Molecular pathology selected abstracts

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Relevance of testing for APOL1 in focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis describes a pattern of kidney injury that causes nephrotic syndrome in approximately 40 percent of adult and 20 percent of pediatric patients. Renal podocytes are specialized cells that maintain the kidney’s ability to filter blood. Podocyte damage and dysfunction due to a variety of mechanisms causes nephrotic syndrome (inappropriate loss of blood proteins in urine), which can lead to significant morbidity. Earlier studies identified the gene apolipoprotein L1 (APOL1), which is associated with an increased risk for focal segmental glomerulosclerosis (FSGS) and other types of kidney disease in people of African ancestry versus European ancestry. Subsequent studies found a set of risk variants (G1 and G2) that confer up to 10-fold greater odds of FSGS-attributed kidney failure. It is estimated that more than 3 million people of African ancestry in the United States carry two risk variants. APOL1 protein is secreted into the blood to form a lytic factor that protects against the parasitic protozoa trypanosomes. Subspecies of trypanosomes present in sub-Saharan Africa developed mechanisms that inactivate APOL1. This led to APOL1 G1 and G2 variants, which inactivated the resistance-associated factors. This adaptation took place after people began migrating from Africa to other continents, which is why these variants occur mainly in African people (primarily West Africans) and in those of recent African descent. Renal podocytes appear to be vulnerable to the damaging effects of G1 and G2 variants, possibly via similar means by which trypanosomes are killed. Yet APOL1 testing has not been widely adopted in the clinical setting, as some believe there is a lack of definitive evidence about the causal link between APOL1 risk variants and health outcomes. The ongoing National Institutes of Health-funded APOLLO study is prospectively assessing the effects of APOL1 renal-risk variants on the outcomes of kidney donors and kidney transplant recipients of recent African ancestry. The New England Journal of Medicine (Egbuna O, et al. 2023;388:969–979) reported data on a single-group, open-label, phase 2a clinical study of inaxaplin, a selective oral, small-molecule inhibitor of APOL1, in participants with two APOL1 pathogenic variants and biopsy-proven FSGS. The primary efficacy outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13. The study showed a rapid and approximately linear mean change in the urinary protein-to-creatinine ratio of −47.6 percent at week 13. In an analysis that included all 16 study participants, regardless of whether they adhered to inaxaplin treatment, the mean change in the urinary protein-to-creatinine ratio at week 13 was −44 percent. One participant did not have a reduction. Preclinical in vitro and in vivo mouse studies were also reported and showed that inaxaplin bound directly to the APOL1 protein, inhibited APOL1 channel function, and reduced proteinuria in a transgenic mouse model of APOL1-mediated kidney disease. The authors noted the limitations of their small-cohort, short-duration, nonplacebo-controlled study but reported that an ongoing phase 2–3 placebo-controlled trial is addressing these concerns. If the trial proves successful and the findings of the APOLLO study affirm the clinical relevance of APOL1, demand for APOL1 clinical testing will likely increase.

Egbuna O, Zimmerman B, Manos G, et al. Inaxaplin for proteinuric kidney disease in persons with two APOL1 variants. N Engl J Med. 2023;388(11):969–979.

Correspondence: Dr. Ogo Egbuna at ogo_egbuna@vrtx.com

Smith JD, Agrawal A, Wicklund C, et al. Implementation of a culturally competent APOL1 genetic testing programme into living donor evaluation: A two-site, non-randomised, pre-post trial design. BMJ. 2023;13. doi:10.1136/bmjopen-2022-067657

Correspondence: Dr. Elisa Gordon at elisa.gordon@vumc.org

Williams WW, Ingelfinger JR. Inhibiting APOL1 to treat kidney disease. N Engl J Med. 2023;388(11):1045–1049.

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