Kidney nontumor / medical renal

• Recently proposed clinicopathological classification divided FSGS based on etiology into 3 categories
  • Primary FSGS
  • Secondary FSGS
  • Genetic FSGS
• In primary FSGS, circulating permeability factors such as soluble urokinase receptor (suPAR), cardiotrophin-like cytokine 1 and angiopoietin-like 4 (Angptl4) have been proposed as the initiating factors of podocyte injury in primary FSGS (Nat Rev Nephrol 2016;12:768)
• Recent description of autoantibodies (e.g., antinephrin) in patients with nephrotic syndrome, especially in MCD forms, suggested an autoimmune etiology for these forms, adding evidences to the link of MCD and primary FSGS (J Am Soc Nephrol 2022;33:238)
• In secondary FSGS, different etiologies are recognized that either cause an excessive stress to the glomerular filtration barrier (maladaptive) or cause podocyte damage
  • Maladaptive forms can be due to systemic hypertension, obesity, increased lean body mass, renal vaso-occlusive disease, cyanotic congenital heart disease, sickle cell anemia, reduced number of functioning nephrons (e.g., unilateral renal agenesis, renal dysplasia, oligomeganephronia, glycogen storage disease, low birth weight) (Biomed Res Int 2016;2016:1630365, J Am Soc Nephrol 2018;29:759)
  • Infection associated forms have been described in association with HIV (established), CMV (probably), parvovirus B19 (possibly), EBV (possibly), HCV (possibly), hemophagocytic syndrome (possibly), COVID-19 (established) (Biomed Res Int 2016;2016:7351964)
  • Drug induced forms are secondary to pamidronate, direct acting antiviral therapy (ledipasvir, sofosbuvir), mTOR inhibitors, calcineurin inhibitors, anthracyclines, heroin (adulterants), lithium, interferon, anabolic steroids (Clin J Am Soc Nephrol 2015;10:1291)
• In genetic FSGS, > 50 genes have been described as potential sites of mutation responsible for monogenic forms of FSGS
  • > 90% of childhood and adolescence onset cases have mutations involving a limited number of genes: NPHS1, NPHS2, WT1, LAMB2, PLCE1, COL4A5 and SCARB2 (Clin Kidney J 2018;11:179)
• Genetic predisposing factor for the development of FSGS, especially in African American ethnicity, is recognized in APOL1 polymorphisms, for which the trigger of environmental factors (e.g., viral infection) most frequently leads to collapsing forms (J Am Soc Nephrol 2011;22:2129)

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Contributed by Vincenzo L’Imperio, M.D. and Giorgio Cazzaniga, M.D.

Contributed by Vincenzo L’Imperio, M.D. and Giorgio Cazzaniga, M.D.

Which of these focal segmental glomerulosclerosis (FSGS) variants is considered the most favorable in terms of outcome?

1. FSGS, cellular variant
2. FSGS, collapsing variant
3. FSGS, perihilar variant
4. FSGS, tip variant

D. FSGS, tip variant. The tip variant of FSGS is considered the most favorable in terms of outcome (BMC Nephrol 2014;15:52). Answer B is incorrect because the collapsing variant has a worse prognosis, especially in the Black population (StatPearls: Focal Segmental Glomerulosclerosis [Accessed 25 April 2023]). Answers C and D are incorrect because other variants show variable outcomes.

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Reference: Focal segmental glomerulosclerosis - general

Which electron microscopy lesion of focal segmental glomerulosclerosis is shown in the image above?

1. Microtubular structures
2. Podocyte effacement
3. Subendothelial immune complex deposits
4. Subepithelial humps

B. Podocyte effacement. The electron micrograph shows a low power view of a glomerulus with extensive foot process effacement of podocytes along the capillary walls. Answer D is incorrect because subepithelial humps are haystack shaped electron dense deposits typical of infection related glomerulonephritis, not usually present in FSGS. Answer A is incorrect because microtubular structures are generally seen in cryoglobulin related glomerulonephritis within the deposits. Answer C is incorrect because subendothelial immune complex deposits can be seen between endothelial cells and GBM in a variety of immune complex glomerulonephritis (e.g., lupus nephritis).

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Reference: Focal segmental glomerulosclerosis - general

Which light microscopy lesion is shown in the image above?

1. FSGS, cellular variant
2. FSGS, collapsing variant
3. FSGS, perihilar variant
4. FSGS, tip variant

D. FSGS, tip variant. FSGS, tip variant is characterized by at least 1 segmental lesion involving the tip domain (outer 25% of tuft next to origin of proximal tubule). Answer A is incorrect because the cellular variant has at least 1 glomerulus with segmental endocapillary hypercellularity occluding lumina, with or without foam cells and karyorrhexis. Answer B is incorrect because the collapsing variant has at least 1 glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia. Answer C is incorrect because the perihilar variant has at least 1 glomerulus with perihilar hyalinosis, with or without sclerosis in > 50% of glomeruli.

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Reference: Focal segmental glomerulosclerosis - general