Genetic risk of APOL1 and kidney disease in children and young adults of African ancestry

Abstract

Purpose of review: Understanding the genetic risk of APOL1 in children and young adults is important given the lifetime risk of hypertension and kidney disease among children of African descent. We review recent epidemiologic and biologic findings on the effects of APOL1 and kidney disease.

Recent findings: APOL1 in children and young adults is associated with hypertension, albuminuria and more rapid decline in kidney function and progression to end-stage kidney disease, especially among those with glomerular causes of kidney disease, and those affected by sickle cell disease or HIV. There are conflicting data on the APOL1 association with cardiovascular disease in children and young adults. APOL1 functions as part of the innate immune system. Podocyte expression of APOL1 likely contributes to the development of kidney disease. In cell culture and model organisms, APOL1 expression disrupts autophagic and ion flux, leads to defects in mitochondrial respiration and induces cell death.

Summary: APOL1 explains almost 70% of the excess risk of kidney disease in those of African descent, and is common in children with glomerular disease. An evolving understanding of the pathogenesis of APOL1-mediated kidney damage may aid in personalized medicine approaches to APOL1 attributable kidney disease.

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Figure 2

Possible pathways for APOL1 risk alleles leading to the development of hypertension and chronic kidney disease. Reprinted with approval received from Kidney International.

Figure 3. Biologic function of APOL1

Left: APOL1 contributes to innate immunity. Secreted APOL1 (depicted in red) circulates in a lipoprotein complex with high density lipoprotein (HDL). The complex is endocytosed by Trypanosoma, whereby APOL1 inserts into membranes and forms pores, leading to lysis of the parasite. Depicted is APOL1 insertion in lysosomes; APOL1 induced mitochondrial dysfunction may also contribute to trypanosomal death. APOL1 genetic variant G2 overcomes T.b. rhodesiense’s serum resistance factor and G1 protects against symptomatic T.b. gambiense infection. Right: APOL1 (depicted in red) localization in the kidney is debated, with different studies identifying plasma membrane, endoplasmic reticulum (ER), endosomal and mitochondrial localization. Expression of APOL1 G1 and G2 variants in cell and animal models has been shown to: 1) disrupt autophagic flux, 2) induce mitochondrial respiration defects with ATP depletion, 3) induce K efflux and stress response pathways (p38 kinase/stat 3). Expression of the variants are cytotoxic, and cell death variably induced by apoptosis, necrosis and inflammatory cell death (pyroptosis). An inducible transgenic mouse model expressing the APOL1 gene variants in podocytes exhibited cell death by pyroptosis, with increased IL-1beta expression and caspase 1 mediated activation of IL-1 beta.