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SPECIAL ARTICLE www.jasn.org

Mayo /Renal Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN

Sanjeev Sethi, Mark Haas, Glen S. Markowitz, Vivette D. D’Agati, Helmut G. Rennke, J. Charles Jennette, Ingeborg M. Bajema, Charles E. Alpers, Anthony Chang, Lynn D. Cornell, Fernando G. Cosio, Agnes B. Fogo, Richard J. Glassock, Sundaram Hariharan, Neeraja Kambham, Donna J. Lager, Nelson Leung, Michael Mengel, Karl A. Nath, Ian S. Roberts, Brad H. Rovin, Surya V. Seshan, Richard J.H. Smith, Patrick D. Walker, Christopher G. Winearls, Gerald B. Appel, Mariam P. Alexander, Daniel C. Cattran, Carmen Avila Casado, H. Terence Cook, An S. De Vriese, Jai Radhakrishnan, Lorraine C. Racusen, Pierre Ronco, and Fernando C. Fervenza

*, Rochester, Minnesota

ABSTRACT Renal pathologists and nephrologists met on February 20, 2015 to establish an research. The focal point of the meet- etiology/pathogenesis-based system for classification and diagnosis of GN, with a ing was to recommend an etiology/ major aim of standardizing the report of GN. On the basis of etiology/ pathogenesis-based classification of pathogenesis, GN is classified into the following five pathogenic types, each with GN and standardize pathology report- specific disease entities: immune-complex GN, pauci-immune GN, antiglomerular ing of GN. This manuscript describes basement membrane GN, monoclonalIgGN, and C3 glomerulopathy. The pathogenesis- the recommendations resulting from based classification forms the basis of the kidney biopsy report. To standardize the this meeting. The manuscript does not report, the diagnosis consists of a primary diagnosis and a secondary diagnosis. The extend to other forms of glomerular primary diagnosis should include the disease entity/pathogenic type (if disease entity diseases, such as membranous ne- is not known) followed in order by pattern of injury (mixed patterns may be present); phropathy, podocytopathies, and score/grade/class for disease entities, such as IgA nephropathy, lupus , and thrombotic microangiopathy. ANCA GN; and additional features as detailed herein. A pattern diagnosis as the sole primary diagnosis is not recommended. Secondary diagnoses should be reported separately and include coexisting lesions that do not form the primary diagnosis. GUIDELINES ON CLASSIFICATION Guidelines for the report format, light microscopy, immunofluorescence microscopy, OF GN electron microscopy, and ancillary studies are also provided. In summary, this consensus report emphasizes a pathogenesis-based classification of GN and pro- GN includes diseases characterized by in- vides guidelines for the standardized reporting of GN. creased glomerular cellularity caused by proliferation of indigenous cells and/or J Am Soc Nephrol 27: 1278–1287, 2016. doi: 10.1681/ASN.2015060612 leukocyte infiltration. On the basis of pathogenesis/pathogenic type, there are five classes of GN: immune-complex GN, A group of renal pathologists and ne- Fulk Foundation. The meeting opened phrologists met at the Mayo Clinic with the identification of a major need (Rochester, MN) on February 20, 2015 for standardization of kidney pathology Published online ahead of print. Publication date to reach a consensus on the standardized reporting in GN. Currently, the classi- available at www.jasn.org. classification and reporting of GN. The fication and reporting of GN are not Correspondence: Dr. Sanjeev Sethi and Dr. Fernando Fervenza, Mayo Clinic, 200 1st Street SW, Rochester, meeting was organized by S.S. and F.C.F. standardized, which is disadvantageous MN 55905. Email: [email protected] or fervenza. of the Mayo Clinic, endorsed by the Renal for patient care, limits the ability to [email protected]

Pathology Society, and funded by an compare data between institutions, and Copyright © 2016 by the American Society of independent educational grant from the hampers multicenter clinical and basic Nephrology

