MORPHOLOGIC DIAGNOSIS OF CRESCENTIC GLOMERULOPATHIES. (CRESCENTIC GLOMERULITIS OR CRGL) HOME PAGE Dr. Ernesto O. Hoffmann. Professor of Pathology. Louisiana State University Medical Center and VA Medical Center. New Orleans, Louisiana, USA. November 2003. CIN 2003  First time abbreviations are in this color. Links are in this color.
INTRODUCTION: Glomerular crescents (CRs), necrosis, endothelio mesangial cell proliferation, inflammation and more remotely thrombosis and mesangial cell proliferation are usually complications closely associated and usually superimposed on other glomerulopathies (GPs). These lesions may be focal or diffuse, segmental or global. The same disease may some times have only one of the lesions mentioned. Some other times it may have all those lesions in the same renal biopsy. For didactic reasons, tradition and because there are truly predominating patterns, we have sub divided this group of complications in five morphologic patterns: 1. Mesangial Glomerulitis (MSGL). 2. Thrombotic Microangiopathic Glomerulitis (TMGL). These two patterns are easier to identify in the renal biopsy and are discussed elsewhere (6). 3. Crescentic GL (CRGL). Here the predominating lesion in the biopsy are crescents. This is the pattern discussed in this page. 4. Vasculitic Glomerulitis (VAGL). Here vasculitis predominates in the biopsy. 5. Necrotizing Glomerulitis (NEGL). Necrosis is the predominating lesion. These two latter patterns are also discussed elsewhere (6). GPs with inflammation (allograft glomerulopathy) or cell proliferation alone (vasculitis, necrotizing GL) are described with the respective glomerulopathies (6). It is obvious that overlapping of these patterns (complications) is frequently seen in renal biopsies and clinical information becomes crucial for the differential diagnosis of disease. In this conference I am presenting a different approach for the morphologic diagnosis and classification of GP with CRs (group 3 above or CRGL). Similar morphologic classification of CRGPs is available in the literature (5). CRESCENTIC GLOMERULITIS (CRGL). A CR is a consolidation of epithelial cells with inflammatory cells (extra capillary proliferation) forming three or more layers of cells in 1/3 or more of the capsule of Bowman in the kidney. Most CRGL are  non specific morphologic complications of severe underlying GPs, rather than  primary events. The presence of CRs in a glomerulopathy (GP) may be: a. The manifestation of a known condition, [Anti Glomerular Basement Membrane Glomerulo Nephritis (Anti-GBM GN) or Goodpasture Syndrome] (1, 8); b. A complication superimposed on another GP [Post infectious GN, Systemic Lupus Erithematosus (SLE), Alport's Syndrome, Fabry's disease, other] (5); c. Associated to other conditions ( leukemia, sepsis, renal infarct); d. Idiopathic or of unknown cause. Has no evidence of associated NP, extra glomerular or extra renal disease]. CRs are found in many seemingly diverse conditions and are important because they are signs of severe activity and poor prognosis. Sometimes CRs are inconspicuous (thrombotic micro angiopathies, periphery of infarcts, metabolic diseases). Some other times they are the most prominent feature of the GP (SLE, Anti-GBM GN, post-infectious GN, Henoch Schonlein GP, vasculitis). CR are usually associated with necrosis, fibrin deposition, cell proliferation, inflammation, thrombosis, sclerosis, fibrosis, and alteration of the capillary tufts. CRs may show different "ages": epithelial, fibro epithelial and fibrous (Illustrations 1). Most authors agree that any GP may show crescents. However, Crescentic Glomerulonephritis (Glomerulopathy) (CRGP) is a term applied to glomerulopathies that share the common lesion of CRs in a "large percentage of glomeruli". However, there is no agreement on the % of glomeruli involved with CR [20% (13). 30% (5). 50% (9, 10). 80% (13)] to call a GP CRGP. CRGP is also called Rapidly Progressive GN but, it is also stated that "CRGP" is not synonymous of rapidly progressive GN since less than 50% of the crescentic glomerulopathies have clinical rapidly progressive NP (5). The reverse is probably also true. There is a large group of CRGP called "Idiopathic or Primary Crescentic GP", this group is divided in three subgroups (9,10): 1. Anti GBM CRGP (or Goodpasture Syndrome). If the cause is known (anti GBM ab) it can not be called Idiopathic. It is not Primary either since it may not be restricted to the kidney (Goodpasture syndrome). 