Almost all of this increased risk is associated with two DNA sequence variants in the APOL1 gene designated G1 and G2. The G1 and G2 alleles are mutually exclusive, never occurring on the same copy of the chromosome, and therefore these risk alleles show an autosomal recessive pattern of inheritance. The inheritance of two risk alleles, either G1/G1, G2/G2, or G1/G2, are required to confer the additional risk of kidney disease, which is characterized by a 7- to 10- increased risk for hypertension-associated end-stage renal disease; 10- to 17- fold increased risk for focal segmental glomerulosclerosis, and a 29- fold increased risk for HIV-associated nephropathy. APOL1 risk variants are also associated with progression to ESRD in African American patients with lupus nephritis. There is no statistically significant difference between the risk of kidney disease in individuals with no risk alleles as compared to those with only one risk allele. The APOL1 G1 and G2 risk alleles are very common in African Americans (30% allele frequency) due to evolutionary selection for their protective effect against parasitic trypanosome infection (African sleeping disease) but are rare in non- African chromosomes.

Findings on renal biopsy which suggest the presence of APOL1 risk alleles include collapsing glomerulopathy in patients with nephrotic syndrome. Histopathologic findings in patients with chronic kidney disease which suggest the presence of APOL1 risk alleles include solidified glomeruli, thyroidization-type tubular atrophy, and microcystic tubular dilatation.

Reasons for Testing:

• Determining risk status in an African American patient, particularly in patients with SLE, membranous glomerulopathy, or HIV
• Patient being considered for kidney donation
• Determination of carrier status in a family member
• Biopsy findings that suggest APOL1 risk alleles (see above)