1278 ISSN : 1046-6673/2705-1278 JAmSocNephrol27: 1278–1287, 2016 www.jasn.org SPECIAL ARTICLE pauci-immune GN, antiglomerular base- Some forms of GN (e.g., ) seen in immune-complex GN or smudgy ment membrane antibody (anti-GBM) may have mixed membranous and prolif- deposits seen in fibrillary GN. Most active GN, monoclonal Ig GN, and C3 glomer- erative patterns. anti–GBM GN is characterized by a severe ulopathy (Table 1). The classification is pri- Pauci–immune necrotizing and cres- necrotizing and crescentic pattern; #25% marily on the basis of the findings by centic GN is characterized by negative or of patients with anti-GBM GN also have immunofluorescence microscopy (IF) or fewIgdepositsonIForIHC21,22;80%– circulating ANCA.26–28 less commonly, immunohistochemistry 90% of patients have serologic evidence Monoclonal Ig GN is characterized by (IHC) integrated with light microscopy of ANCA, and as such, this category has monotypic Ig deposits in the glomeruli (LM) and electron microscopy (EM). been referred to as ANCA-associated GN and/or along tubular basement mem- Immune-complex GN is characterized (ANCA GN) whereas the remaining pa- branes on IF or IHC.29–31 Monoclonal Ig by granular deposits of polyclonal Ig on IF tients are termed ANCA-negative GN.23,24 GN is associated with an underlying or IHC. Complement is often codeposited The principal antigens targeted by ANCA monoclonal gammopathy/paraproteinemia along with the Ig. The type and location of include myeloperoxidase (MPO) and pro- in many but not all patients.32 Specific the immune deposits often point to the teinase 3 (PR3). On the basis of the clinico- disease entities in this category that underlyingetiology.Immune-complexGN pathologic findings ANCA GN is classified have diagnostic features by IF/IHC includes specific disease entities, such as according to the Chapel Hill Consensus as and EM include proliferative forms of IgA nephropathy, lupus nephritis, and microscopic polyangiitis, granulomatosis monoclonal Ig deposition disease, fibrillary GN,1–4 with the understanding with polyangiitis, or eosinophilic immunotactoid GN, and rare patients that fibrillary GN may not represent true granulomatosis with polyangiitis.25 The of fibrillary GN with monoclonal Ig de- immune–complex GN in the sense of diagnosis of ANCA GN should include posits.3,4,33,34 In the absence of these dis- antigen-antibody complexes. Immune- both the clinicopathologic phenotype tinct patterns, GN with monotypic Ig complex GN also includes GN resulting and the ANCA specificity (e.g.,MPO- glomerular deposits on IF/IHC and from and autoimmune diseases ANCA microscopic polyangiitis).25 mesangial/capillary wall deposits on EM other than SLE.5–14 Indeed, infections are Cellular, fibrocellular, and fibrous cres- is labeled as proliferative GN with an important cause of immune-complex cents may be present depending on the monoclonal Ig deposits.29–31,35 Although GN in both developing and developed stage of the disease process. a membranoproliferative pattern is most countries.15–20 The pattern of glomerular Anti-GBMGNischaracterized by linear common, other patterns, including injury is variable, and depending, in part, deposits of Ig, most often IgG, and fre- mesangial proliferative, diffuse prolifera- on the etiology, there may be no lesion by quently, C3 along the GBM on IF or IHC, tive, necrotizing and crescentic, or scleros- LM, mesangial proliferative, endocapillary and it is confirmed by detection of circu- ing, may be present. proliferative, exudative, membranoprolif- lating anti–GBM antibodies. The linear Ig C3 glomerulopathy is characterized erative, necrotizing and crescentic, scleros- staining characterizes this form of GN and by the presence of dominant C3 deposits ing, or a combination of these patterns. contrasts with the granular deposits usually in the glomeruli with minimal or no Ig

Table 1. Classification of GN Pathogenic Type Specific Disease Entity Pattern of Injury: Focal or Diffuse Scores or Class Immune-complex IgA nephropathy, IgA , lupus Mesangial, endocapillary, exudative, Oxford/MEST scores for GNa nephritis, -related GN, fibrillary membranoproliferative, necrotizing, IgA nephropathy GN with polyclonal Ig deposits crescentic, sclerosing, or multipleb ISN/RPS class for lupus nephritis Pauci-immune GN MPO-ANCA GN, proteinase 3-ANCA GN, Necrotizing, crescentic, sclerosing, Focal, crescentic, mixed, or ANCA-negative GN or multipleb sclerosing class (Berden/EUVAS class) Anti-GBM GN Anti-GBM GN Necrotizing, crescentic, sclerosing, or mixedb Monoclonal Ig GNa Monoclonal Ig deposition disease, Mesangial, endocapillary, exudative, proliferative GN with monoclonal Ig membranoproliferative, necrotizing, deposits, immunotactoid glomerulopathy, crescentic, sclerosing, or multipleb fibrillary GN with monoclonal Ig deposits C3 glomerulopathy C3 GN, dense deposit disease Mesangial, endocapillary, exudative, membranoproliferative, necrotizing, crescentic, sclerosing, or multipleb MEST, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy; ISN/RPS, International Society of Ne- phrology/ Society; EUVAS, European vasculitis study group. aSome pathologists use the terms immune complex–mediated GN, monoclonal Ig–associated GN, etc. It is up to the discretion of the pathologist to use these terms. bMultiple patterns include two or more patterns of injury. The patterns should be stated (e.g., focal mesangial proliferative, crescentic, and sclerosing or diffuse necrotizing, crescentic, and sclerosing).