2. CRGP with underlying immune complex GP. (Caused by immune complexes, also idiopathic??. Also includes processes not restricted to the kidney (Henoch-Schonlein GN, SLE GN)] therefore, also not Primary. 3. CRGPs without immune complexes or anti GBM antibodies or "Pauci-immune" CRGP. Anti neutrophil cytoplasmic antibodies test (ANCA) (3) is said to be a marker for the latter group 3. However, ANCA positive tests have also been reported in anti-GBM GN, immune complex GN, other GP and in extra-renal diseases (7). ANCA positivity alone, in the absence of appropriate pathologic findings, should not be used to substantiate a morphologic diagnosis of vasculitis (Wegener's or Micro Polyarteriris nodosa) (4, 12). "ANCA Associated GN" is not a morphologic term therefore, I suggest not to be used as a morphologic diagnosis. The search for "Crescentic glomerulonephritis" in the Internet yields a large number of pauci-immune GPs with CRs that have no association with vasculitis therefore, that term is erroneously used to single out ANCA positive GPs. Crescentic glomerulopathies are apparently a very rich soil for the "fabricators of new diseases". When the pathologist is confronted with the renal biopsy and finds a GP with CRs, some of the previous definitions and concepts are of no help and frequently they are very confusing. I believe that it is easier and less problematic for the Pathologist to make a morphologic diagnosis according to what he sees in the renal biopsy, regardless of the clinical nomenclature, ANCA tests, definitions and other controversial concepts published in the literature.
Reading the renal biopsy by the pathologist:
The sample is adequate: The first step in examining a renal biopsy is to determine if the sample is adequate. Most renal GPs have focal or focally accentuated lesions. If only 10% of the glomeruli in the kidneys are involved by a focal process, a biopsy sample with ten glomeruli has a 35% probability of missing the diagnostic lesions. When 25% of the glomeruli are involved it is still a 5% chance of missing the diagnostic lesions (2, 15). The number of glomeruli in the biopsy is even more crucial for the assessment of the grade (activity) and stage (chronicity) of the process. Hence, a biopsy with at least 20 to 25 glomeruli is sufficient for this purpose (2, 15). The report of the pathologist must include the # of glomeruli in the biopsy to give the clinician an idea on how accurate the pathologists report may be according the size of the biopsy.
In Renal Pathology, diagnostic accuracy and precise quantitation of the lesions, depend on the adequacy of the sample.  To confirm the adequacy of the sample, there is no substitution for the microscopic examination of the renal biopsy at bed side. IT IS THE RESPONSIBILITY OF THE PATHOLOGIST TO PRODUCE AN ACCURATE MORPHOLOGIC DIAGNOSIS. HOWEVER, IT IS THE RESPONSIBILITY OF THE NEPHROLOGIST OR TRANSPLANT SURGEON TO PROVIDE HIM WITH AN ADEQUATE BIOPSY TO MAKE THAT ACCURATE DIAGNOSIS POSSIBLE.
1. The renal biopsy has CRs and underlying GP (Illustrations 2): Estimate the % of glomeruli with CRs (1% to 100%), the age of the CRs and % of CRs with necrosis or fibrin. Identify the underlying GP by looking especially to the glomeruli without crescents. The underlying GP may be: (To be aquainted with the new standardized morphologic nomenclature proposed by us for the GPs see ref. # 6 or see the table below). 1.1. Immune complex GN (GN). Due to the severe changes inflicted to the glomerular structures by the crescentic process, immune complexes may be present but, the underlying GP may not be recognizable. This cases should be reported as: Immune Complex Glomerulonephritis (type not recognized) with 90% crescents (60% fibro epithelial and 30% fibrous). No necrosis; 1.2. GP with metabolic or other non-immune deposits (GO); 1.3. GP with derangement of the anatomic components of the glomeruli (GD); 1.4. Other glomerulitis or complications (GL). Report the GP with the current name and % of crescents, age and necrosis. Examples: Post Infectious GN with 45% fibro epithelial crescents, 10% with necrosis; Alport's Glomerulopathy with 10% epithelial crescents and no necrosis; Thrombotic microangiopathy with 5% epithelial crescents and no necrosis. The best glomeruli to identify the underlying GP are those without CRs. The CRGP has no underlying GP or due to the collapse and destruction of the glomerular tufts, the underlying GP can not be recognized, see if it fits into one of the groups below.
