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• W2000637899 abstract "IN 1957, ARNOLD RICH1Rich A.R. A hitherto undescribed vulnerability of the juxta-medullary glomeruli in lipoid nephrosis.Bull Johns Hopkins Hosp. 1957; 100: 173-186PubMed Google Scholar described segmental sclerosis involving juxtamedullary glomeruli in autopsy specimens of children dying of nephrotic syndrome caused by apparent lipoid nephrosis. He hypothesized that the development of glomerulosclerosis accounted for the progression to renal failure seen in a subset of children with idiopathic nephrotic syndrome. However, it was not until the 1970s, in a report by the International Study of Kidney Diseases in Children, that focal segmental glomerulosclerosis (FSGS) emerged as a separate clinicopathologic entity distinguished from minimal change disease by its greater steroid resistance and progression to renal failure.2Churg J. Habib R. White R.H. Pathology of the nephrotic syndrome in children A report for the International Study of Kidney Disease in Children .Lancet. 1970; 760: 1299-1302Abstract PubMed Scopus (442) Google ScholarDuring the past 4 decades, concepts of FSGS have been refined in more detailed clinicopathologic studies from numerous centers. FSGS is defined as a clinicopathologic syndrome manifesting with proteinuria, usually of nephrotic range, associated with lesions of focal and segmental glomerular sclerosis and foot-process effacement.3Habib R. Focal glomerulosclerosis.Kidney Int. 1973; 4: 355-361Crossref PubMed Scopus (173) Google Scholar, 4Southwest Pediatric Nephrology Study GroupFocal segmental glomerulosclerosis in children with idiopathic nephrotic syndrome.Kidney Int. 1985; 27: 442-449Crossref PubMed Scopus (131) Google Scholar Early in the disease process, the pattern of glomerular sclerosis is focal, involving a subset of glomeruli, and segmental, involving a portion of the glomerular tuft. As the disease progresses, a more diffuse and global pattern of sclerosis evolves. Alterations of the podocyte constitute the major ultrastructural findings.The approach to a diagnosis of FSGS is problematic because morphological features are nonspecific and can occur in a variety of other conditions or superimposed on other glomerular processes.5D'Agati V. The many masks of focal segmental glomerulosclerosis.Kidney Int. 1994; 46: 1223-1241Crossref PubMed Scopus (287) Google Scholar, 6Rennke H. Klein P.S. Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis.Am J Kidney Dis. 1989; 13: 443-455Abstract Full Text PDF PubMed Scopus (226) Google Scholar Primary (or idiopathic) FSGS must be differentiated from secondary forms with recognized etiologic associations, including genetic mutations in podocyte-associated proteins (such as α-actinin-4, podocin, Wilm's tumor [WT]-1 protein, and β integrin),7Kaplan J.M. Kim S.H. North K.N. et al.Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis.Nat Genet. 2000; 24: 251-256Crossref PubMed Scopus (1033) Google Scholar, 8Boute N. Gribouval O. Roselli S. et al.NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet. 2000; 24: 349-354Crossref PubMed Scopus (1186) Google Scholar, 9Denamur E. Bocquet N. Mougenot B. et al.Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases.J Am Soc Nephrol. 1999; 10: 2219-2223PubMed Google Scholar, 10Kambham N. Tanji N. Seigle R.L. et al.Congenital focal segmental glomerulosclerosis associated with β4 integrin mutation and epidermolysis bullosa.Am J Kidney Dis. 2000; 36: 190-196Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar viruses (such as human immunodeficiency virus [HIV] type 1 and parvovirus B19),11D'Agati V. Suh J.-I. Carbone L. Appel G.B. Pathology of HIV-associated nephropathy A detailed morphologic and comparative study .Kidney Int. 1989; 35: 1358-1370Crossref PubMed Scopus (340) Google Scholar, 12Moudgil A. Nast C.C. Bagga A. et al.Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy.Kidney Int. 2001; 59: 2126-2133Crossref PubMed Google Scholar and drug toxicities (such as heroin, interferon, lithium, and pamidronate)13Rao T.K. Nicastri A.D. Friedman E.A. Natural history of heroin-associated nephropathy.N Engl J Med. 1974; 290: 19-23Crossref PubMed Scopus (116) Google Scholar, 14Shah M. Jenis E.H. Mookerjee B.K. et al.Interferon-alpha-associated focal segmental glomerulosclerosis with massive proteinuria in patients with chronic myeloid leukemia following high-dose chemotherapy.Cancer. 