KIDNEY BIOPSY TEACHING CASE An Overlapping Etiology of Rapidly Progressive Glomerulonephritis Glen S. Markowitz, MD, Jai Radhakrishnan, MD, and Vivette D. D’Agati, MD INDEX WORDS: Anti– glomerular basement membrane (GBM) disease; antineutrophil cytoplasmic antibody (ANCA); rapidly progressive glomerulonephritis; crescentic glomerulonephritis. R APIDLY progressive glomerulonephritis (RPGN) is a clinical term that is defined by the sudden and accelerated development of renal insufficiency (“rapidly progressive”) due to cellular proliferation within and inflammation of glomeruli (“glomerulonephritis”). Common diag- nostic criteria for RPGN include a 50% loss of renal function over 3 months and evidence of glomerular injury, in the form of an active uri- nary sediment including hematuria. In the over- whelming majority of cases of RPGN, renal biopsy reveals a crescentic glomerulonephritis (GN). Crescents are extracapillary proliferations composed predominantly of parietal epithelial cells as well as infiltrating inflammatory cells. Crescents typically accompany severe forms of glomerular damage leading to glomerular base- ment membrane (GBM) rupture. The term “cres- centic glomerulonephritis” is generally applied when greater than 50% of glomeruli contain crescents. Crescentic GN is not a single diagnostic entity, but encompasses a large spectrum of glomerular diseases. When a crescentic GN is encountered on renal biopsy, the essential diagnostic tool is immu- nofluorescence. The immunofluorescence pattern will allow classification of the crescentic GN into 1 of 3 categories: immune complex–mediated, anti- GBM–mediated, or pauci-immune. In the setting of crescentic GN, the immunoflu- orescence finding of granular deposits indicates the presence of immune complex GN, such as lupus nephritis, acute postinfectious GN, immu- noglobulin A (IgA) nephropathy, or fibrillary GN, to name a few. By light microscopy, all of these disease entities are associated with cellular proliferation in the underlying glomerular tuft (mesangial and/or endocapillary). Integration of the clinical history and serologies with the pat- tern of glomerular proliferation, the composition of the deposits by immunofluorescence, and the distribution and appearance of the deposits by electron microscopy allows determination of the specific diagnosis. Smooth, linear staining of the GBMs for IgG is encountered in anti-GBM dis- ease. In the third category, immunofluorescence fails to reveal significant positivity (pauci- immune). In this case, patients typically have an underlying small vessel vasculitis and seroposi- tivity for antineutrophil cytoplasmic antibodies (ANCAs) with antigenic specificity for either proteinase 3 (anti-PR3) or myeloperoxidase (anti- MPO). Pauci-immune crescentic GN and ANCA seropositivity are seen in Wegener’s granuloma- tosis, microscopic polyangiitis, and Churg- Strauss syndrome. Anti-PR3 antibodies are more common in Wegener’s granulomatosis, while anti- MPO antibodies predominate in the latter 2 con- ditions. In both anti-GBM disease and pauci- immune crescentic GN, light microscopy reveals predominantly segmental necrotizing lesions as- sociated with GBM rupture and neutrophil infil- tration. In glomeruli devoid of necrosis, there is minimal to absent cellular proliferation. In both conditions, electron microscopy reveals few or no electron-dense deposits. Thus, in the absence of overt vasculitis, a finding that strongly favors the diagnosis of pauci-immune crescentic GN, 1 the light microscopic and ultrastructural findings in anti-GBM disease and pauci-immune crescen- tic GN are virtually identical and the best modali- ties to distinguish between them are immunoflu- orescence and serologic testing. Determination of the relative frequency of the 3 categories of crescentic GN is dependent on the From the Departments of Pathology and Medicine, Colum- bia University, College of Physicians & Surgeons, New York, NY. Received May 21, 2003; accepted in revised form June 20, 2003. Address reprint requests to Glen S. Markowitz, MD, Department of Pathology, Columbia University, College of Physicians & Surgeons, 630 West 168 th St, VC14-224, New York, NY 10032. E-mail: gsm17@columbia.edu © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4302-0028$30.00/0 doi:10.1053/j.ajkd.2003.06.005 American Journal of Kidney Diseases, Vol 43, No 2 (February), 2004: pp 388-393 388