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    Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury

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    Author
    Iatrino, Rossella
    Lanzani, Chiara
    Bignami, Elena
    Hamlyn, John M.
    Date
    2019-04-01
    Journal
    American Journal of Kidney Diseases
    Publisher
    W.B. Saunders
    Type
    Article
    
    Metadata
    Show full item record
    See at
    http://dx.doi.org/10.1053/j.ajkd.2018.10.012
    Abstract
    Rationale & Objective: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. Study Design: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. Setting & Participants: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. Exposure: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. Outcomes: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. Analytical Approach: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. Results: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P = 0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14 ± 0.29 vs 1.25 ± 0.08 ng/g; P < 0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (−4.39 ± 1.18 mL/min/1.73 m 2 per year) than in the AC or CC genotype groups (−1.07 ± 0.55 and −2.00 ± 0.45 mL/min/1.73 m 2 per year respectively; P = 0.03). Limitations: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. Conclusions: These findings support the potential value of LSS rs2254524 genotype–based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension. © 2018 The Authors
    Keyword
    cardiovascular surgery
    endogenous ouabain (EO)
    estimated glomerular filtration rate (eGFR)
    genetic mutation
    Lanosterol synthase (LSS)
    renal damage
    Acute Kidney Injury
    Biomarkers
    Hypertension
    Polymorphism, Single Nucleotide
    Risk Factors
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    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85059956855&origin=inward; http://hdl.handle.net/10713/8528
    ae974a485f413a2113503eed53cd6c53
    10.1053/j.ajkd.2018.10.012
    Scopus Count
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    UMB Open Access Articles 2019

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