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370) A 34-year-old African American man is found to have renal insufficiency and nephrotic range proteinuria on routine evaluation. A renal biopsy is performed and reveals the glomerular lesion shown in the image. Which of the following statements is TRUE?

Variations in the apolipoprotein L1 (APOL1) gene have more recently been identified as risk factors for the development of this lesion in African American patients. The glomerular endothelial cell is the primary target of injury in this condition. Electron microscopy is likely to reveal granular immune-type, electron-dense deposits. Urinalysis and urine microscopy show many red blood cells (RBCs) with RBC casts. This condition almost never recurs in an allograft after renal transplantation.

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• Focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular injury in which sclerosis initially affects a subset of glomeruli (i.e., focal) and involves a portion of the glomerular tuft (i.e., segmental).

• Podocyte injury is a feature common to all types of FSGS. Podocyte injury leads to effacement of podocyte foot processes, which are critical to the integrity of the glomerular filtration barrier.

• FSGS has long been known to have an increased incidence in African Americans. More recently, variations in the APOL1 gene have been found to confer a considerable portion of this increased risk. The APOL1 variants that are present at increased frequency in patients of African descent appear to help the host fight certain subspecies of trypanosomes (the parasites that cause sleeping sickness). Being a heterozygote for certain APOL1 variants is protective against infection, but being a homozygote causes an increased risk of FSGS and end-stage renal disease.

• Patients with end-stage renal disease as a result of primary FSGS who undergo renal transplantation have a significant rate of recurrent disease in the allograft (40%). FSGS recurrence can be seen within hours after transplantation; this provides evidence that in some patients a circulating permeability factor is responsible for podocyte injury. In early recurrence, plasmapheresis to remove the circulating factor may induce remission.

• A classification of FSGS into five histologic variants has been proposed. The image in this question demonstrates FSGS not otherwise specified. The other variants are perihilar FSGS (most of the lesions of FSGS are located at the glomerular vascular pole), cellular FSGS (characterized by expansile “cellular” lesions typically containing foam cells and leukocytes), glomerular tip lesion (defined by the location of FSGS lesions at the tubular pole of glomeruli), and collapsing FSGS (showing implosive glomerular tuft collapse with hyperplasia and hypertrophy of overlying epithelial cells).

D’Agati VD, Fogo AB, Bruikn JA, et al: Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 2004;43(2):368-382.

D’Agati VD, Kaskel FJ, Falk RJ: Focal segmental glomerulosclerosis. N Engl J Med 2011;365(25):2398-2411.

Genovese G, Friedman DJ, Ross MD, et al: Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010;329(5993):841-845.

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Anatomic Pathology: Renal Pathology

370) A 34-year-old African American man is found to have renal insufficiency and nephrotic range proteinuria on routine evaluation. A renal biopsy is performed and reveals the glomerular lesion shown in the image. Which of the following statements is TRUE?

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