FSGS & HIV Nephropathy: Causes, Symptoms, Diagnosis & Pro...

Focal Segmental Glomerulosclerosis & HIV-Associated Nephropathy --- Focal Segmental Glomerulosclerosis (FSGS) Definition: Sclerosis affecting some but not all glomeruli (focal) and within affected glomeruli, only a portion of the capillary tuft is involved (segmental). Epidemiology: Most common cause of nephrotic syndrome in adults overall Most common cause of nephrotic syndrome in Black adults Can occur at any age Classification — Settings in Which FSGS Occurs: Type Examples --- --- Primary (idiopathic) Most common; cause unknown Secondary — associated conditions HIV, heroin addiction, sickle cell disease, morbid obesity Secondary — scarring of prior lesions IgA nephropathy, focal GN Adaptive response to nephron loss Unilateral renal agenesis, reflux nephropathy, hypertensive nephropathy Inherited forms Mutations in podocin (NPHS2), α-actinin 4, TRPC6 Pathogenesis: Considered a podocytopathy — primary injury directed at podocytes Mechanisms include: Inherited mutations in structural podocyte genes (podocin, α-actinin 4, TRPC6) → disruption of glomerular filtration barrier Circulating permeability factors (cytokines) — autoantibodies found in serum include antinephrin, antiannexin A2, anti-UCHL1 Mechanical stress — hypertension and obesity cause physical stress on podocytes Viral injury (HIV, parvovirus B19) — direct podocyte infection Drug-induced (pamidronate) These mechanisms → progressive podocyte loss → podocytopenia → increased unselective filtration through bare GBM → collapse and occlusion of capillary loops → adhesion to Bowman's capsule → segmental sclerosis Link with Minimal Change Disease: MCD and primary FSGS may represent a spectrum of the same podocyte injury — same circulating autoantibodies found in both Morphology: Light microscopy: Focal and segmental lesions — may involve only a minority of glomeruli; biopsy must contain sufficient glomeruli or lesions are missed Sclerotic segments show: collapse of capillary loops, increased matrix, segmental hyalinosis (plasma protein deposition along capillary wall) Lipid droplets and foam cells often present Non-sclerotic glomeruli may show increased mesangial matrix With progression: more glomeruli involved → global sclerosis → tubular atrophy and interstitial fibrosis Immunofluorescence: IgM and C3 in sclerotic areas and/or mesangium Electron microscopy: Diffuse effacement of foot processes in both sclerotic and non-sclerotic areas Focal detachment of epithelial cells and denudation of underlying GBM Collapsing Glomerulopathy — Morphologic Variant: Retraction and/or collapse of the entire glomerular tuft Proliferation and hypertrophy of glomerular visceral epithelial cells — characteristic feature Associated with: HIV-associated nephropathy, pamidronate toxicity, idiopathic Accompanied by prominent tubular injury — microcyst formation, interstitial inflammation Poor prognosis Clinical Features: Nephrotic syndrome or non-nephrotic proteinuria (acute or subacute onset) Hypertension, microscopic haematuria, azotemia commonly present at diagnosis Little tendency for spontaneous remission in idiopathic FSGS Variable response to corticosteroids Children have better prognosis than adults Prognosis: About 20% follow a rapid course — intractable proteinuria → renal failure within 2 years Factors associated with rapid progression: degree of proteinuria, renal insufficiency at diagnosis, collapsing histologic variant Tip variant has relatively good prognosis Recurrence after transplantation: 25–50% --- HIV-Associated Nephropathy Definition: A severe form of the collapsing variant of FSGS occurring in HIV-infected individuals. Epidemiology: Reported in 5–10% of HIV-infected individuals in older series More frequent in Black patients than White patients — linked to APOL1 risk alleles Incidence significantly reduced with antiretroviral therapy (ART) Pathogenesis: Not fully understood Primarily linked to G1/G2 risk alleles of APOL1 gene — explains racial disparity HIV can directly infect tubular epithelial cells and podocytes Direct viral injury → podocyte damage → collapsing FSGS pattern Morphology — Three Distinguishing Features: 1. High frequency of collapsing variant of FSGS 2. Striking focal cystic dilation of tubule segments filled with proteinaceous material + interstitial inflammation and fibrosis 3. Large numbers of tubuloreticular inclusions within endothelial cells on electron microscopy Also present in SLE Represent modifications of endoplasmic reticulum induced by circulating interferon-α Not present in idiopathic FSGS — therefore have diagnostic value on biopsy Clinical Features: Heavy proteinuria, often nephrotic range Rapid progression to renal failure Kidneys may be enlarged on imaging (unlike most chronic kidney diseases) Blood pressure often normal despite advanced disease Management: Antiretroviral therapy is the cornerstone — can stabilize or improve renal function ACE inhibitors/ARBs for proteinuria reduction --- Section 6: MPGN, Dense Depos