J Am Soc Nephrol 27: 1278–1287, 2016 Consensus Report on GN 1279 SPECIAL ARTICLE www.jasn.org deposits on IF or IHC.36–40 C3 glomer- GUIDELINES FOR mesangial proliferative, exudative, endo- ulopathy is associated with abnormalities NOMENCLATURE FOR THE capillary proliferative, membranoprolif- in regulation of the alternative pathway of PRIMARY DIAGNOSIS erative, crescentic, necrotizing, and complement. C3 glomerulopathy is further sclerosing GN. The percentage of glomer- categorized as dense deposit disease The primary diagnosis (examples are uli with crescents should be mentioned. or C3 GN on the basis of EM findings. shown in Table 3) is composed of three Multiple patterns may be present, and in The pattern of glomerular injury in C3 or four components in the following or- such patients, the different patterns should glomerulopathy is variable and can be der: (1) disease entity or pathogenesis/ be listed. A pattern diagnosis as the sole mesangial proliferative, diffuse endocapillary pathogenic type (when specificdisease primary diagnosis is not recommended. proliferative, membranoproliferative, entity is not known), (2) pattern of glo- The definitions of glomerular lesions and necrotizing and crescentic, or sclerosing merular injury, (3) scores and/or class of patterns are given in Table 4. GN.38,39 the disease entity where appropriate, and Third, standardized scores and/or (4) additional disease–related features. classes of the GN should be added as In some instances, when two distinct part of the primary diagnosis as appli- GUIDELINES FOR BASIC processes are contributing to the pa- cable. Thus, Oxford/MEST (mesangial STRUCTURE OF THE KIDNEY tient’s renal dysfunction, more than hypercellularity, endocapillary hypercel- BIOPSY REPORT one primary diagnosis may be listed in lularity, segmental sclerosis, interstitial order (e.g., ANCA GN and IgA nephrop- fibrosis/tubular atrophy) score, Interna- The basic report structure should include athy). tional Society of Nephrology/Renal the following reporting fields: specimen First, the disease entity or pathogen- Pathology Society class for lupus nephri- type, diagnosis (which includes a primary esis/pathogenic type should be written. If tis, and prognostic (Berden/European diagnosis and secondary diagnoses if pre- the disease entity is known, it takes pre- vasculitis study group) class for ANCA sent), comment, clinical data, gross de- cedence over the pathogenesis/pathogenic GN should be part of the primary di- scription, LM description, IF findings, EM type. agnosis.1,2,41 description, and addendum for special Second, the pattern of injury should Fourth, additional features, including studies (Table 2). The main sections of be listed. The GN may be focal or diffuse clinical modifiers (where appropriate), the kidney biopsy report are discussed in and segmental or global. The basic pat- that suggest the underlying etiology may the following paragraphs. terns of injury include no lesion by LM, be stated here. For example, an infection- related GN that is IgA dominant on IF suggests an underlying staphylococcal Table 2. Basic format of kidney biopsy report infection, and if known, pathogen and (1) Specimen type: needle biopsy, wedge, etc. the site of infection may be stated here (2) Diagnosis (e.g.,associatedwithStaphylococcus 9,11,42 Primary diagnosis aureus cellulitis). In patients with Disease process/pathogenic type (e.g., IgA nephropathy, lupus GN, ANCA GN, C3 GN) anti-GBM nephritis with both anti- Pattern of glomerular injury (e.g., mesangial proliferative, membranoproliferative, GBM antibody and positive ANCA se- necrotizing/crescentic, and focal and segmental sclerosing) rology, the clinical modifier anti-GBM Histologic scores or grade (e.g., Oxford/MEST for IgA nephropathy and ISN/RPS for lupus antibody and ANCA-associated/clinical nephritis) should be added. An immune-complex Additional features (e.g., degree of global , IFTA, vascular sclerosis, GN with a membranoproliferative pat- fi clinical modi ers, such as cryoglobulin/clinical HCV, bacterial endocarditis/clinical, tern of injury and polyclonal IgM/IgG staphylococcal cellulitis/clinical) on IF suggesting an infectious etiology Secondary diagnoses (list; e.g., acute interstitial nephritis and diabetic glomerulosclerosis); fi these are not felt to be part of the primary disease may require a clinical modi er such as (3) Comment/narrative associated with /clinical if the Can be used for summarizing/clarifying morphologic basis of primary and/or secondary infectious agent is known or associated diagnoses or clinicopathologic correlations, providing prognostic information, discussing with cryoglobulinemia and hepatitis C/ differential diagnosis, and providing appropriate references clinical if both cryoglobulins and hepa- (4) Summary of clinical data titis C are known to be present. In the (5) Gross description setting of monoclonal Ig GN, the pres- (6) LM description ence of cryoglobulin-like deposits on (7) IF/IHC LM and IgMk on IF may require a mod- (8)EM ifier (Waldenström macroglobulinemia/ (9) Addendum for special studies clinical) if the patient is known to have MEST, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/ tubular atrophy; ISN/RPS, International Society of Nephrology/Renal Pathology Society; EUVAS, Euro- Waldenström macroglobulinemia. A pean vasculitis study group; HCV, hepatitis C virus. clinical modifier to indicate that a