1998; 83: 1938-1946Crossref PubMed Scopus (38) Google Scholar, 15Markowitz G.S. Radhakrishnan J. Kambham N. et al.Lithium nephrotoxicity A progressive combined glomerular and tubulo-interstitial nephropathy .J Am Soc Nephrol. 2000; 11: 1439-1448PubMed Google Scholar, 16Markowitz G.S. Appel G.B. Fine P.L. et al.Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate.J Am Soc Nephrol. 2001; 12: 1164-1172PubMed Google Scholar (Table 1). In addition, primary FSGS must be distinguished from the large group of secondary FSGS caused by structural-functional adaptations mediated by intrarenal vasodilatation, increased glomerular capillary pressures and plasma flow rates, and other maladaptive processes6Rennke H. Klein P.S. Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis.Am J Kidney Dis. 1989; 13: 443-455Abstract Full Text PDF PubMed Scopus (226) Google Scholar (Table 1). Such maladaptive glomerular alterations can arise through a reduction in the number of functioning nephrons (such as after unilateral renal agenesis, surgical ablation, oligomeganephronia, or any advanced primary renal disease) or by mechanisms that place hemodynamic stress on an initially normal nephron population (as in morbid obesity, cyanotic congenital heart disease, and sickle cell anemia).6Rennke H. Klein P.S. Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis.Am J Kidney Dis. 1989; 13: 443-455Abstract Full Text PDF PubMed Scopus (226) Google Scholar Finally, primary and secondary forms of FSGS also must be differentiated from the nonspecific pattern of focal and segmental glomerular scarring that can follow a variety of inflammatory, proliferative, thrombotic, and hereditary conditions, such as chronic glomerulonephritis, Alport's syndrome, and mitochondrial cytopathies.6Rennke H. Klein P.S. Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis.Am J Kidney Dis. 1989; 13: 443-455Abstract Full Text PDF PubMed Scopus (226) Google Scholar, 17Fogo A.B. Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases.Kidney Int Suppl. 2000; 75: S15-S21Crossref PubMed Scopus (81) Google Scholar, 18Kashtan C.E. Gubler M.C. Sisson-Ross S. Mauer M. Chronology of renal scarring in males with Alport syndrome.Pediatr Nephrol. 1998; 12: 269-274Crossref PubMed Scopus (33) Google Scholar, 19Guery B. Choukroun G. Noel L.H. et al.The spectrum of systemic involvement in adults presenting with renal lesion and tRNA (Leu) gene mutation.J Am Soc Nephrol. 2003; 14: 2099-2108Crossref PubMed Scopus (96) Google ScholarTable 1Etiologic Classification of FSGSPrimary (idiopathic) FSGSSecondary FSGS1. Familial/geneticA. Mutations in α-actinin 4B. Mutations in podocinC. Mutations in WT-1D. Mutations in β integrin2. Virus-associatedA. HIV-1 (HIV-associated nephropathy)B. Parvovirus B193. Drug-inducedA. Heroin (heroin nephropathy)B. Interferon-αC. LithiumD. Pamidronate4. Mediated by adaptive structural-functional responsesA. Reduced renal massOligomeganephroniaUnilateral renal agenesisRenal dysplasiaReflux nephropathySequela to cortical necrosisSurgical renal ablationChronic allograft nephropathyAny advanced renal disease with reduction in functioning nephronsB. Initially normal renal massHypertensionAtheroemboli or other acute vaso-occlusive processesObesityCyanotic congenital heart diseaseSickle cell anemia Open table in a new tab During the past 20 years, a growing number of publications have addressed the morphological heterogeneity of primary and secondary FSGS.5D'Agati V. The many masks of focal segmental glomerulosclerosis.Kidney Int. 1994; 46: 1223-1241Crossref PubMed Scopus (287) Google Scholar, 6Rennke H. Klein P.S. Pathogenesis and significance of non-primary focal and segmental glomerulosclerosis.Am J Kidney Dis. 1989; 13: 443-455Abstract Full Text PDF PubMed Scopus (226) Google Scholar, 20Schwartz M.M. Korbet S.M. Rydell J. et al.Primary focal segmental glomerular sclerosis in adults Prognostic