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AMKD HAS A GENETIC CAUSE

APOL1-mediated kidney disease is a genetic disease caused by 2 risk variants of the APOL1 gene (G1/G1, G1/G2, or G2/G2) and a second hit.1 APOL1 risk variants cause damage to the podocytes and glomerular endothelial cells by creating channels in these cells, resulting in glomerular dysfunction and proteinuria.2-7 Not all people with 2 risk variants will develop AMKD.8 A second hit of infection or inflammation is required to trigger disease.1,9,10 The second hit that triggered the disease may not be obvious to the patient or physician.11
    Genome association studies have shown that AMKD has a genetic cause. See how much 2 APOL1 risk
    variants significantly increase the risk of proteinuric kidney diseases.
    Genome association studies have shown that AMKD has a genetic cause. See how much 2 APOL1 risk variants significantly increase the risk of proteinuric kidney diseases.
    Genome association studies have shown that AMKD has a genetic cause. See how much 2 APOL1 risk variants significantly increase the risk of proteinuric kidney diseases.

    (Some odds ratios have been rounded. See referenced literature for more detailed ranges)

    (Some odds ratios have been rounded. See referenced literature for more detailed ranges)

    (Some odds ratios have been rounded. See referenced literature for more detailed ranges)

    HIV-associated nephropathy12,13:

    29xto89x

    FSGS12:

    17x

    hypertension-attributed
    end-stage kidney disease14:

    7x

    Lupus nephritis with end-stage
    kidney disease or collapsing features15,16:

    2.5xto5x

    Chronic kidney disease without diabetes8:

    3xto4x

    AMKD occurs in people of African Ancestry

     

    Despite accounting for only ~13% of the US population, African Americans make up 30% of dialysis patients.17 While the factors driving this disparity are complex, it is now known a significant portion of kidney disease in nondiabetic African Americans is attributable to 2 APOL1 risk variants.18-21
    APOL1 risk variants developed in people living in Africa, because the risk variants provided enhanced protection against the parasite that causes human African trypanosomiasis.8 Trypanosomiasis and AMKD are like malaria and sickle cell disease: a gene conferred an evolutionary advantage against one disease and, at the same time, created a new disease burden.22

    genetics Of AMKD

    All people carry the APOL1 gene with two alleles. Risk alleles (or variants) are known as G1 and G2, whereas the G0 allele is not a risk allele. A patient with chronic kidney disease must have 2 APOL1 risk variants to be diagnosed with AMKD.1
    AMKD can present in CKD patients of African ancestry with compound heterozygous risk variants (G1/G2 or G2/G1), or homozygous risk variants (G1/G1 or G2/G2).1,23-26

    Click through the hypothetical scenario below to see the potential genetic implications of APOL1 inheritance in family members of the patient depicted.

    Genetic Implications for Your AMKD Patient and Their Family

    HYPOTHETICAL PATIENT

    An outline of a hypothetical AMKD patient and the disease’s genetic implications. The diagram shows two risk variants of the APOL1 gene (G1, G2).

    AMKD

    Nonrisk variant (G0) Risk variant (G1 or G2) AMKD

    Click the red arrow to see how the parents of your AMKD patient may have impacted their APOL1 status.

    Tap “next” to see how the parents of your AMKD patient may have impacted their APOL1 status.

    Tap “next” to see how the parents of your AMKD patient may have impacted their APOL1 status.

    Parents

    MOTHER

    An outline of the parents of a hypothetical AMKD patient and the disease’s genetic implications. The diagram shows the mother and father. The mother has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The father has one risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk carrier

    Low-Risk carrier

    Low-Risk
    carrier

    FATHER

    An outline of the parents of a hypothetical AMKD patient and the disease’s genetic implications. The diagram shows the mother and father. The mother has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The father has one risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk carrier

    Low-Risk carrier

    Low-Risk
    carrier

    Nonrisk variant (G0) Risk variant (G1 or G2) AMKD

    Because your AMKD patient has 2 APOL1 risk variants, each parent must have at least 1 APOL1 risk variant. In this example, neither parent has kidney disease and carries only 1 APOL1 risk variant.

    Click the red arrow to see the potential impact of APOL1 risk variants on your patient’s siblings.

    Tap “next” to see the potential impact of APOL1 risk variants on your patient’s siblings.

