APOL1 and Nephropathy Progression in Populations of African Ancestry☆,☆
Section snippets
Classifying Kidney Disease in Populations of African Ancestry: Hypertension-Attributed Nephropathy Resides in the Spectrum of FSGS
High blood pressure is reported by nephrologists as the inciting cause of ESKD in approximately 35% of African Americans initiating renal replacement therapy in the United States12; however, this clinical diagnosis frequently is incorrect.13, 14 APOL1-associated forms of glomerulosclerosis are present in the majority of African Americans labeled with hypertension-attributed ESKD and hypertension-attributed nephropathy.15, 16 Recent genetic analyses in African American Study of Kidney Disease
HIV-Associated Collapsing Glomerulopathy
Of all common kidney diseases, HIVAN shows the most marked African American to European American disparity in incidence rates.25 In the early days of the acquired immune deficiency syndrome (AIDS) epidemic, AIDS was reported as a cause of FSGS in African Americans residing in the northeastern and southeastern United States.26 Subsequent reports from the West Coast failed to detect this association, prompting many to attribute FSGS on the East Coast to the effects of intravenous drug use, not
Sickle Cell Disease–Associated Nephropathy, Progressive IgA Nephropathy, and Lupus Nephritis
Variations in APOL1 (and MYH9) recently was shown to underlie risk for sickle cell disease (hemoglobin SS)-associated nephropathy in African Americans.31 In addition, individuals with sickle cell trait (hemoglobin AS) do not face an increased risk of nephropathy, before or after adjustment for APOL1.32 A report in Han Chinese with progressive IgA nephropathy also detected MYH9 association.11
Our initial report in small numbers of African Americans with lupus nephritis (LN)-associated ESKD
APOL1 Associations with Mild Nephropathy
Although African Americans have higher rates of severe kidney disease relative to European-derived populations,12 they do not appear to have excess rates of early nephropathy.36 This fact, along with the markedly weaker APOL1 association with milder forms of nephropathy, strengthens the hypothesis that APOL1 is a risk factor for nephropathy progression.
Friedman et al37 evaluated African Americans from the large population-based Dallas Heart Study with a mean age of 44.8 years (SD, 10.3 y).
Genetic Prediction of Outcomes after Kidney Transplantation
APOL1 variation appears to underlie the poorer allograft survival rates in kidney transplants from deceased African American donors, relative to European Americans.39 As for the caveolin 1 and the drug transporter P-glycoprotein genes (encoded by the adenosine triphosphate-binding cassette, subfamily B, member 1 gene) on kidney allograft survival transplant outcomes, effects are associated with donor genotypes, not those of recipients.40, 41
APOL1 risk variants were genotyped in 106 African
Second Hits and Modifying Factors
All individuals inheriting two APOL1 risk variants will not develop nephropathy. For example, HIVAN develops in approximately 50% of untreated African Americans with HIV infection.9 A smaller percentage of non–HIV-infected individuals with two APOL1 risk variants are expected to develop kidney disease. Therefore, modifying factors such as environmental exposures or second gene interactions likely are involved in APOL1-associated nephropathy.46, 47, 48 We believe that different modifiers likely
Disease Pathogenesis
Mechanisms underlying the development of progressive nephropathy in individuals with two APOL1 risk variants remain unknown (Table 3). There appears to be a consensus developing that APOL1 is expressed in podocytes and ApoL1 protein is present in these cells.51, 52, 53 It is less clear whether the gene is expressed in renal tubular cells, glomerular endothelial cells, and intimal and medial cells of small intrarenal blood vessels. Only a few small studies have been performed to date and results
Response to Treatment
APOL1-associated nephropathies are often severe, lead to rapid progression of chronic kidney disease, and present with earlier ages at onset of ESRD.57, 58 Although little is known about response rates to standard therapies for FSGS, Kopp et al9 reported that after 8 or more weeks of steroid therapy, African American patients with FSGS and two APOL1 risk variants had a 29% (12 of 42) response rate, relative to 33% (5 of 15) of patients with 0 or 1 risk variants (P > .5). FSGS associated with
Conclusions
Much of the existing epidemiology regarding nondiabetic ESKD in African Americans was based on the assumption that mild to moderate essential hypertension commonly initiated nephropathy. Instead, it is now clear that a spectrum of APOL1-associated proteinuric and nonproteinuric disorders manifesting as FSGS and FGGS with interstitial and vascular changes exists in those previously labeled with hypertension-attributed nephropathy. These disorders relate to selection for trypanolytic gene
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Cellular and molecular heterogeneity in systemic lupus erythematosus
2021, Seminars in ImmunologyCitation Excerpt :These associations persisted despite adjustment for socioeconomic and geographical variables [12–14] implying the significant role of intrinsic biological factors. In fact, the distribution of protective and risk alleles varies across ancestral groups [15–25] indicating that distinct pathogenic mechanisms may be favored perhaps explaining the higher resistance to treatment [26–28]. In a minority of patients, SLE is associated with rare but highly penetrant single gene mutations [29].
Social determinants of racial and socioeconomic disparities in CKD and ESRD
2020, Psychosocial Aspects of Chronic Kidney Disease: Exploring the Impact of CKD, Dialysis, and Transplantation on PatientsChronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes
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2017, Kidney International SupplementsCitation Excerpt :A better understanding of these interactions will provide insights into important patient subgroups and facilitate efforts aimed at the identification of targeted therapies and prevention. One of the best examples of gene-environment (GxE) interactions is the association of the apolipoprotein L1 (APOL1) gene with the development of CKD in African Americans in the United States.38 MYH9 variants initially associated with CKD in African Americans were found to be in linkage disequilibrium with APOL1 variants.9,64
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Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC
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Financial disclosure and conflict of interest statements: none.