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Table 3. Some examples of GN diagnoses thrombotic microangiopathy is associ- (1) IgA nephropathy ated with antiphospholipid antibodies Primary diagnosis: IgA nephropathy in lupus nephritis should be included Pattern of injury: diffuse mesangial and focal segmental endocapillary proliferative and here if it is felt that these reflect a com- sclerosing GN ponent of the primary disease. Score/grade: Oxford classification: M1 E1 S1 T1 Additional features also include the Additional features: focal global glomerulosclerosis (20%), moderate tubular atrophy and proportion of globally sclerotic glomer- fi interstitial brosis (30%), mild arteriosclerosis and hyaline arteriolosclerosis uli, extent of interstitial fibrosis and Secondary diagnoses: , mild tubular atrophy (IFTA), and severity of (2) Lupus nephritis vascular changes, including arterial in- Primary diagnosis: (1) lupus nephritis and (2) thrombotic microangiopathy Pattern of injury: diffuse proliferative and sclerosing GN with focal (10%) cellular crescents timal sclerosis (arteriosclerosis) and ar- Score/grade: ISN/RPS class IV-G (A/C) teriolar thickening and hyalinization Additional features: thrombotic microangiopathy associated with antiphospholipid (arteriolosclerosis). The severity of vas- antibodies/clinical, focal global glomerulosclerosis (10%), mild tubular atrophy and cular sclerosis may be reported as mild, interstitial fibrosis (10%), moderate arteriosclerosis, and moderate hyaline arteriolosclerosis moderate, or severe. (3) Hepatitis C–associated immune–complex GN Although the report deals with GN, Primary diagnosis: immune-complex GN chronic changes may result from addi- Pattern of injury: membranoproliferative GN tional lesions present on the biopsy. In Additional features: with features of cryoglobulinemic GN (hepatitis C/clinical), focal such patients, the contribution of the fi global glomerulosclerosis (20%), moderate tubular atrophy and interstitial brosis (30%), separate lesions to the chronic changes moderate arteriosclerosis, and moderate hyaline arteriolosclerosis may be mentioned in the comment (4) Infection-related GN Primary diagnosis: IgA–dominant infection–related GN section. Pattern of injury: diffuse exudative GN The distinct advantage of this format Additional features: associated with S. aureus cellulitis infection/clinical, focal global of reporting is that it is etiology and – glomerulosclerosis (30%), moderate tubular atrophy and interstitial fibrosis (30%), moderate pathogenesis oriented.43 45 The report is arteriosclerosis, and moderate hyaline arteriolosclerosis adaptable to include new diseases, it is Secondary diagnoses: diabetic nephropathy, moderate suitable to fit databases, and it is stan- (5)ANCAGN dardized and most importantly, patient a Primary diagnosis: proteinase 3-ANCA GN centered by providing relevant informa- Pattern of injury: necrotizing and crescentic GN tion for targeted, mechanism–based $ Prognostic class: focal ( 50% normal glomeruli) treatment approaches. Additional features: clinicopathologic features of granulomatosis with polyangiitis (proteinase 3 and cytoplasmic ANCA/clinical), focal global glomerulosclerosis (10%), mild tubular atrophy and interstitial fibrosis (10%), mild arteriosclerosis, and moderate hyaline arteriolosclerosis GUIDELINES ON SECONDARY (6)Anti-GBMGN DIAGNOSES Primary diagnosis: anti-GBM GN Pattern of injury: necrotizing and crescentic GN, severe Secondary diagnoses include coexisting Additional features: clinicopathologic features of (anti-GBM lesions that do not form the primary antibody/clinical), focal global glomerulosclerosis (40%), moderate tubular atrophy and diagnosis. These include underlying interstitial fibrosis (40%), mild arteriosclerosis, and moderate hyaline arteriolosclerosis glomerular diseases, such as diabetic (7) Monoclonal Ig GN glomerulosclerosis and thin GBM ne- Primary diagnosis: monoclonal Ig GN phropathy. Similarly, tubulointerstitial Pattern of injury: membranoproliferative GN with intracapillary hyaline thrombi or vascular findings unrelated to the pri- (pseudothrombi) – Additional features: IgM k-staining of glomerular intracapillary deposits consistent with type 1 mary diagnosis, such as drug induced in- cryoglobulins (Waldenström macroglobulinemia/type 1 cryoglobulins/clinical), focal global terstitial nephritis, acute tubular injury, glomerulosclerosis (30%), moderate tubular atrophy and interstitial fibrosis (40%), moderate atheroembolic disease, etc., should also be arteriosclerosis, and moderate hyaline arteriolosclerosis listed as secondary diagnoses. However, (8) C3 glomerulopathy glomerular findings etiologically related Primary diagnosis: C3 GN to the primary diagnosis, such as throm- Pattern of injury: membranoproliferative GN botic microangiopathy in lupus nephritis, Additional features: focal global glomerulosclerosis (20%), mild tubular atrophy and interstitial should be included within the primary fi brosis (20%), mild arteriosclerosis, and moderate hyaline arteriolosclerosis diagnosis with a clinical modifier, such as lu- ISN/RPS, International Society of Nephrology/Renal Pathology Society; A/C, active/chronic. pus anticoagulant/clinical or anticardiolipin aIf MPO/PR3 titers are not known, it is acceptable to label as ANCA GN. antibody/clinical if these are known (Table 3, example 2). Tubulointerstitial

