Perspective Etiology-Based Diagnostic Approach to Proliferative Glomerulonephritis Sanjeev Sethi, MD, PhD Proliferative glomerulonephritis (GN) often is classified based on the pattern of injury. The pattern of injury does not reveal the underlying cause. New insights into the causes of proliferative GN suggest that deter- mining the type of deposits is more likely to provide clues to the underlying cause than determining the pattern of injury. This article proposes a new classification of proliferative GN that links findings from both immuno- fluorescence and light microscopy. The basis of the classification is whether the proliferative GN is immune complex mediated, pauci-immune, or complement mediated; the type of immunoglobulin deposits and com- plement factors then determine or suggest the underlying cause. One of the aims of the proposed classification system is to focus on the pathophysiology of the GN with emphasis on the underlying cause, leading to appropriate evaluation and management. The second aim is to simplify and standardize the classification of proliferative GN. Am J Kidney Dis. 63(4):561-566. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Glomerulonephritis; classification; membranoproliferative glomerulonephritis; C3 glomer- ulonephritis; complement. G lomerular deposition of immunoglobulin (Ig) and/or complement factors causes glomerular injury, which leads to an inflammatory response resulting in proliferative glomerulonephritis (GN). The proliferative GN ensues from 2 basic inflamma- tory responses: first, the proliferation of indigenous cells of the glomerulus, such as mesangial cells, endothelial cells, and parietal epithelial cells, and/or infiltrating mononuclear or polymorphonuclear cells; and second, the synthesis of matrix material such as mesangial matrix, basement membrane material, and fibrin. Thus, proliferative GN is defined by an in- crease in glomerular cellularity and typically occurs due to infiltration and proliferation of leukocytes within the glomerulus or from proliferation of endogenous cells such as mesangial cells and parietal epithelial cells. Proliferative GN results in patterns that can be identified under the light microscope depending on the location of injury, type of cells involved, and glomerular response to the injury. Thus, GN currently is classified based on the pattern of proliferation. Classifications include mesangial pro- liferative GN, diffuse (endocapillary) proliferative GN, membranoproliferative GN, crescentic and necrotizing GN, and focal/diffuse global glomerulo- sclerosis. The pattern of proliferative GN forms the diagnostic line of a kidney biopsy report. New insights in both immune complex (IC)- and complement-mediated proliferative GN warrant another look at how we classify this condition. 1,2 In this report, I suggest that GN should be classified based on identification of the type of deposits causing the injury rather than the pattern of injury resulting from those deposits. Correct identification of the type of deposits will lead to proper evaluation and understanding of the underlying cause of the prolifer- ative GN, which in turn will lead to appropriate man- agement and treatment. Many forms of proliferative GN, such as IgA nephropathy, lupus nephritis, anti– glomerular basement membrane antibody–mediated crescentic GN, and postinfectious GN, already are based on identifying the type of deposits causing the injury. Now, with new insights into complement- mediated GN, it is time to revisit how we classify GN. WHAT THE PATTERN OF PROLIFERATIVE GN TELLS US The pattern of proliferative GN is dictated by the location, severity, and acuteness versus chronicity of the injury. Thus, mesangial deposition of Ig and/or complement results in a mesangial proliferative GN, whereas subendothelial or intramembranous deposits (capillary wall deposits) result in diffuse endocapil- lary proliferative GN or membranoproliferative GN. The difference in diffuse proliferative GN and mem- branoproliferative GN lies in the acuteness of the injury: acute deposition results in diffuse proliferative GN, whereas chronic and possibly smaller deposits From the Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Received August 23, 2013. Accepted in revised form November 15, 2013. Originally published online January 2, 2014. Address correspondence to Sanjeev Sethi, MD, PhD, Depart- ment of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: sethi.sanjeev@mayo. edu Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.11.019 Am J Kidney Dis. 2014;63(4):561-566 561