Focal Segmental Glomerulosclerosis Classification



Focal Segmental Glomerulosclerosis Classification


A. Brad Farris, III, MD








Light microscopy of a case of collapsing FSGS shows a glomerulus with areas of sclerosis image (silver stain).






Immunofluorescence for C3 shows a predominantly segmental pattern of staining in the mesangium and in areas of glomerular capillary loop collapse in a case of FSGS.


TERMINOLOGY


Abbreviations



  • Focal segmental glomerulosclerosis (FSGS)


Definitions



  • Group of podocytopathies (of varied etiology) that share the feature of focal segmental glomerulosclerosis, typically with moderate to heavy proteinuria


CLASSIFICATION SYSTEMS


Morphologic Classification



  • Based on glomerular morphology categories defined by the Columbia classification



    • Collapsing variant


    • Glomerular tip lesion


    • Cellular variant


    • Perihilar variant


    • FSGS not otherwise specified (NOS)


Etiologic Classification



  • Based on identified causes of FSGS: Some correspondence with morphologic variants


  • Familial/genetic



    • Increasing number of genes identified



      • β-integrin mutations


      • α-actinin-4 mutations


      • WT-1 mutations


      • Podocin mutations


  • Drug-induced



    • Pamidronate


    • Heroin (heroin nephropathy)


    • Lithium


    • Interferon-α and -β


  • Virus



    • HIV (HIV-associated nephropathy [HIVAN])


    • Parvovirus B19


  • Adaptive, structural-functional responses



    • Secondary to congenital or acquired reduction in nephrons relative to body mass



      • Oligomeganephronia, unilateral renal agenesis, renal dysplasia, reflux nephropathy, hypertension, anabolic steroids


  • Vascular



    • Hypertension


    • Thrombotic microangiopathy


    • Atheromatous emboli


    • Calcineurin inhibitor toxicity


  • Idiopathic



    • Usual primary form, either NOS or collapsing variant


    • Plasma factor responsible, identity sought


EPIDEMIOLOGY


Incidence



  • Most common cause of nephrotic syndrome in adults


  • Apparent increased incidence over past 2 decades



    • ˜ 25% of adult nephropathies, compared with < 10% 20 years ago


History



  • Focal and segmental glomerular hyalinization and capillary loop degradation described by Fahr in 1925


  • Arnold Rich described juxtamedullary glomerulosclerosis in children dying with nephrotic syndrome in 1957


  • FSGS was recognized as a distinct entity by International Study of Kidney Diseases in Children in the 1970s


  • Collapsing variant was recognized by Mark Weiss in the 1980s and later as usual pattern of HIVAN



ETIOLOGY/PATHOGENESIS


Pathogenesis



  • Now classified as podocytopathies



    • Familial podocyte protein defects



      • Mutations in TRPC6, a calcium-permeable cation channel, lead to abnormal podocyte function and hereditary FSGS


      • FSGS with defects in α-actinin-4 (ACTN4), podocin (NPHS2, defective in corticosteroid-resistant nephrotic syndrome), and nephrin (NPHS1, defective in congenital nephrotic syndrome of the Finnish type) are relatively rare familial forms of FSGS


      • Nephrin interacts with CD2-associated protein (CD2AP), and podocin interacts with the nephrin-CD2AP complex


      • Mutations in WT1 transcription factor, which regulates several podocyte genes, lead to FSGS syndromes (Denys-Drash and Frasier syndromes)


    • Abnormal cytokines are now thought to play major role in idiopathic FSGS development



      • Circulating factor identified in patients who have recurrent FSGS after transplant, typically occurring within months after transplantation


    • Podocyte dysregulation/dysfunction



      • Differentiation markers of podocytes (e.g., Wilms tumor WT-1 protein, podocalyxin, and synaptopodin) disappear in collapsing FSGS and HIVAN


    • Loss of podocytes leads to adhesions


    • Risk factor in African descent is APOL1 gene


  • Relationship with minimal change disease (MCD) unclear



    • Dystroglycan, an integral component of the GBM, is decreased in MCD but maintained in nonsclerotic segments in FSGS


CLINICAL IMPLICATIONS


Prognosis



  • Generally poor with substantial fraction progressing to end-stage renal disease


Clinical Presentation



  • Proteinuria


  • Nephrotic syndrome


  • Azotemia


Treatment



  • Plasmapheresis has been used to induce remission in some patients with recurrent FSGS


MACROSCOPIC FINDINGS


General Features



  • Pale yellow kidneys due to lipid in tubules


MICROSCOPIC FINDINGS


General Features



  • Glomeruli



    • Sclerosis involves some glomeruli (focal) and only a portion of glomerular tuft (segmental)



      • Diagnosed even when only 1 glomerulus involved


      • Global sclerosis may be an incidental finding and is not particularly useful in making diagnosis of FSGS


    • Adhesions (synechiae) of glomerular tuft to Bowman space often accompany segmental sclerosis and are often seen early in sclerosis process


    • Hyalinosis



      • Portion of glomerular involvement has a smooth, glassy (hyaline) appearance


      • Typically thought to occur from insudation of plasma proteins


    • Increased matrix with obliteration of glomerular capillary lumen


    • FSGS has zonal distribution, beginning in corticomedullary (juxtamedullary) junction (CMJ)



      • Important to note whether sampling of CMJ is included


    • Glomerular hypertrophy often accompanies FSGS



      • Potential surrogate marker in cases without sampled segmental sclerosis


  • Tubules



    • Tubular epithelial cells contain PAS(+) reabsorption droplets due to glomerular proteinuria


    • Tubular atrophy is typically only focal early in course of FSGS



      • TBM thickened in areas of atrophy


      • Tubular atrophy may be more prominent late in course of the disease


    • Tubulointerstitial changes pronounced in collapsing variants of FSGS and in HIVAN



      • Cystic dilatation and more prominent lymphoid infiltrate


  • Interstitium

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Focal Segmental Glomerulosclerosis Classification

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