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Table 4. Definitions of glomerular lesions derived from the Oxford classification of supporting or opposing each potential IgA nephropathy1,64 and patterns of GN derived from the ISN/RPS lupus diagnosis. If pertinent, the comment classification22 should explain the score/grade, progno- Glomerular lesions sis of the disease, and riskof recurrence in Mesangial hypercellularity .3 Mesangial cells per mesangial area renal allografts. Key literature references Cellular crescent Extracapillary cell proliferationof morethan two cell layers with may be added in this section. .50% of the lesion occupied by cells Fibrocellular crescent An extracapillary lesion comprising cells and extracellular , , matrix, with 50% cells and 90% matrix GUIDELINES ON CLINICAL DATA Fibrous crescent Extracapillary crescents with .90% matrix Endocapillary hypercellularity Hypercellularity caused by an increased no. of cells within glomerularcapillary lumina, causingnarrowing ofthelumina A brief overview of the clinical data Fibrinoid necrosis Disruption of the GBM with fibrin exudation should be included in the report. These Sclerosis Obliteration of the capillary lumen by increased extracellular data must be provided by the nephrol- matrix with or without hyalinosis or foam cells ogist who submits the specimen for Patterns of GN pathologic evaluation. These consist of Minimal mesangial GNa Normal glomeruli by LM but mesangial immune deposits by IF the patient’s age, sex, ethnicity, acute Mesangial proliferative GNa Purely mesangial hypercellularity versus CKD, and in- a Active (proliferative) GN Any or all of the following glomerular lesions: endocapillary dication for the kidney biopsy (e.g., fi hypercellularity, karyorrhexis, brinoid necrosis, rupture of , , elevated creati- fi GBMs, cellular or brocellular crescents, subendothelial nine, or others [for example, biopsy for deposits identifiable by LM, and intraluminal immune prognostic purposes]). Pertinent clinical aggregates fi Necrotizing GN Segmental or global fibrinoid necrosis ndings, such as fatigue, , short- Crescentic GN $50% Glomeruli with cellular, fibrocellular, or fibrous ness of breath, hemoptysis, rash, infec- crescents (with percentage of crescents always noted in the tion, etc., should be included. Coexisting diagnostic line, even when ,50%)b diseases, such as , , Membranoproliferative GN Mesangial and/or endocapillary hypercellularity and and lymphoproliferative disorders, and a thickening of capillary walls caused by subendothelial Ig brief drug history (including pertinent and/or complement factors past exposures) should be mentioned Exudative GN Neutrophils accounting for .50% of glomerular as well as any relevant family history. hypercellularity fi a Laboratory ndings to be included are Sclerosing GN Any or all of the following glomerular lesions: glomerular serum , urinalysis and pro- sclerosis, fibrous adhesions, and fibrous crescents teinuria per 24 hours or urine protein- ISN/RPS, International Society of Nephrology/Renal Pathology Society. aExcept for the first two patterns, multiple patterns can occur together in a single specimen (derived from to-creatinine ratio, serum complement the ISN/RPS lupus classification22). levels (C3 and C4), protein electropho- bThe term crescentic GN is used when crescents are present in at least 50% of glomeruli, and applies to resis, and serologic findings, such as an- immune-complex GN/C3 glomerulopathy. This does not apply to ANCA GN and anti-GBM GN, where less than 50% of the glomeruli may be involved by crescents. tinuclear antibody and anti-double stranded DNA titers, ANCA (anti-MPO and anti-PR3), hepatitis serologies, and inflammation or acute tubular injury biopsy, and the GN may be the sec- cryoglobulin titers as appropriate. Any that is a component of the primary dis- ondary diagnosis; also, there may be pertinent microbiology results should ease may be listed with the primary di- more than one primary diagnosis if be stated. agnosis or simply described in the LM the pathologist feels that they are of report (e.g., mild to moderate inflamma- similar clinical importance (Table 3, tion that often accompanies crescentic example 2). GUIDELINES ON GROSS and other severe forms of GN). This is DESCRIPTION at the discretion of the renal pathologist and should relate to the severity of the GUIDELINES ON COMMENT The number, size of cores, and fixative(s) tubulointerstitial process and its per- in which the tissue is received for LM, IF, ceived contribution to the patient’s clin- The comment should summarize the and EM should be stated. Poorly pre- ical presentation. biopsy findings and discuss their impli- served tissue (e.g., dry tissue with no Also note that, although the main focus cations and how they relate to the clinical fixative or leaking fixative) should be of the report is on GN, a nonproliferative presentation. If required, a differential documented. Documentation should glomerular, tubulointerstitial, or vascular diagnosis of the findings may be included be made if tissue from a single (e.g., lesion may be the primary diagnosis in with a discussion of why one diagnosis formalin) vial is allocated for EM as light of the clinical indications of the might be favored and the evidence well as LM.

