The Pathology of Lupus Nephritis Melvin M. Schwartz Summary: An international working group of clinicians and pathologists met in 2003 under the auspices of the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) to revise and update the 1982 and 1995 World Health Organization classification of lupus glomerulonephritis. This article compares and contrasts the ISN/RPS classification and the antecedent World Health Organization classifications. Although systemic lupus erythem- atosus is the prototypical systemic immune-complex disease, several non–immune-complex mechanisms of glomerular injury and dysfunction have been proposed, and this article summarizes the evidence supporting the pathogenic mechanisms of lupus vasculitis, glomer- ular capillary thrombosis, and lupus podocytopathy. The most significant and controversial feature of the ISN/RPS classification is the separation of diffuse glomerulonephritis into separate classes with either segmental (class IV-S) or global (class IV-G) lesions. Several groups have tested the prognostic significance of this separation, and this article discusses the implications of these studies for the ISN/RPS classification. Semin Nephrol 27:22-34 © 2007 Elsevier Inc. All rights reserved. Keywords: Systemic lupus erythematosus, pathology, ISN/RPS classification, immune com- plex disease, in situ immune complex disease, podocytopathy, collapsing FSGS, thrombotic microangiopathy, vasculitis, TTP-like lemperer et al1 were the first to describe jury have been described in patients with SLE. the light microscopic renal pathology of This article focuses on 2 aspects of the renal Ksystemic lupus erythematosus (SLE) glo- pathology of SLE that are of concern both to the merulonephritis (GN) with cellular proliferation, clinician, who uses the renal biopsy to assess wire-loops, hematoxylin bodies, and fibrin prognosis and to guide therapy, and to the thrombi in autopsied patients dying with the un- investigator, who uses the biopsy findings to treated disease. However, informed by pathoge- gain pathogenetic insight. The first is the re- netic insights and the newer techniques of im- cently proposed classification of lupus glomer- munopathology and electron microscopy, the ular disease developed under the auspices of interpretation and the prognostic and thera- the International Society of Nephrology and the peutic implications of the pathology have Renal Pathology Society (ISN/RPS classifica- evolved. Early in the renal biopsy era, the tion).2,3 The second is the non–immune-com- demonstration of immune deposits by fluores- plex pathogenetic mechanisms proposed to be cence and electron microscopy led to the con- operative in SLE renal disease. clusion that all of the pathology observed in SLE renal disease was immune-complex mediated. However, despite the strong evidence support- THE ISN/RPS ing the existence of DNA–anti-DNA immune CLASSIFICATION OF GLOMERULAR DISEASE complexes in the circulation and aggregates Early renal biopsy studies in SLE patients containing DNA and anti-DNA antibodies in the showed a spectrum of glomerular disease4 and glomeruli, other mechanisms of glomerular in- prognosis was a function of the underlying glo- merular lesion,5 and the glomerular pathology Department of Pathology, Rush University Medical Center, Chicago, IL. Address requests for reprints to Melvin M. Schwartz, MD, Department of included segmental (focal), diffuse (global), and Pathology, Rush University Medical Center, 1753 W. Congress Pkwy, membranous forms of GN.6,7 According to Chicago, IL 60612. E-mail: [email protected] 2,3 0270-9295/07/$ - see front matter Weening et al, Robert McCluskey codified © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.09.005 the first histologic classification of lupus ne- 22 Seminars in Nephrology, Vol 27, No 1, January 2007, pp 22-34 Pathology of lupus nephritis 23 Table 1. Comparison Between the Modified WHO (1982) and the ISN/RPS (2004) Classifications Class Modified WHO (1982) Critique of WHO 1982 ISN/RPS Classification (2004) I Normal glomeruli No normal in pathologic Minimal mesangial lupus a) all techniques classification nephritis. Normal by LM. b) EM/FM deposits EM/FM deposits II Pure mesangial No shown clinical Mesangial proliferative lupus alterations difference between nephritis with mesangial a) Mild hypercellularity classes a) and b) proliferation of any degree b) Moderate hypercellularity III Focal segmental GN* 1) Problem of focal Focal lupus nephritis† global GN Ͻ50% glomerular involvement 2) No quantitative definition of focal IV Diffuse GN* 1) Category comprise Diffuse lupus nephritis† Ն50% widely distributed glomerular involvement segmental and global a) IV-S Ն50% of glomeruli lesions have segmental lesions 2) No quantitative b) IV-G Ն50% of