    Tap “next” to see the potential impact of APOL1 risk variants on your patient’s siblings.

    Siblings

    HYPOTHETICAL PATIENT

    An outline of the siblings of a hypothetical AMKD patient and the disease’s genetic implications. This diagram shows the AMKD patient and their three siblings. One sibling has two nonrisk variants (G0) and is a no-risk carrier. The second sibling has a nonrisk variant (G0), a risk variant (G2) of the APOL1 gene and is a low-risk carrier. The third sibling has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    AMKD

    SIBLING

    An outline of the siblings of a hypothetical AMKD patient and the disease’s genetic implications. This diagram shows the AMKD patient and their three siblings. One sibling has two nonrisk variants (G0) and is a no-risk carrier. The second sibling has a nonrisk variant (G0), a risk variant (G2) of the APOL1 gene and is a low-risk carrier. The third sibling has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    No-Risk

    SIBLING

    An outline of the siblings of a hypothetical AMKD patient and the disease’s genetic implications. This diagram shows the AMKD patient and their three siblings. One sibling has two nonrisk variants (G0) and is a no-risk carrier. The second sibling has a nonrisk variant (G0), a risk variant (G2) of the APOL1 gene and is a low-risk carrier. The third sibling has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk

    Sibling

    An outline of the siblings of a hypothetical AMKD patient and the disease’s genetic implications. This diagram shows the AMKD patient and their three siblings. One sibling has two nonrisk variants (G0) and is a no-risk carrier. The second sibling has a nonrisk variant (G0), a risk variant (G2) of the APOL1 gene and is a low-risk carrier. The third sibling has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk

    Nonrisk variant (G0) Risk variant (G1 or G2) AMKD

    Since the parents of your AMKD patient each have 1 APOL1 risk variant, there are 3 other possible inheritance scenarios for the patient’s siblings. All scenarios would result in a sibling inheriting 1 APOL1 risk variant, or none, from either parent.

    Click the red arrow to see the potential impact of APOL1 risk variants on your patient’s children.

    Tap “next” to see the potential impact of APOL1 risk variants on your patient’s children.

    Tap “next” to see the potential impact of APOL1 risk variants on your patient’s children.

    Children

    HYPOTHETICAL PATIENT

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    AMKD

    Partner

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk

    Child

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    High-risk

    Child

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk

    CHILD

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    High-risk

    Child

    An outline of a hypothetical AMKD patient, their family, and the disease’s genetic implications. The diagram shows the AMKD patient, their partner, and their four children. The partner has a risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The first child has two risk variants (G1) of the APOL1 gene and is a high-risk carrier. The second child has one risk variant (G1) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier. The third child has two risk variants (G2, G1) of the APOL1 gene and is a high- risk carrier. The fourth child has a risk variant (G2) of the APOL1 gene, a nonrisk variant (G0), and is a low-risk carrier.

    Low-Risk

    Nonrisk variant (G0) Risk variant (G1 or G2) AMKD

    Each child will inherit 1 APOL1 risk variant from your AMKD patient and have a 50% chance of inheriting a second APOL1 risk variant from the patient’s partner.

    Click the red arrow to learn when family members should be genetically tested for APOL1 risk variants.

    Tap “next” to learn when family members should be genetically tested for APOL1 risk variants.

    Tap “next” to learn when family members should be genetically tested for APOL1 risk variants.

    Test CKD Patients of African Ancestry for APOL1

    A hypothetical family tree of a patient with AMKD. The parents, siblings, partner, and children of the AMKD patient are included.

    AFRICAN ANCESTRY

    Kidney function decline
    Nonrisk variant (G0) Risk variant (G1 or G2) AMKD

    Remember: a second hit (e.g., HIV, COVID-19, interferons) is required to trigger AMKD. Therefore, it is important to consider genetic testing for family members with reduced kidney function.

