Int. 2004)
class III and IV => A and/or C
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
LN immunhistochemy – Fullhouse Pattern
C3c
IgA IgG
IgM
C1q
7-15-5418
LN – Immunofluorescence / Immunhistochemy – Fullhouse Pattern
Cave: Fullhouse-Pattern is not specific for LN ( i.e. infectious GN in endocarditis)
LN – Electron microscopy
Heptinstall´s Pathology of the Kidney, Seventh Edition
LN – Electron microscopy subendothelial osmiophilic depots
7-16-809 7-15-7768
LN – Electron microscopy subepithelial osmiophilic depots
7-16-809
LN – Electron microscopy Fingerprints
7-16-809
LN – Electron microscopy Tubuloreticular structures
7-15-271
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
II. Mesangioproliferative LN
LM: Hypercellularity or mesangial matrix expansion
IF /EM:
Immune deposits within the mesangium and/or few subepi-thelial and/or subendothelial
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 !
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
Wire loops LN III or IV
subendothelial immunecomplex deposits = wire loops
Differences between class IV-G and IV-S
Heptinstall´s Pathology of the Kidney, Seventh Edition
ANCA positivity in LN ?
(Turner-Stokes KI 2017)
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
VI. Sclerotic LN
>= 90% sclerosed glomeruli
(usually not seen in a renal biopsy!)
Distributions of classes according ISN/RPS 2003
Heptinstall´s Pathology of the Kidney, Seventh Edition
Switch of LN classes
Heptinstall´s Pathology of the Kidney, Seventh Edition
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 ?
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
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
Vascular manifestationen of SLE – anti-phospholipid syndrome
7-16-2032 TMA
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
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