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Table 5. Guidelines for LM glomeruli involved by crescents should be Table 6. Guidelines for IF Glomeruli mentioned. Lobular accentuation of the No. of glomeruli, including no. of globally No. of glomeruli, including no. of globally glomerular tufts may be present. Mesangial sclerosed glomeruli or with other evident and segmentally sclerosed and ischemic expansion and capillary wall thickening lesions glomeruli should be mentioned. Intracapillary fibrin Intensity of staining: negative, 6, 1+, 2+, Focal versus diffuse and segmental versus thrombi, hyaline thrombi (pseudothrombi), and 3+ global findings and wire loops should be noted. The pres- Staining pattern: granular, linear, semilinear, Hypercellularity: mesangial, endocapillary, ence of GBM changes, such as vacuoles/ smudgy, and linear accentuation or exudative pinholes, spikes, or double contours, Location: focal or diffuse; segmental or global; Crescents: no./percentage, type (cellular, and mesangial, glomerular capillary wall, should be described. fibrocellular, or fibrous), and size or both (segmental or circumferential) Next, the tubular and interstitial Interstitial and tubular basement membrane Fibrinoid necrosis and karyorrhexis pathology should be described. This staining: if present fl Wire loops, pseudo-(hyaline) microthrombi, includes interstitial in ammation, char- Segmental trapping of C3 and IgM is common and fibrin thrombi acteristics of the infiltrate, and presence in areas of segmental sclerosis or scarring: Mesangial matrix expansion and presence or absence of granulomas. The location segmental glomerular tuft or coarse of mesangiolysis of the infiltrates (i.e., in preserved areas segmental staining GBM thickening/thinning, double-contour or areas of IFTA) should be mentioned. Internal controls: albumin along TBM and formation, and other GBM abnormalities To indicate the severity of IFTA, which GBM, C3 in vessels, and polyclonal IgA casts (e.g., spikes) is a key prognostic indicator in many if in tubules Disruption of GBM not all forms of GN, the estimated per- TBM, tubular basement membrane. Disruption of Bowman’s capsule centage of IFTA in the cortical area Tubules and interstitium 46 Interstitial inflammation: type of infiltrate should be given (rounded off to the by Chang et al. and Table 6, which and location nearest 5% or 10%). Grades of IFTA summarize essential information to be – Casts, crystals, and cysts scored as mild (10% 25%), moderate included in the biopsy report. The opti- Acute tubular injury (26%–50%), and severe (.50%) are an mum panel of stains includes IgG, IgM, Tubular basement abnormalities acceptable form of reporting, with the IgA, C3, C1q, fibrinogen, albumin, and IFTA: absent, mild, moderate, or severe percentages mentioned in parentheses k-andl-light chains, and the report Vessels after the grade. If the amount of intersti- should separately address findings in glo- Arteritis, emboli, and thrombosis tial (mononuclear cell) infiltrate is con- meruli, tubules, interstitium, and blood Arteriosclerosis and arteriolosclerosis: cordant with the amount of IFTA and vessels. The results can be reported in absent, mild, moderate, or severe limited exclusively or mainly to areas of paragraph or tabular form at the discre- IFTA, it should not be described as a tion of the renal pathologist. chronic interstitial nephritis to avoid For glomerular staining, the report GUIDELINES ON LM REPORT the misinterpretation that a separate or should clearly state whether staining for superimposed interstitial nephritis is each immune reactant is seen in some or General guidelines for LM examination present. If it seems evident that an inter- all glomeruli, whether this is segmental of medical renal have been de- stitial nephritis is present and distinct or global, and the location(s) of staining scribed by Chang et al.,46 and essential from the chronic fibrotic changes, this within glomeruli: mesangial, capillary information to be included in the biopsy should be described here but also, listed wall, or both. The results should also report is summarized in Table 5; we will as a secondary diagnosis, with its differ- specify the type of staining. Potential focus here on those aspects most specific ential diagnosis given in the comment. descriptors include (1)granular,(2) to evaluation of GN. The pattern of in- Finally, vascular lesions should be semilinear (e.g., for conditions associ- jury should be described, including described. Lesions most pertinent to GN ated with subendothelial deposits, in- whether the lesion is focal or diffuse include arteritis, thrombotic microangiop- cluding immune-complex GN with a and segmental or global. Key features in- athy, and arterio- and arteriolosclerosis membranoproliferative pattern and dif- clude mesangial and endocapillary hy- caused by hypertension associated with the fuse proliferative lupus nephritis), (3) percellularity; infiltration of capillary GN. The severity of vascular sclerosis may be coarsely granular (e.g., infection-related tufts by leukocytes and whether these reported as mild, moderate, or severe. GN), (4)linear(e.g., anti-GBM GN and are mononuclear cells, neutrophils, or monoclonal Ig deposition disease), and both; presence of necrosis; karyorrhexis (5)smudgy(e.g., fibrillary GN). Impor- and/or crescents; and rupture of GBMs GUIDELINES ON IF REPORT tantly, segmental staining for IgM, C3, and/or Bowman’s capsule. Crescents and occasionally, C1q is common in may be cellular, fibrocellular, or fibrous, Again, we will focus on those aspects areas of segmental sclerosis; this finding and they may be segmental or circumfer- most specific to evaluation of GN; for should not be described with any of ential (or nearly so). The percentage of general guidelines, refer to the work the descriptors provided above. One