value of histologic variants .Am J Kidney Dis. 1995; 25: 845-852Abstract Full Text PDF PubMed Scopus (80) Google Scholar However, a standardized approach to the subclassification of disease is lacking. The time has come to consider subclassifying FSGS based on morphological features, although there is considerable controversy surrounding the significance and definition of these variants. Precedents for a consensus-based morphological approach to the subclassification of renal disease can be found in the World Health Organization (WHO) classification of lupus nephritis,21Churg J. Bernstein J. Glassock R.J. World Health Organization morphologic classification of lupus nephritis (modified).in: Renal Disease Classification and Atlas of Glomerular Disease . (ed 2). Igaku-Shoin, New York, NY1995: p 152Google Scholar the Chapel Hill nomenclature of systemic vasculitides,22Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides. Proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Scopus (3675) Google Scholar and the Banff working classification of renal transplant pathology.23Racusen L.C. Solez K. Colvin R.B. et al.The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Crossref PubMed Scopus (2761) Google Scholar As in the latter conditions, the pathologic spectrum of FSGS is sufficiently complex that there is a compelling need for a consensus classification based on a synthesis of the literature and the knowledge of experts. The classification presented here is a working proposal predicated on a large body of peer-reviewed literature. It attempts to define more precisely and codify existing concepts to provide a standardized approach to the morphological subclassification of FSGS.Historic approach to histological subclassification of FSGSPrimary and secondary FSGS include a number of morphological subtypes that may have different prognostic and therapeutic implications. Historically, the early descriptions of Rich1Rich A.R. A hitherto undescribed vulnerability of the juxta-medullary glomeruli in lipoid nephrosis.Bull Johns Hopkins Hosp. 1957; 100: 173-186PubMed Google Scholar depicted discrete segmental scars with hyalinosis, predominantly affecting juxtamedullary glomeruli. In the early 1980s, the pathologic heterogeneity of FSGS was increasingly appreciated. The lesions of FSGS differed in both their topographic location within the glomerular tuft and the quality of endocapillary and extracapillary alterations.Schwartz and Lewis24Schwartz M.M. Lewis E.J. Focal segmental glomerular sclerosis The cellular lesion .Kidney Int. 1985; 28: 968-974Crossref PubMed Scopus (129) Google Scholar were the first to draw attention to the “cellular lesion” of FSGS, in which endocapillary and extracapillary hypercellularity may be seen, including endocapillary foam cells, infiltrating leukocytes, and pyknotic cellular debris. They noted that cellular features correlated with a shorter time course from onset of clinical disease to renal biopsy, suggesting that they represent an early stage in the development of the segmental scars.24Schwartz M.M. Lewis E.J. Focal segmental glomerular sclerosis The cellular lesion .Kidney Int. 1985; 28: 968-974Crossref PubMed Scopus (129) Google Scholar Although these investigators were the first to coin the term “cellular” FSGS, observations on this lesion were made as early as 1970 by Churg et al2Churg J. Habib R. White R.H. Pathology of the nephrotic syndrome in children A report for the International Study of Kidney Disease in Children .Lancet. 1970; 760: 1299-1302Abstract PubMed Scopus (442) Google Scholar and 1975 by Velosa et al.25Velosa J.A. Donadio J.V. Holley K.A. Focal sclerosing glomerulonephropathy A clinicopathologic study .Mayo Clin Proc. 1975; 50: 121-133PubMed Google ScholarAfter the emergence and recognition of HIV-associated nephropathy as a collapsing form of FSGS in the 1980s,11D'Agati V. Suh J.