Young BA, Blacksher E, Cavanaugh KL, Freedman BI, Fullerton SM, Kopp JB, Umeukeje EM, West KM, Wilson JG, Burke W, APOL1 Stakeholders Project: Apolipoprotein L1 Testing in African Americans: Involving the Community in Policy Discussions. Am J Nephrol DOI 10.1159/000502675
About 3.5 million African-Americans (A-A of West African ancestry) and some Hispanics possess two high alleles (G1 and/or G2) of apolipoprotein L1 (APOL1) at the APOL1 locus on chromosome 22. While protection from African trypanosomiasis is afforded by this genotype, possession of these risk alleles potentially increases the risk of progressive non-diabetic kidney disease, even among apparently healthy donors of a kidney for transplantation. Genetic testing for such allele is readily available at a modest cost. What then should be the role of APOL1 risk allele testing in clinical medicine including nephrology) in the emerging era of “precision medicine”?
This controversial topic was extensively discussed in a “stakeholders” Conference held in Bethesda, MD in March 2018, sponsored by the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK). The preparations for, the discussions held, and the recommendations emanating from this unique conference were summarized by Bessie Young and colleagues. While a great deal has been learned about APOL1 since its discovery in 2001 and its relationship to CKD beginning in 2010, it has not yet been possible to fully define the mechanisms underlying the connection between APOL1 risk alleles and CKD, although mitochondrial dysfunction and defective autophagy of glomerular podocytes may play prominent roles. It is also not possible to predict which subject with the high risk allele profile will actually develop overt disease. A multi-hit process is very likely. APOL1- associated nephropathy is usually a disease of podocytes and a collapsing form of focal segmental glomerulosclerosis (FSGS) is especially prominent. HIV infection is a vivid expression of the interaction of APOL1 risk alleles and an infectious disease.
After an extensive discussion of the ethics, unintended consequences, uncertainties, and potential medical benefits of testing for APOL1 risk alleles, the stakeholders came up with several statements:
- Routine testing of APOL1 alleles in asymptomatic individuals of A-A or Hispanic ancestry is not presently indicated
- APOL1 allele testing in patients with non-diabetic CKD is of uncertain value as it will have little or no impact on treatment decision making
- APOL1 allele testing in potential living donors of A-A (or Hispanic) ancestry is not universally supported and no consensus recommendation could be made
- APOL1 allele testing should be made available to those who chose to seek this information, but it should be carried out with careful counselling
- Broader education of the A-A (and Hispanic) communities is needed concerning APOL1
Interestingly, the interaction of low birth weight (and thus lower nephron endowment) and APOL1 risk alleles received little attention. Based on currently available data, I would strongly advise a potential living A-A donor who has knowledge of a low-birth weight, to undergo APOL1 risk allele testing, and if two risk alleles are present, my advice would be to not proceed with donation.
In general, this topic is ripe for aggressive basic and clinical research targeted at identifying the mechanism(s) of podocyte injury, susceptibility and multi-hit factors, and discovery of effective preventative and treatment strategies. The stakeholders identified and endorsed the need for continued broad discussion as new data emerge. I agree. The paper describing the stakeholders conference is a valuable starting point for this ongoing discussion. I recommend reading it in its original form to everyone who deals with these subjects and patients.
Quoted Karger Article