glomeruli definition of diffuse have global lesions3 V Diffuse membranous GN 1) No demonstrated Membranous lupus nephritis clinical difference a) Pure a) With or without mesangial between classes a) b) Plus class II proliferation or deposits and b) c) Plus class III b) In biopsies with mixed 2) Mixed classes d) Plus class IV membranous and focal combining (class III) or diffuse (IV) GN, membranous with the glomerular lesions are active lesions in class diagnosed separately III and IV confusing VI Advanced sclerosing GN No quantitative Advanced sclerosing lupus definition of advanced nephritis Ն90% global sclerosis without residual activity *Subcategories: active necrotizing, active and sclerosing, and sclerosing lesions. †Subcategories: active, active and chronic, and chronic lesions. phritis, and, after modification by the Pathol- the interpretation and clinical implications of the ogy Committee of the International Study of distinction between focal segmental (class III) and Kidney Disease in Children, it was published diffuse (class IV) GN in the WHO classification. in 1982 by the World Health Organization To some, segmental GN represented a different (WHO) (Table 1).8 Although the WHO classi- form of glomerular pathology and a different fication provided the pathologic context for pathogenetic mechanism from the diffuse many clinical studies, it was not universally global lesion seen in many cases of class IV accepted. The impetus to revisit the classifi- lupus glomerulonephritis. Others believed that cation was the concern that the 1982 classi- class III and IV lesions represented quantitative fication and the 19959 version with 6 classes differences in the same pathologic process. Al- and many subclasses were too cumbersome though distinguishing between classes III and to apply, in certain aspects difficult to under- IV by the proportion of glomerular involvement stand, and key terms were undefined. without considering sample size leads to mis- Differences that are more fundamental were classification of a significant number of biopsy 24 M.M. Schwartz specimens,10 the latter interpretation prevailed, deposits seen by electron microscopy. This def- and the ISN/RPS classification uses 50% glomer- inition eliminates the distinction drawn be- ular involvement as the cut-off level between tween mild and moderate mesangial hypercel- classes III and IV. The implications of this deci- lularity (categories IIA and IIB) in the WHO sion are discussed later (see section “Applying classification because clinicopathologic studies the ISN/RPS Classification”). have produced no outcome data to support the An international working group of clinicians separation of mesangial lupus nephritis based and pathologists met under the auspices of the on the degree of mesangial cellularity. ISN and the RPS with “the major objective of standardizing definitions, emphasizing clini- ISN/RPS Class III: Focal Lupus Nephritis cally relevant lesions, and encouraging uniform Class III is defined by the proportion of glomer- and reproducible reporting between centers.” uli with any active lesion or scar involving less The classification of lupus GN that was proposed than 50% of the glomeruli (Fig 1). It is not is based on the 1982 WHO classification. Table 1, defined by the character of the pathology or its in which the 1982 WHO classification is com- intraglomerular distribution. Although most of pared with the ISN/RPS classification, lists spe- the active lesions seen in focal lupus nephritis cific criticisms and problems that were of are, in fact, segmental in their intraglomerular concern to the working group. This is a mor- distribution, this strictly quantitative definition phologic classification of lupus GN that does replaces the descriptive category III, “Focal seg- not include coagulopathies, podocytopathy, or mental GN,” in the WHO classification. It non-immunoglobulin-mediated glomerular cap- should be noted that morphologically identical illary necrosis (vasculitis) (see later). If present, focal segmental GN may be distributed more the working group recommends separate diag- widely, but when 50% or more of glomeruli are noses for these glomerular lesions and nonglo- involved, the biopsy specimen is classified as merular vascular lesions, and tubulointerstitial diffuse lupus nephritis (see section “Class IV: nephritis. The salient features of the 6 classes of lupus glomerular pathology in the ISN/RPS clas- sification are presented below and in Table 1, along with significant changes from the modi- fied 1982 and 1985 WHO classifications. ISN/RPS Class I: Minimal Mesangial Lupus Nephritis The glomeruli are normal by light microscopy, but they must have mesangial immune deposits by fluorescence microscopy or electron-dense deposits