-I. Carbone L. Appel G.B. Pathology of HIV-associated nephropathy A detailed morphologic and comparative study .Kidney Int. 1989; 35: 1358-1370Crossref PubMed Scopus (340) Google Scholar there was increasing awareness that similar histological lesions existed in some patients with primary FSGS, although these cases lacked endothelial tubuloreticular inclusions at the ultrastructural level.26Weiss M.A. Daquioag E. Margolin E.G. Pollak V.E. Nephrotic syndrome, progressive irreversible renal failure, and glomerular “collapse.” A new clinico-pathologic entity?.Am J Kidney Dis. 1986; 7: 20-28Abstract Full Text PDF PubMed Scopus (151) Google Scholar, 27Detwiler R.K. Falk R.J. Hogan S.L. Jennette J.C. Collapsing glomerulopathy A clinically and pathologically distinct variant of focal segmental glomerulosclerosis .Kidney Int. 1994; 45: 1416-1424Crossref PubMed Scopus (265) Google Scholar, 28Valeri A. Barisoni L. Appel G.B. D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis A clinico-pathologic study .Kidney Int. 1996; 50: 1734-1746Crossref PubMed Scopus (236) Google Scholar The relationship of this collapsing lesion to the previously described cellular lesion has been a point of contention, and clearly, overlap exists between these forms with respect to the extracapillary cellularity caused by podocyte hyperplasia. Cases of primary FSGS with collapsing features were noted by several groups to be more prevalent in African Americans and to have more severe renal insufficiency at presentation, more severe markers of nephrotic syndrome, and a more rapidly progressive course to renal failure than noncollapsing forms.27Detwiler R.K. Falk R.J. Hogan S.L. Jennette J.C. Collapsing glomerulopathy A clinically and pathologically distinct variant of focal segmental glomerulosclerosis .Kidney Int. 1994; 45: 1416-1424Crossref PubMed Scopus (265) Google Scholar, 28Valeri A. Barisoni L. Appel G.B. D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis A clinico-pathologic study .Kidney Int. 1996; 50: 1734-1746Crossref PubMed Scopus (236) Google ScholarThe importance of the location of segmental lesions with respect to the perihilar and peripheral segments also has been debated. Perihilar lesions have been reported to be more common in adults versus children29Fogo A. Glick A.D. Horn S.L. Horn R.G. Is focal segmental glomerulosclerosis really focal? Distribution of lesions in adults and children.Kidney Int. 1995; 47: 1690-1696Crossref PubMed Scopus (52) Google Scholar and in secondary forms mediated by glomerular hyperfiltration/hypertension, such as obesity-related glomerulopathy30Verani R.R. Obesity-associated focal segmental glomerulosclerosis Pathologic features of the lesion and relationship with cardiomegaly and hyperlipidemia .Am J Kidney Dis. 1992; 20: 629-634Abstract Full Text PDF PubMed Scopus (143) Google Scholar, 31Kambham N. Markowitz G.S. Valeri A.M. et al.Obesity-related glomerulopathy An emerging epidemic .Kidney Int. 2001; 59: 1498-1509Crossref PubMed Scopus (993) Google Scholar and hypertensive nephrosclerosis with proteinuria.32Harvey J.M. Howie A.J. Lee S.J. et al.Renal biopsy findings in hypertensive patients with proteinuria.Lancet. 1992; 340: 1435-1436Abstract PubMed Scopus (82) Google Scholar It has been hypothesized that the predisposition for sclerosis to occur in the perihilar segment may relate to greater filtration pressures in the more proximal portions of the glomerular capillary bed.5D'Agati V. The many masks of focal segmental glomerulosclerosis.Kidney Int. 1994; 46: 1223-1241Crossref PubMed Scopus (287) Google ScholarLesions arising in the periphery at the tubular pole have been termed “tip lesions” by Howie and Brewer.33Howie A.J. Brewer D.B. The glomerular tip lesion A previously undescribed type of segmental glomerular abnormality .J Pathol. 1984; 142: 205-220Crossref PubMed Scopus (97) Google Scholar Evidence from several groups suggests that cases of tip lesion may have a clinical course more like that of minimal change disease, with greater likelihood of steroid responsivity and more favorable outcome.34Haas M. Yousefzadeh N. Glomerular tip lesion in minimal change nephropathy A study of autopsies before 1950 .Am J Kidney Dis. 2002; 39: 1168-1175Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 35Beaman M. Howie A.J. Hardwicke J. et al.The glomerular tip lesion; A steroid responsive nephrotic syndrome.Clin Nephrol. 