J Am Soc Nephrol 27: 1278–1287, 2016 Consensus Report on GN 1283 SPECIAL ARTICLE www.jasn.org possible terminology is segmental glo- walls. To avoid confusion with anti- pathology (e.g., early changes of diabetic merular tuft, avoiding the need to spec- GBM GN, the linear staining seen in di- nephropathy). Examination of stained ify as mesangial or glomerular capillary abetic glomerulosclerosis can be called 1-mm-thick sections of tissue processed wall. The overwhelming majority of linear accentuation, which is commonly for EM should be considered as part of biopsies will exhibit at least mild staining observed for IgG and albumin. the histologic examination of the biopsy for C3 in blood vessels, and tubular casts Monoclonal Ig GN is characterized by and should be done by the pathologist nearly always will stain for k-andl-IgA. monotypic Ig deposits in the glomeruli. and not by a technologist. Glomeruli se- It is important to maintain awareness of In the setting of proliferative GN with lected for EM study should be represen- these as internal positive controls. monoclonal Ig, the deposits frequently tative of the LM findings, and glomeruli stain for a heavy chain (most commonly, showing global or extensive segmental IgG, less commonly, IgM, and rarely, sclerosis or ischemic changes should be KEY DISEASE–SPECIFIC IgA) and one of the light chains, either k avoided. If the EM sample contains no COMMENTS and l.29–31,49 In some instances, the glomeruli or only sclerotic/ischemic glo- monotypic deposits may be composed meruli, paraffin-embedded tissue The type, relative intensity, and pattern of either a heavy or light chain only. should be reprocessed for EM when of distribution of the various immune One caveat is that l-staining may signif- possible. Exceptions to this would be in reactants are critical to properly diagnose icantly exceed k-staining in IgA ne- patients with a diagnosis that is well the type of immune-complex GN. Thus, phropathy. Granular C3 is often present established by LM and IF/IHC; EM on IgA nephropathy is characterized by the along the monoclonal Ig. deparaffinized tissue with its inherent presence of mesangial dominant or co- If the intensity of staining for C3 limitations (e.g., accurate determination dominant IgA; lupus nephritis is charac- exceeds the intensity of staining for all of GBM thickness51) is unlikely to add terized by presence of mesangial and/or other immune reactants by two orders of additional diagnostic information. capillary wall deposits of multiple classes of magnitude (i.e.,3+versus1+and2+ The EM portion of the biopsy report Ig, including IgG, IgA, IgM, and Sjögren versus 6), the most likely diagnosis is may be written in narrative or tabular syndrome by IgM/IgG; and infection- C3 glomerulopathy or an infection- form and should contain the number of related GN is usually associated with cap- related GN if an obvious history of in- blocks processed, the number of blocks illary wall deposits of IgG/IgM in many fection is present. cut, the total numberof glomeruli on 1-mm bacterial infections, dominant IgA in Awareness of situations in which pos- sections cut from these blocks, the num- staphylococcal infections, and IgM/IgG in itive staining may be incorrectly inter- ber of globally and segmentally sclerotic viral infections. C3 is often present and less preted as signifying immune-complex glomeruli, the number(s) of glomeruli commonly, C1q along with the Ig in most GN is essential. Examples include (1)C3 with other lesions (e.g., crescents), and patients of immune-complex GN. and IgM in areas of segmental scarring tubulointerstitial and vascular lesions if In pauci-immune GN, the intensity of or segmental sclerosis, (2) IgG in areas of present. EM findings pertinent to GN staining for Ig and complement is typ- fibrinoid necrosis in ANCA GN, and (3) to be included in the biopsy report are ically in the range of negative to 1+ but IgG and/or IgA in protein droplets summarized in Table 7. can reach 2+ in areas of necrosis. Greater within podocytes in proteinuric states. intensity of staining or staining for IgA or Ischemic and sclerosed glomeruli may Table 7. Guidelines for EM IgG in areas not involved by necrosis be negative for Ig in immune-complex GN. No. of glomeruli studied by EM, including no. should raise the possibility of the overlap globally sclerosed or with other evident of two separate disease processes (e.g., lesions ANCA GN and IgA nephropathy or ANCA GUIDELINES ON EM REPORT Glomerular deposits: location, type, quantity, GN and membranous glomerulopathy). size, and substructure Fibrinogen may be present in the distri- EM is a crucial diagnostic tool for glo- GBM: architecture, thin/thick, duplication, bution of glomerular necrotizing lesions merular diseases. Data indicate that 20% ischemic changes, and rupture and/or crescents. of renal biopsies cannot be accurately Endothelium: fenestrations, swelling, and presence of tubuloreticular inclusions Anti-GBM GN is defined by intense diagnosed without EM, and nearly all Mesangial matrix: normal/increased and 50 and diffuse linear staining for IgG along of these are glomerular diseases. mesangiolysis the GBM. There is linear GBM staining Processing a sample of renal cortex for Mesangial cellularity: normal/increased for k-andl-light chains with similar in- EM is recommended for all native renal Podocytes: preserved or effaced (%), protein tensity. Rarely, linear staining for mono- biopsies. Although there is a small subset reabsorption granules, and microvillus clonal IgG occurs,47 or linear IgA rather of glomerular diseases for which, when change than IgG may be present, indicating an diagnostically well established by LM Leukocytes//fibrin in capillary IgA class of anti-GBM antibodies.48 C3 is and IF or IHC, elective deferment of lumen/Bowman’s space often present in a semilinear or granular EM might be considered, this is done Tubular epithelial and basement membrane pattern along the glomerular capillary at a risk of missing possible underlying abnormalities when present

