Histopathologic Classification of
ANCA-associated Glomerulonephritis
Annelies Berden
Leiden University Medical Center, the Netherlands
ANCA-associated vasculitis
• Systemic small vessel vasculitis
• Incidence 10-20 persons/million/yr
• Mean age at onset 65-74 yr
• Men and women equally affected
• GPA (Wegener’s) / MPA
Autoimmune disease
Neutrophil
+
Infection
+
ANCA
TNF-α
Priming
ANCAneutrophil
interaction
Vasculitis
Adopted from Trends Immunol 26: 561-564 Heeringa et al.
End organ damage
• Kidneys
• Most frequent cause of RPGN
• Dialysis, transplantation
• Lungs
• Alveolar hemorrhage
• Ear-nose-throat
• Saddle nose deformity
• Joints, skin, nervous system
Prognosis and treatment
• Untreated → fatal disease
• 1 year mortality 80%
• 1960’s/1970’s → dramatic improvement with
corticosteroids and cyclophosphamide
• > 90% of patients achieving remission at 1 year
• Induction and remission maintenance therapy
• Cyclophosphamide, rituximab
• Azathioprine, methotrexate, mycophenolate mofetil
Immunosuppressive therapy: a double-edged sword
• Complications of therapy
• Infertility
• Infections
• Malignancies
• Limited long term effectiveness
• 80% survival 5-8 yr fu
• 20-40% ESRF 3-5 yr fu
• 50% relapse within 5 yr fu
The renal biopsy
• Gold standard for diagnosis
• Hallmark microscopy findings:
• (IF) Pauci-immune staining pattern
• Little-no glomerular staining for immunoglobulin or complement
• (LM) Crescents (cellular- fibrocellular – fibrous)
• (LM) Fibrinoid necrosis
• (EM) Subendothelial edema, microthrombosis,
degranulation of neutrophils
• Prognostic value?
Standardized scoring form
• Diagnostically description ‘necrotizing, crescentic GN’ suffices
• Scoring form devised to assess prognostic value
• Systematically quantify the extent to which various morphological
parameters appear in a biopsy
• Assess which are most valuable in predicting renal outcome
• Scoring of an extensive number of lesions quantitatively or
dichotomously (present/absent scale)
• In general better intra- and interobserver agreement on
quantitative data (such as crescents and glomerulosclerosis)
Bajema et al. NDT‘96
Scoring form glomerular lesions
Bajema et al. NDT‘96
Scoring form interstitial lesions
Bajema et al. NDT‘96
Using the scoring system to assess prognostic value…
Tubular lesions predict renal outcome in AAGN after rituximab therapy. EUVAS, JASN ‘12
Clinical and histologic determinants of renal outcome in AAV: A prospective analysis of 100
patients with severe renal involvement. EUVAS, JASN ‘06
An index for renal outcome in AAGN. EUVAS, AJKD ‘03
Determinants of outcome in AAGN: a prospective clinico-histopathological analysis of 96
patients. EUVAS KI ‘02
Long-term renal injury in AAV: analysis of 31 pts with follow-up biopsies. EUVAS, NDT ‘02
Renal histology in AAV: differences between diagnostic and serologic subgroups.
EUVAS KI ‘02
Kidney biopsy as a predictor for renal outcome in AAGN. KI ‘99
Prognostic value of renal histologic lesions
• Positive predictors of (long-term) renal outcome
• Normal glomeruli
• Cellular crescents
• Negative predictors of (long-term) renal outcome
• Globally sclerotic glomeruli
• Fibrous crescents
• Tubular atrophy
Towards a classification system
• Abundance of literature on prognostic value of histologic
parameters in the renal biopsy
• >15 years of experience in renal histology group EUVAS
• Incentive for development of classification system
Any classification system should comprise the following:
• Enhance the quality of communication, especially
between experts involved in the field
• Provide a logical structure for categorization of groups for
epidemiologic, prognostic or interventional studies
(clinical trials)
• Assist in the management of individual patients; to this
extent, categories should be mutually exclusive and
predictive of the subsequent behavior of the disease
(prognosis)
Glassock 2004
Proposed classification system
• Four general categories:
• Focal class ≥ 50% normal glomeruli
• Crescentic class ≥ 50% cellular crescents
• Mixed class
• Sclerotic class ≥ 50% globally sclerotic glomeruli
• Hinges on recognition of:
• normal glomeruli, cellular crescents, global
glomerulosclerosis
Normal glomeruli
• No vasculitic lesions or global sclerosis
• May show subtle changes as result of ischemia or a minimum
number of inflammatory cells (<4 neutrophils, lymphocytes or
monocytes)
• Exclusion criteria:
• Synechiae
• Local/segmental glomerulosclerosis
• Extensive ischemic changes (splitting of Bowman’s capsule,
wrinkling of the GBM)
• Any other lesion unrelated to vasculitis (amyloid, tram tracking)
Crescents
• Cellular crescents (classification)
• Purely cellular lesions or with cellular components >10%
• Fibrous crescents
• Fibrotic (sclerotic) lesions with fibroblasts filling Bowman’s space
• >90% of crescent consists of extracellular matrix
Development of a crescent, early stage
Development of a crescent, later stage
Development of a crescent: fibrous crescent
Development of a crescent (Atkins, 1998)
Global glomerulosclerosis
• Sclerotic changes in the glomerulus comprising more than
80% of the tuft
• Irrelevant whether global glomerulosclerosis is attributable to
ANCA-associated GN or not
Four histopathological classes of ANCA-associated GN
Prognostic value
• Renal survival 1yr
• Focal 93%
• Crescentic 84%
• Mixed 69%
• Sclerotic 50%
First validation study
Discussion/ Conclusions
• Straightforward classification system for ANCA-ass. GN
developed by international group of renal pathologists
• Proved practical and of predictive value
• Needs further validation and according amendments
• Prospective studies
• Tubulointerstitial lesions  in our hands no relevant increase in
predictive value and because of semi-quantitative lesions
expected increase in intra/interobserver variation
• Not validated for overlap syndromes (such as with anti-GBM
disease)
Thank you for your attention!
Morita, Suzuki and Churg, 1973
Important observation 1:
* Three stages of crescent development were observed:
cellular – fibrocellular – fibrous
Morita, Suzuki and Churg, 1973
Important observation 2:
* Breaks in the basement membrane of capillary loops were
often found: it is agreed that formation of crescents is
provoked by a substance or substances that escape from the
glomerular capillaries into Bowman’s space, most often fibrin
Morita, Suzuki and Churg, 1973
Important observation 3:
* Macrophages were noticed, as well as fibrin, red blood cells,
white blood cells and fine strands suggestive of basement
membrane (numerous in fibrous strands)
Light microscopy of breaks in the GBM leading to
crescent formation
Morita, Suzuki and Churg, 1973
Important observation 4:
* EM: Podocytes participated in crescent formation to a limited
extent
Podocyte (PC)
attached to the
crescent cells by
intercellular
junctions
(arrows), x 5700.
The crescent
What is it:
a lesions at the location of Bowman’s space, multilayered, consisting of epithelial cells, macrophages,
inflammatory cells, fibrin, fibrinoid necrosis, other cells. It
may be segmental or circumferential, cellular – fibrocellular
or fibrous
What causes it:
breaks in the GBM
disturbed process of regeneration of podocytes
What is the outcome:
depends on the type of renal disease they appear in
strong relation to outcome in AAV