Mechanisms of injury in APOL1-associated kidney disease

Background An improved understanding of the pathogenesis in apolipoprotein L1 gene (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 manuscript 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" (APOLLO) Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation. Support: NIH R01 DK084149 (BIF), R01 DK070941 (BIF), R01 MD009055 (JD & BIF), U01 DK116041 (BIF) Disclosures: Wake Forest University Health Sciences and Barry Freedman have rights to an issued United States patent related to APOL1 genetic testing (www.apol1genetest.com). Dr. Freedman is a consultant for Ionis and AstraZeneca Pharmaceuticals. Author contributions: LM, JD and BIF all contributed to the research design, preparation of the manuscript and performance of the research contained in the manuscript. Correspondence: Barry I. Freedman, MD, Internal Medicine – Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157 USA. Email: bfreedma@wakehealth.edu. Phone: 336-716-6461. Fax: 336-716-4318 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2DazQ9I