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KEY DISEASE–SPECIFIC or interrupted band–like deposits involving studies show electron dense deposits. COMMENTS large segments of the GBM.39 The de- Recommendation: C. posits are also found as rounded deposits EM studies are helpful in confirming in the mesangium and in many patients, C4d stain to distinguish immune- the electron dense deposits of immune- Bowman’s capsule and tubular base- complex GN versus C3 glomerulopathy. complex GN, monoclonal Ig GN, and C3 ment membranes. However, C3 GN is Recommendation: C. glomerulopathy. characterized by mostly mesangial and Immune-complex GN is characterized subendothelial and sometimes, intra- C4d as a prognostic marker for IgA ne- by mesangialand/orcapillarywallelectron membranous and subepithelial deposits. phropathy. Recommendation: C. densedeposits.Endocapillary proliferative In some patients, there may be multiple Mass spectrometry to determine the and membranoproliferative patterns of layers of electron dense deposits and composition of deposits. Recom- injury are associated with capillary wall basement membrane material, resulting mendation: U. deposits, usually subendothelial and in in thickening and fraying of the GBMs. somepatients,intramembranousandsub- The deposits appear less discrete, more epithelial. However, a mesangial prolifer- ill-defined, and confluent compared ative pattern of injury is usually associated with the electron dense deposits of SUMMARY with mesangial deposits. Subepithelial immune-complex GN. humps are typically seen in infection- This manuscript provides guidelines for related GN but may be present in C3 classification, diagnosis, and reporting of glomerulopathy as well.9,11,39,52,53 Fibril- GUIDELINES ON USE OF GN.Themainconclusionoftheconsensus lary GN is characterized by deposits of ANCILLARY STUDIES meeting was that the kidney biopsy report nonbranching, randomly oriented fibrils should be etiology and pathogenesis with a diameter typically exceeding that of – These include IF on pronase digested driven. The kidney biopsy diagnosis amyloid fibrils (generally 15–24 nm).3,4 fi paraf n material (or possible IHC on should consist of a primary diagnosis Tubular substructures may be present in- fi paraf n material), IgG subclass determi- that includes the disease entity or patho- dicating cryoglobulins, and other sub- nation by IF, C4d staining in GN, and genic type (if disease entity is not known) structures, such as fingerprints, suggest mass spectrometry to determine the followed by pattern ofinjury,a score/grade an along with tubu- 29,55–61 composition of deposits. The rec- of the disease if appropriate, and addi- loreticular inclusions (IFN signature) in ommendations for ancillary studies are tional findings directly related to the endothelial cells. strong (A; established as contributory to primary disease entity. The diagnosis ANCA GN and anti-GBM GN show diagnosis or ), moderate (B; should also include separate secondary fewor no electron dense depositsbut may probably contributory to diagnosis or diagnoses ifpresent. GuidelinesforLM, IF, show crescents/fibrinoid necrosis with prognosis), possibly contributory to di- and EM and ancillary studies are also fibrin in the glomerular tufts/Bowman’s agnosis or prognosis (C), and insuffi- provided. This should be regarded as a space. cient data (U). working document, much like the Banff EM findings are variable in monoclo- classification for renal allograft pathol- nal Ig GN.54 Mesangial and mostly, When frozen tissue is not available for IF, ogy,62 subject to modification at future subendothelial and less commonly, sub- salvage techniques should be available. meetings and as new data evolve regarding epithelial electron dense deposits are These include IF after pronase digestion the pathogenesis of and relationships be- present in proliferative GN with mono- using formalin–fixed, paraffin–embedded tween different glomerular diseases. The clonal Ig deposits.29,30 Punctate, finely tissue or immunoperoxidase staining flexibility of the Banff schema has been granular deposits in the mesangium on paraffin-embedded material. Recom- one of its greatest strengths; whereas the along the inner (subendothelial) aspect mendation: A. initial version of that classification, like of GBMs and in tubular basement mem- this document, was on the basis of con- branes are present in monoclonal Ig depo- Subtyping of IgG (i.e., IgG1, IgG2, IgG3, sensus opinions of experts in the field sition disease. However, microtubules and IgG4) should be performed in rather than actual data, later iterations of measuring 20–60 nm, often in parallel patients with monoclonal IgG GN. Banff have been more data driven.63 arrays, are present in immunotactoid glo- Recommendation: A. merulopathy. Substructures may also be present in deposits in monoclonal Ig GN, The salvage technique of pronase di- ACKNOWLEDGMENTS particularly when cryoglobulins are gestion may also be used in some in- present. stances where masked monotypic Ig We thank Julie Ray for the arrangements with For C3 glomerulopathy, dense de- deposits are suspected in setting of the consensus meeting. posit disease is characterized by highly monoclonal gammopathy and when This study was supported by the Fulk osmiophilic intramembranous, continuous, routine IF studies are negative but EM Foundation.

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See related editorial, “A Systematic Method for Colon S, Borza D-B: Antigenic heterogeneity Mod Pathol 28: 854–860, 2015 Categorizing GN,” on pages 1265–1266.

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