1987; 27: 217-221PubMed Google Scholar It is possible that this lesion arises through physical stress placed on the paratubular segment of the tuft in the setting of severe nephrotic syndrome by the flux of protein-rich filtrate toward the tubular pole, and a role for glomerular prolapse as a precursor to tip lesion formation has been proposed.36Howie A.J. Ferreira M.A. Majumdar A. Lipkin G.W. Glomerular prolapse as precursor of one type of segmental sclerosing lesions.J Pathol. 2000; 190: 478-483Crossref PubMed Scopus (21) Google Scholar The existence of tip lesions in a variety of glomerular diseases manifesting proteinuria (such as immunoglobulin A [IgA] nephropathy, membranous glomerulopathy, and diabetic nephropathy) would support this contention.37Huppes W. Hene R.J. Kooiker C.J. The glomerular tip lesion A distinct entity or not? .J Pathol. 1988; 154: 187-190Crossref PubMed Scopus (22) Google Scholar The potential reversibility of the tip lesion and how this lesion should be viewed within the minimal change disease-FSGS spectrum remain to be defined.Working group methodsThe histological subclassification of FSGS has been hampered by lack of conformity in the definition of the variants and lack of agreement about the pathologic terminology and usage. To achieve uniformity in the approach to the pathologic classification of FSGS, an international group of renal pathologists with mutual interest in FSGS convened at Columbia University, New York, NY, from November 4 to 5, 2000. The goals of the meeting were to define terms and formulate a classification of the histological variants of FSGS on which to base future clinical-pathologic studies. First, cases from each of the participating centers illustrating the broad scope of morphological presentations of FSGS were reviewed using a multiheaded microscope. After extensive discussion of the morphological characteristics of the lesions, a set of histological terms was defined (Table 2). Once a consensus on the meaning and proper usage of these descriptive terms was reached, a working classification of the variants of FSGS was formulated (Table 3, Table 4). After the consensus meeting in New York, the participants collected a spectrum of FSGS biopsy specimens from their respective practices (42 specimens total) and circulated them among each other to evaluate the applicability of the definitions and classification. There was agreement among participating pathologists on the application and usage of the proposed classification.Table 2Glossary of TermsAdhesion: continuity of collagenous matrix between the glomerular tuft and Bowman's capsuleCollapse: implosive glomerular capillary wall collapse with wrinkling of glomerular basement membranes causing obliteration of the capillary lumen/lumina, without increase in intracapillary matrix or cellsConfluence of podocytes with parietal or tubular epithelial cells at the tubular lumen or neck: direct cellular contact of podocytes with the parietal epithelial cells or tubular epithelial cells at the tubular lumen or neckEndocapillary hypercellularity: occlusion of glomerular capillaries by absolute increase in the number of intraluminal cells, which can include foam cells, endothelial cells, macrophages, and other leukocytes, sometimes associated with hyalinosis, karyorrhexis, and rarely fibrin, often producing an expansile lesionFocal: involving some, but not all, glomeruliGlobal: affecting the entire glomerular tuftGlomerulomegaly: glomerular tuft larger than that in age-matched controls (by measurement, glomerular area >1.5 × normal)Hyaline: glassy smooth eosinophilic accumulation of proteinaceous materialMesangial hypercellularity: >3 mesangial cells surrounded by mesangial matrix in an intact glomerular segment in 3-μm thick sectionsPerihilar: segmental involvement contiguous with the glomerular hilusPodocyte hyperplasia: increased number of podocytes, often with crowding and multilayering; unlike true crescents, these lesions typically lack cell spindling, pericellular matrix, extracapillary fibrin, or continuity with parietal epithelial cellsPodocyte hypertrophy: increased size of the podocyte with or without intracytoplasmic protein resorption droplets, vacuoles, nuclear