Focal Segmental Glomerulosclerosis, Secondary



Focal Segmental Glomerulosclerosis, Secondary


A. Brad Farris, III, MD





Key Facts


Terminology



  • FSGS secondary to imbalance of glomerula-functional capacity and demand


Etiology/Pathogenesis



  • Adaptive structural-functional response



    • Reduced nephron mass: Oligomeganephronia, reflux nephropathy, renal agenesis/dysplasia/ablation/necrosis, advanced renal disease


    • Normal nephron mass: HTN, obesity, atheroemboli/vaso-occlusion, sickle cell anemia, congenital heart disease, drugs (anabolic steroids, calcineurin inhibitors)


  • Glomerular HTN


Clinical Issues



  • Proteinuria and systemic HTN


Microscopic Pathology



  • Glomerulomegaly


  • FSGS in perihilar distribution


  • Compensatory tubular hypertrophy


  • Often arteriolar hyalinosis, arteriosclerosis


  • IF: Most notable for segmental IgM and C3


  • EM: Segmental podocyte foot process effacement (FPE)



    • Increased thickness of otherwise normal GBM


Top Differential Diagnoses



  • Primary FSGS


  • Segmental scars from GN


Diagnostic Checklist



  • Routinely assess glomerular size in biopsies


  • Normal is < 50% of diameter of 40x field







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.


TERMINOLOGY


Abbreviations



  • Secondary focal segmental glomerulosclerosis (2° FSGS)


Definitions



  • “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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • Incidence



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


Presentation



  • 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)


Treatment

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

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