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Mechanisms of Injury in APOL1-associated Kidney Disease

Ma, Lijun, MD, PhD1; Divers, Jasmin, PhD2; Freedman, Barry I., MD1

doi: 10.1097/TP.0000000000002509
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Background. An improved understanding of the pathogenesis in apolipoprotein L1 (APOL1) gene–associated chronic kidney disease (CKD) arose from observations in kidney transplantation. APOL1 genotyping could soon improve the safety of living kidney donation in individuals with recent African ancestry and alter the allocation of deceased donor kidneys.

Methods. This article reviews the potential mechanisms that underlie development of APOL1-associated nephropathy. Roles for circulating APOL1 protein versus intrinsic renal expression of APOL1 are discussed, as well as the requirement for modifying genetic and/or environmental factors.

Results. Abundant evidence supports local kidney production of APOL1 renal-risk variant protein in the development of nephropathy; this is true in both native kidney disease and after renal transplantation. Only a minority of kidneys from individuals with APOL1 high-risk genotypes will develop CKD or manifest shorter renal allograft survival after transplantation. Therefore, modifying factors that explain why only a subset of kidneys develops nephropathy remain critical to identify. It appears likely that environmental exposures, as opposed to major APOL1-second gene interactions, will prove to be stronger modifiers of the risk for nephropathy.

Conclusions. The evolving understanding of the pathogenesis in APOL1-associated nephropathy will identify biomarkers predicting nephropathy in individuals at high genetic risk and lead to novel therapies to prevent or slow native CKD progression and prolong survival of transplanted kidneys. In the interim, the National Institutes of Health–sponsored “APOL1 Long-term Kidney Transplantation Outcomes” Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation.

1Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC.

2Division of Public Health Sciences, Department of Biostatistical Sciences; Wake Forest School of Medicine, Winston-Salem, NC.

Received 12 September 2018. Revision received 8 October 2018.

Accepted 21 October 2018.

Support: NIH R01 DK084149 (BIF), R01 DK070941 (BIF), R01 MD009055 (JD & BIF), U01 DK116041 (BIF).

L.M., J.D., and B.I.F. all contributed to the research design, preparation of the article, and performance of the research contained in the article.

Wake Forest University Health Sciences and B.I.F. have rights to an issued United States patent related to APOL1 genetic testing (www.apol1genetest.com). B.I.F. is a consultant for Ionis and AstraZeneca Pharmaceuticals.

Correspondence: Barry I. Freedman, MD, Internal Medicine-Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (bfreedma@wakehealth.edu).

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