2. The renal biopsy has CRs but no recognizable underlying GP. TEM, HRLM and FM are negative for immune deposits. FM shows linear pattern with C3 and IgG along the GBM (Illustrations 2): Report: Anti-GBM Glomerulitis with 90% epithelial crescents, 30% with necrosis. If pulmonary component is confirmed, report: Goodpasture Syndrome with 90% epithelial crescents, 30% with necrosis. Anti-TBM may also be positive with interstitial nephritis. Warning: Linear pattern (with or without CRs) may be seen in autopsy material, aggressive GPs (SLE, allograft rejection) and diabetes mellitus. Anti GBM GN is not an idiopathic GP since the cause is known (anti GBM ab), and may or may not be a primary GP since may or may not be restricted to the kidney (5).
3. The renal biopsy shows glomerular CRs but no recognizable underlying GP. FM, HRLM and TEM are negative for Immune deposits. No linear pattern by immunohistology (Illustrations 2). Search for extra glomerular and extra renal diseases (vasculitis, leukemia, sepsis, medications).           3.1. Biopsy positive for vasculitis: Report type of vasculitis and % of CRs and necrosis. Example: Micro Polyarteritis Nodosa with 40% crescents. 10% epithelial crescents with necrosis, 20% fibro epithelial crescents without necrosis, 10% fibrous crescents without necrosis. History of positive P-ANCA. Positive C-ANCA, presence of granulomata (Glomerular or extra glomerular) or periglomerulitis with rupture of the capsule of Bowman, are suggestive but not pathognomonic of Wegener's GP. However, do not use ANCA results to classify morphologically CRGPs. 3.2. Biopsy negative for vasculitis: 3.2.1: C-ANCA or P-ANCA is positive. Report: Glomerulopathy with % CRs and % necrosis. History of ANCA positive. Or Consistent with ANCA positive GP. Do not report type of vasculitis based on ANCA tests, report vasculitis only if you see it in the biopsy. 3.2.2. Positive history of Leukemia, infections, infarct (ANCA??). Report: CRGL with % CRs, % necrosis and age. History of, or associated to, or consistent with: Leukemia, renal infarct, infections.
4. No underlying GPs, FM negative, HRLM and TEM are non contributory, no vasculitis, no sepsis, no medication toxicity, no renal infarct (ANCA??). (Illustrations 2). Report: Idiopathic GP with 40% crescents ( 30% fibro epithelial, 10 % fibrous). No necrosis. A large number of biopsies with CRs may end up in this latter group. Due to the collapse and destruction of the glomerular tufts, the underlying GP can not be recognized and/or there is no clinical history available. This is a true "idiopathic" group, the cause is unknown (5).