enlargement and vesiculation, and prominent nucleoliSclerosis: increased glomerular extracellular matrix with obliteration of the glomerular capillary lumen/luminaSegmental: <100% glomerular tuft involvement with some residual patent glomerular capillariesTip domain: outer 25% of the tuft next to the origin of the proximal tubule (the tubular pole must be identified)Tuft: the glomerular globe, not including Bowman's capsule or Bowman's space Open table in a new tab Table 3Morphological Classification of FSGSVariantInclusion CriteriaExclusion CriteriaFSGS (NOS)At least 1 glomerulus with segmental increase in matrix obliterating the capillary lumina There may be segmental glomerular capillary wall collapse without overlying podocyte hyperplasiaExclude perihilar, cellular, tip, and collapsing variantsPerihilar variantAt least 1 glomerulus with perihilar hyalinosis, with or without sclerosis >50% of glomeruli with segmental lesions must have perihilar sclerosis and/or hyalinosisExclude cellular, tip, and collapsing variantsCellular variantAt least 1 glomerulus with segmental endocapillary hypercellularity occluding lumina, with or without foam cells and karyorrhexisExclude tip and collapsing variantsTip variantAt least 1 segmental lesion involving the tip domain (outer 25% of tuft next to origin of proximal tubule) The tubular pole must be identified in the defining lesion The lesion must have either an adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck The tip lesion may be cellular or sclerosingExclude collapsing variant Exclude any perihilar sclerosisCollapsing variantAt least 1 glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasiaNone Open table in a new tab Table 4Morphological Features of Histological Variants of FSGSVariantLocation of Defining LesionsDistribution of Defining LesionsDefining FeaturesHyalineAdhesionPodocyte Hypertrophy/HyperplasiaGlomerulomegalyMesangial HypercellularityArteriolar Hyalinosis1. FSGS (NOS)AnywhereSegmentalSegmental increase in matrix obliterating capillary lumina (also segmental collapse without overlying podocyte hyperplasia) Exclude 2,3,4, and 5+/−++/−−/++/−−/++/−2. FSGS perihilar variantPerihilarSegmentalAt least 1 glomerulus with perihilar hyalinosis +/− sclerosis >50% of glomeruli with segmental lesions must have perihilar sclerosis and/or hyalinosis Exclude 3,4, and 5++/−+++/−−/++++/−−/+++/−3. FSGS cellular variantAnywhereSegmentalAt least 1 glomerulus with segmental endocapillary hypercellularity occluding lumina, +/− foam cells, +/− karyorrhexis Exclude 4 and 5−/+−/+++/−−/+−/+−/+4. FSGS tip variantAt tip domainSegmentalAt least 1 segmental lesion involving tip domain (outer 25% of tuft next to origin of proximal tubule) The tubular pole must be identified Lesion must have either an adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck Lesions can be sclerosing (in <25% of tuft) or cellular (in <50% of tuft) No perihilar sclerosis Exclude 5+/−+++/−++/−−/+−/+−/+5. FSGS collapsing variantAnywhereSegmental or globalAt least 1 glomerulus with collapse and overlying podocyte hypertrophy and hyperplasia−/+−/++++/− Often with droplets/vacuoles−/+−/+−/+NOTE. Plus (+) and minus (−) indicate the range of possible findings in all the involved glomeruli of a given biopsy specimen with the most frequent finding to the left and the least frequent finding to the right of the virgule. Open table in a new tab ProposalRecommendations for tissue processing and interpretation of immunofluorescence and electron microscopyWe recommend that renal biopsy specimens be processed by a skilled technologist, cut at 3 μm or less, optimally studied by at least 15 serial sections, and stained with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), Masson trichrome, and Jones methenamine-silver (JMS). H&E will provide an excellent assessment of the glomerular cellularity, podocyte alterations, and presence of foam cells or infiltrating leukocytes. Areas of sclerosis will be highlighted as blue, and areas of hyalinosis as red or orange, by Masson trichrome stain. PAS and JMS stains show the state of the glomerular basement membrane and delineate areas of collapse and