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    FSGS: focal segmental glomerulosclerosis
    References: 1. Friedman DJ, Pollak MR. APOL1 and kidney disease: from genetics to biology. Annu Rev Physiol. 2020;82:323-342. doi:10.1146/annurev-physiol-021119-034345 2. Giovinazzo JA, Thomson RP, Khalizova N, et al. Apolipoprotein L-1 renal risk variants form active channels at the plasma membrane driving cytotoxicity. eLife. 2020;9:e51185. doi:10.7554/eLife.51185 3. Olabisi OA, Zhang JY, VerPlank L, et al. APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases. Proc Natl Acad Sci U S A. 2016;113(4):830-837. doi:10.1073/pnas.1522913113 4. Olabisi OA, Heneghan JF. APOL1 nephrotoxicity: what does ion transport have to do with it? Semin Nephrol. 2017;37(6):546-551. doi:10.1016/j.semnephrol.2017.07.008 5. Schaub C, Verdi J, Lee P, et al. Cation channel conductance and pH gating of the innate immunity factor APOL1 are governed by pore-lining residues within the C-terminal domain. J Biol Chem. 2020;295(38):13138-13149. doi:10.1074/jbc.RA120.014201 6. Chen TK, Tin A, Peralta CA, et al. APOL1 risk variants, incident proteinuria, and subsequent EGFR decline in blacks with hypertension-attributed CKD. Clin J Am Soc Nephrol. 2017;12(11):1771-1777. doi:10.2215/CJN.01180117 7. Ma L, Divers J, Freedman BI. Mechanisms of injury in APOL1-associated kidney disease. Transplantation. 2019;103(3):487-492. doi:10.1097/TP.0000000000002509 8. Friedman DJ, Pollak MR. APOL1 nephropathy: from genetics to clinical applications. Clin J Am Soc Nephrol. 2021;16(2):294-303. doi:10.2215/CJN.15161219 9. May RM, Cassol C, Hannoudi A, et al. A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19). Kidney Int. 2021;100(6):1303-1315. doi:10.1016/j.kint.2021.07.015 10. Nichols B, Jog P, Lee JH, et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015;87(2):332-342. doi:10.1038/ki.2014.270 11. Bruggeman LA, O’Toole JF, Sedor JR. APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function? Am J Physiol Renal Physiol. 2019;316(1):F1-F8. doi:10.1152/ajprenal.00426.2018 12. Kopp JB, Nelson GW, Sampath K, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129-2137. doi:10.1681/ASN.2011040388 13. Kasembeli AN, Duarte R, Ramsay M, et al. APOL1 risk variants are strongly associated with HIV-associated nephropathy in black South Africans. J Am Soc Nephrol. 2015;26(11):2882-2890. doi:10.1681/ASN.2014050469 14. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic APOL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841-845. doi:10.1126/science.1193032 15. Freedman BI, Langefeld CD, Andringa KK, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014;66(2):390-396. doi:10.1002/art.38220 16. Larsen CP, Beggs ML, Saeed M, Walker PD. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol. 2013;24(5):722-725. doi:10.1681/ASN.2012121180 17. Kidney disease statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed August 5, 2024. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease?dkrd=/health-information/kidney-disease/race-ethnicity 18. Hung AM, Assimon VA, Chen H-C, et al. Genetic inhibition of APOL1 pore-forming function prevents APOL1-mediated kidney disease. J Am Soc Nephrol. 2023;34(11):1889-1899. doi:10.1681/ASN.0000000000000219 19. Quiñones J, Hammad Z. Social Determinants of Health and Chronic Kidney Disease. Cureus. 2020;12(9):e10266. doi:10.7759/cureus.10266 20. Kao WH, Klag MJ, Meoni LA, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet. 2008;40(10):1185-1192. doi:10.1038/ng.232 21. Freedman BI, Cohen AH. Hypertension-attributed nephropathy: what’s in a name? Nat Rev Nephrol. 2016;12(1):27-36. doi:10.1038/nrneph.2015.172 22. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. doi:10.1038/nrdp.2018.10 23. Freedman BI, Burke W, Divers J, et al. Diagnosis, education, and care of patients with APOL1-associated nephropathy: a Delphi consensus and systematic review. J Am Soc Nephrol. 2021;32(7):1765-1778. doi:10.1681/ASN.2020101399 24. Freedman BI, Kopp JB, Sampson MG, Susztak K. APOL1 at ten years: progress and next steps. Kidney Int. 2021;99(6):1296-1302. doi:10.1016/j.kint.2021.03.013 25. Peralta CA, Bibbins-Domingo K, Vittinghoff E, et al. APOL1 genotype and race differences in incident albuminuria and renal function decline. J Am Soc Nephrol. 2016;27(3):887-893. doi:10.1681/ASN.2015020124 26. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502-517. doi:10.2215/CJN.05960616
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