Glomerulopathies With Crescents by Histologic Appearance.   Crescents. Other lesions. Immuno studies. Glomerulopathy-Disease. 1. The sample has Crescents and Recognizable Underlying Glomerulopathy: 1.1. CR with Underlying immune complex GN. Variable # of crescents. Variable age. Cell proliferation, rare necrosis (except SLE). Other lesions according to underlying GP. Ig and C according to underlying GN. Glomerulonephritis: MSGN, PPGN, APGN, MBGN, MPGN, DDGN, TCGN, FIGN, UCGN. (6) 1.2. Crescents with underlying metabolic diseases. Focal CR variable age. Deposits other than immune (metabolic). Ig and C are negative. Glomerulosis: Fabry's, Glycogenosis I, LCAT, lipoproteinosis, cystinosis, Gaucher's . 1.3. Crescents with Glomerular dysmorphism. Focal CR , variable age. Other lesions according the underlying GP. Ig and C are negative Glomerular Dysmorphism: Malignant FSGS, diabetic nephropathy, Alport's disease, benign nephrosclerosis, Infantile mesangial sclerosis, Sickle cell glomerulopathy, other (6). 1.4. Crescents with other Complications (Glomerulitis). Variable # Crescents. Variable age. Glomerular thrombi and thrombotic micro angiopathy. Ig and C are negative.   Glomerulitis: HUS, Malignant hypertension, anti phospholipid syndrome, scleroderma, cyclosporine toxicity, other. MPC, Collapsing GP. Ig and C are negative. Glomerulitis: collapsing GP MPC.         2. The sample has CRs but no recognizable underlying GP. HRLM and TEM negative for immune deposits. FM shows linear pattern with C3 and IgG along the GBM (occasionally also anti TBM): Early stages focal crescents. Latter diffuse (Usually > 80% involvement). Same age crescents, necrosis. Interstitial inflammation if anti TBM Ab also positive. Positive IgG and C3 with linear pattern along GBM. Anti TBM may be positive. Anti GBM Glomerulitis (Kidney only) or Goodpasture Syndrome (Kidney and lung). Warning: Linear pattern alone (IgG, C3) is not diagnostic of anti GBM GN. Autopsy material, diabetic nephropathy, SLE, transplanted kidneys may show positive IgG and/or C3 with linear pattern. Circulating anti GBM tests are very helpful for the diagnosis of Anti GBM GN.         3. The renal biopsy shows glomerular CRs but no recognizable GP. FM, HRLM and TEM are negative for immune deposits. No linear pattern by FM: 3.1. Biopsy positive for vasculitis: Vasculitis, Granuloma, Interstitial nephritis. Periglomerulitis. Ig and C negative. ANCA  Positive. Wegener's vasculitis, PAN (Micro and Macro), Churg-Strauss, Takayasu). 3.2. Biopsy negative for vasculitis: Variable number and age crescents.   Interstitial nephritis. C-ANCA or P-ANCA is positive. Hist. of Wegener's vasculitis, PAN (Micro and Macro), Churg-Strauss, Takayasu, other. Sepsis, leukemia, infarct, medications. ANCA?? Hist. of sepsis, leukemia, renal infarct, medications. Renal biopsies without vasculitis but proven extra renal vasculitis may show pure endothelio mesangial cell proliferation, pure necrosis or pure crescents. This is especially true in smaller biopsies (10 glomeruli or less).         4. No underlying GPs by HRLM, TEM. ANCA??, FM is negative, no vasculitis, no others, no clinical history.  Variable number and age crescents. Non specific changes. Negative tests or no clinical information. Idiopathic crescentic GL. GP of known cause should not be included here. Idiopathic CRGP is usually the largest group of "CR GPs" in Pathology Centers away from Nephrology Centers. Due to the collapse and destruction of the glomerular tufts the underlying GP can not be recognized and/or there is no clinical history available. I believe these CRGPs should not be called "Primary CRGN" unless it is confirmed to be limited to the kidney. These are "Idiopathic" since the cause is unknown.
CONCLUSION: It is true that certain GPs (Anti GBM GN, SLE, Post infectious GN, Henoch Schonlein, MPGN, IgA GN, Vasculitis, Cryoglobulinemia, Membranous GN) are more frequently complicated with a high % of crescents than others. What is difficult to understand is that if the presence of CRs is a sign of aggressive disease, why a GP (including the GP listed above) with lower number of CRs should be ignored? especially, when there is no consensus on what is the % of glomeruli involved in a GP to call it CRGN. A descriptive report facilitates de morphologic diagnosis of GP with CRs, standardizes the report of the pathologist, does not interfere with the clinical nomenclature and concepts and does not presume etiology or pathogenesis of the CRs. Finally it gives the clinician freedom for reaching a diagnosis and establishing the prognosis based not only on the pathologists report but also on clinical data and other laboratory tests (ANCA, anti GBM ab, ASO titers, anti nuclear ab, others) and using the clinical nomenclature of his preference.
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