APOL1 testing in clinical practice and opportunities for new therapies

The spectrum of kidney diseases caused by variation in the apolipoprotein L1 ( APOL1 ) gene was identified in 2010 among patients with recent African ancestry. In the United States, inheriting two APOL1 risk variants (high-risk genotypes) markedly increases risk for solidified glomerulosclerosis, focal segmental glomerulosclerosis, collapsing glomerulopathy, lupus nephritis, and sickle cell nephropathy. Kidneys from African American deceased donors with APOL1 high-risk genotypes also fail more rapidly after transplant. One risk variant increases nephropathy risk in Africa. This review focuses on novel therapies targeting APOL1 and the changing landscape of APOL1 genotyping in patients at risk for APOL1 -mediated kidney disease (AMKD).

Renin-angiotensin-aldosterone system blockade and sodium-glucose cotransporter 2 inhibitors slow nephropathy progression but are not curative. Medications directly targeting APOL1 mRNA and blocking APOL1 protein effects are undergoing clinical trials in AMKD, including APOL1 small molecule inhibitors, an APOL1 antisense oligonucleotide, and a Janus kinase (JAK) signaling inhibitor to reduce APOL1 expression. Early results are promising and provide hope for well tolerated and effective therapies. If successful, more patients will need to be considered for APOL1 genotyping, and our approach to diagnosing and treating chronic kidney disease in populations with recent African ancestry will change dramatically.

Mechanisms of APOL1 risk variant nephrotoxicity remain unclear; nonetheless, specific therapies for AMKD show great promise and may improve understanding of disease processes. With ongoing clinical trials and the potential for effective AMKD treatments, more widespread APOL1 genotyping will likely be needed.