APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease

Tzur, Shay; Rosset, Saharon; Skorecki, Karl; Wasser, Walter G.

doi:10.1093/ndt/gfr796

Cited by 86 publications

(79 citation statements)

References 37 publications

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“…However, several studies have suggested an association of a single-copy APOL1 risk variant in patients with both categorical and time-to-event renal phenotypes. 2,13,19,42,43 These prior studies support our observation that a single risk variant may contribute to disease pathogenesis, and a better understanding of CKD phenotypes or biologic mechanisms may clarify additive versus recessive effects. Ultimately, the biologic mechanism of APOL1-associated CKD is currently unknown and cannot be presumed on the basis of statistical genetic analyses; rather, it must be determined empirically.…”

Section: Discussionsupporting

confidence: 76%

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

Bruggeman

O’Toole

Ross

et al. 2014

Journal of the American Society of Nephrology

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Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to ,60 ml/min per 1.73 m 2 (eGFR,60 cohort) or protein-to-creatinine ratios became .3.5 g/g (nephrotic proteinuria cohort).Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR,60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR,60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.

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Section: Discussionsupporting

confidence: 76%

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

Bruggeman

O’Toole

Ross

et al. 2014

Journal of the American Society of Nephrology

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“…However, this survey was conducted .30 years ago and did not include an assessment of urinary albumin or serum cystatin C. Our findings in a larger, contemporaneous, and diverse cohort suggest that differences in CKD prevalence across background groups are explained by modifiable factors, including diabetes mellitus, hypertension, and cardiovascular disease. Nonetheless, future work is needed to explore the importance of additional risk factors, including genetic susceptibility (e.g., the presence of atrisk variants of apolipoprotein L1, which have been associated with increased risk of progression to ESRD in Hispanics with a greater degree of African ancestry) (15).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Correlates of CKD in Hispanics/Latinos in the United States

Ricardo¹,

Flessner²,

Eckfeldt³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives The prevalence of ESRD among Hispanics/Latinos is 2-fold higher than in non-Hispanic whites. However, little is known about the prevalence of earlier stages of CKD among Hispanics/Latinos. This study estimated the prevalence of CKD in US Hispanics/Latinos. Results The overall prevalence of CKD among Hispanics/Latinos was 13.7%. Among women, the prevalence of CKD was 13.0%, and it was lowest in persons with South American background (7.4%) and highest (16.6%) in persons with Puerto Rican background. In men, the prevalence of CKD was 15.3%, and it was lowest (11.2%) in persons with South American background and highest in those who identified their Hispanic background as "other" (16.0%). The overall prevalence of CKD was similar in HCHS/SOL compared with non-Hispanic whites in NHANES. However, prevalence was higher in HCHS/SOL men and lower in HCHS/SOL women versus NHANES non-Hispanic whites. Low income, diabetes mellitus, hypertension, and cardiovascular disease were each significantly associated with higher risk of CKD.Conclusions Among US Hispanic/Latino adults, there was significant variation in CKD prevalence among Hispanic/Latino background groups, and CKD was associated with established cardiovascular risk factors.

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“…Disease etiologies include focal global glomerulosclerosis (FGGS) historically ascribed to hypertension, nonmonogenic forms of FSGS, HIV-associated nephropathy (HIVAN), sickle cell kidney disease, and severe lupus nephritis (LN) (7,8,(22)(23)(24)(25). The APOL1 risk variants also account for younger age of onset of ESRD and may also be associated with poorer outcome of kidney grafts from African-ancestry donors (26)(27)(28).…”

Section: Apol1-associated Nephropathymentioning

confidence: 99%

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

Freedman

Skorecki

2014

Clinical Journal of the American Society of Nephrology

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Molecular genetics have revolutionized the understanding of susceptibility to the broad spectrum of kidney diseases with light microscopic appearance of FSGS, particularly in populations with recent African ancestry. These disorders include idiopathic FSGS, HIV-associated nephropathy, severe lupus nephritis, sickle cell nephropathy, and the primary kidney disorder focal global glomerulosclerosis, which had historically been ascribed to systemic hypertension. FSGS was once thought to include a multitude of unrelated disorders with similar histologic appearance. However, variation in the apolipoprotein L1 gene locus is now known to account for the vast majority of such cases in African Americans as well as nearly all the excess risk for FSGS and related forms of progressive nondiabetic nephropathy in populations with recent African ancestry, relative to European ancestry. Inheriting two coding apolipoprotein L1 gene nephropathy risk variants is necessary for susceptibility to CKD; however, these variants alone are insufficient to produce disease. This work reviews the evidence supporting second hits or modifying factors that affect risk for apolipoprotein L1 gene-associated nephropathy and produce the protean manifestations of this common and complex syndrome. Targeting modifiable second factors will lead to preventive therapies for slowing progression of nondiabetic nephropathy in many patients possessing two apolipoprotein L1 gene risk variants. This model of genetic risk coupled with modifiable second hits will serve as a paradigm applicable to patients with CKD of various etiologies as well as a host of other complex disorders.

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APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease

Cited by 86 publications

References 37 publications

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD

Prevalence and Correlates of CKD in Hispanics/Latinos in the United States

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

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