Histopathologic Classification ofANCA-associated Glomerulonephritis

Annelies BerdenLeiden 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

Adopted from Trends Immunol 26: 561-564 Heeringa et al.

Infection + ANCA

Vasculitis

Priming

TNF-α

ANCA-neutrophil interaction

Neutrophil +

Autoimmune disease

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, multi-

layered, 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 GBMdisturbed process of regeneration of podocytes

What is the outcome:depends on the type of renal disease they appear instrong relation to outcome in AAV