solidification by matrix material. Serial sections will provide a thorough sampling of the tissue and allow tracking of particular lesions through different levels of the paraffin block to assess their relationship to the vascular and tubular poles.Complete workup of the biopsy specimen requires immunofluorescence and electron microscopy. Integration of immunofluorescence and ultrastructural findings with light microscopy and clinical history will allow differentiation of primary and secondary forms of FSGS from the nonspecific pattern of segmental sclerosis that can occur in other primary glomerular diseases (such as the chronic scarred phase of IgA nephropathy, pauci-immune glomerulonephritis, lupus nephritis, or hereditary nephritis).By immunofluorescence, FSGS typically shows focal and segmental granular deposition of IgM, C3, and, more variably, C1 in the distribution of the segmental glomerular sclerosis and hyalinosis. More generalized weak mesangial deposition of IgM and C3 also may be present. Staining for albumin and some immunoglobulins (particularly IgA, as well as IgG) may be found within the podocytes, corresponding to intracytoplasmic protein resorption droplets. Similarly, intracytoplasmic staining for albumin, immunoglobulins, and, sometimes, C3 may be found in proximal tubules, reflecting protein resorption. Substantial (ie, numerous or >1+ intensity) glomerular deposits of IgG or IgA in mesangial, subendothelial, or subepithelial locations are incompatible with a diagnosis of FSGS.By electron microscopy, the lesions of segmental sclerosis show wrinkling and retraction of glomerular basement membrane and accumulation of inframembranous hyaline, with resulting narrowing or occlusion of the glomerular capillary lumina. Hyaline deposits are electron dense and may contain curvilinear membranous particles or entrapped electron-lucent lipid globules. Endocapillary foam cells appear as large intracapillary cells containing abundant electron-lucent vacuoles. Sparse small electron densities may be identified in the mesangium. However, the presence of sizeable or regular electron-dense deposits in the subendothelial or subepithelial location of nonsclerotic capillaries is incompatible with a diagnosis of FSGS.Directly overlying the lesions of segmental sclerosis, there usually is complete effacement of foot processes, accompanied by podocyte alterations that include hypertrophy, increased organellar content, and focal microvillous transformation. This microvillous appearance is caused by the formation of slender cellular projections resembling villi along the surface of podocytes facing the urinary space. The hypertrophied podocytes show rounded cell bodies that adhere smoothly to the glomerular basement membrane, with frequent loss of primary processes. There may be detachment of podocytes from the sclerosing segment. In these areas, intervening accumulation of lamellated neomembrane material is often observed between the naked glomerular basement membrane and retracted podocyte cell body. The major ultrastructural finding involving nonsclerotic glomerular capillaries is foot-process effacement, which may vary from mild to severe. In areas of foot-process effacement, there usually is loss of recognizable slit diaphragms and mat-like condensations of cytoskeletal filaments oriented parallel to the glomerular basement membrane. Thus, although the lesions of FSGS are focal and segmental at the light microscopic level, podocyte alterations are relatively diffuse and global at the electron microscopic level. Glomerular basement membranes of nonsclerotic capillaries usually are normal in thickness and texture. Extensive thinning or lamellation of glomerular basement membranes (typical of disorders of collagen IV) should be excluded.Proposed classification of histological variants of FSGsGeneral approachThe morphological categorization outlined next encompasses the spectrum of primar" @default.
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• W2000637899 title "Pathologic classification of focal segmental glomerulosclerosis: a working proposal" @default.
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