Focal Segmental Glomerulosclerosis, Secondary

Focal Segmental Glomerulosclerosis, Secondary

A. Brad Farris, III, MD

Secondary FSGS is often manifested by glomerulomegaly image and a perihilar distribution of the glomerular adhesions image. This case also shows interstitial foam cells image and tubular atrophy image.

High-power view of a silver stain in a 21-year-old man with nephrotic syndrome and perihilar segmental GS shows that intracapillary hyaline image is present in the segmental sclerosis lesion.



  • Secondary focal segmental glomerulosclerosis (2° FSGS)


  • “Primary” and “secondary” FSGS terminology confusing since specific causal mechanisms are being identified in both

  • Here, 2° FSGS is defined as FSGS that arises as maladaptive response to loss of nephrons or increased demand, probably due to increased filtration/perfusion of glomeruli and podocyte stress


Adaptive Structural-Functional Response

  • Imbalance between glomerular capacity and metabolic demands

    • Thought to act through glomerular hypertension (HTN), increased filtration, and podocyte stress

    • ↑ glomerular capillary pressures and flow rates

  • Arises from several pathways

    • Failure to develop normal number of glomeruli

      • Unilateral renal agenesis, dysplasia, oligomeganephronia, and other congenital renal developmental diseases

    • Acquired disease that causes ↓ of functional nephrons

      • Sequelae of chronic renal disease of any etiology that destroys nephrons: Final common pathway

      • Reflux nephropathy, Alport syndrome, HTN, cortical necrosis, and virtually any other chronic renal disease

    • Normal number of glomeruli but increased “demand”

      • Obesity, body builders, anabolic steroids, possibly HTN

Specific Mechanisms

  • Obesity-related glomerulopathy (ORG)

    • Receptor for advanced glycation end products (RAGE) may mediate obesity-associated renal injury

    • RAGE may also be important to diabetes, doxorubicin-induced nephropathy, HTN, lupus nephritis, ischemic renal injury, and renal amyloidosis

    • RAGE antagonism may be useful in treating chronic kidney disease

  • Calcineurin inhibitors (CNIs)

    • Arteriolar constriction leads to variable glomerular perfusion

    • Particularly important in renal transplant recipients since FSGS can sometimes be ascribed to CNIs

  • Anabolic steroids used in bodybuilding

    • Possibly due to direct nephrotoxic effect of anabolic steroids and ↑ lean body mass

  • Sleep apnea

    • Hypoxia leads to sympathetic nervous system activation and stimulates renin-angiotensin system

  • Unilateral renal agenesis

    • Higher risk of FSGS than general population

      • Loss of 1 kidney later in life does not appear to cause same risk for FSGS in remaining kidney

      • When 1 kidney and portion of other are lost in adults, ↑ risk of FSGS development

Pathologic Consequences

  • Glomerular hypertrophy

    • ↑ diameter and number of mesangial cells

    • Thickened GBM

    • Relative deficiency of podocytes, which have limited replicative ability

  • Segmental glomerular capillary scars and adhesions to Bowman capsule

    • Classically, adhesion and hyaline in perihilar region

    • Known as the “hilar” variant of FSGS

Animal Models

  • 5/6 nephrectomy in rats

    • Widely used model

    • Removal/infarction of upper and lower pole of kidney followed by contralateral nephrectomy

    • Results in HTN, glomerulomegaly, and, later, FSGS over 8-12 weeks with proteinuria and loss of renal function

    • Ameliorated by inhibitors of renin-angiotensin system (angiotensin II receptor inhibitors)

    • Strain differences in rats and mice



  • Incidence

    • Coincident with ↑ in obesity incidence: Apparent ↑ incidence of ORG


  • Proteinuria

    • Proteinuria is often > 3.5 g/d but usually without hypoalbuminemia, hypercholesterolemia, and edema

    • Specifically, ORG shows lower incidence of nephrotic syndrome than idiopathic FSGS

  • Renal dysfunction

    • Most have ↑ serum creatinine and ↓ GFR preceding development of nephrotic proteinuria

      • ORG is notable exception since it may have ↑ GFR (supernormal, > 120 mL/min) 2° to hyperfiltration/overwork state caused by ↑ ratio of body mass to renal mass

  • Hypertension

  • ORG patients typically have a BMI > 30

    • BMI 30-34.9, grade 1 obesity; BMI 35.0-39.9, grade 2 obesity; and BMI ≥ 40, grade 3 obesity (morbid obesity)


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

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