PubMed · 12042568
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Kenneth D Rosenberg, Juan Manuel Acuna, Frances J Mather. 2002. Incorrect outcome variable?. https://doi.org/10.1542/peds.109.6.1186
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BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.
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The association of hysterectomy with increased coronary risk is controversial, and previous studies have reached differing conclusions as to whether the excess risk is confined to women who have also undergone bilateral oophorectomy. This analysis uses the Framingham algorithm to evaluate the hypothesis that hysterectomy with or without ovarian preservation is associated with increased coronary risk, using a cross-sectional analysis of baseline data from 1,501 participants of the Women's Health Initiative. Framingham risk scores, derived from the algorithm in the National Cholesterol Education Program Adult Treatment Panel III guidelines, which include age, smoking, systolic blood pressure, total and high-density lipoprotein cholesterol, were determined in a subgroup of Women's Health Initiative participants with measured plasma lipids and known ovariectomy status. Women with hysterectomy had fewer years of education than those without hysterectomy (30% with college degree vs 41%, p <0.0001) and higher body mass index (29 vs 28 kg/m(2), p <0.0001), consumed less alcohol, exercised less, and had a higher Framingham risk of myocardial infarction or coronary death (46% vs 41% with 10-year risk >/=4%, p = 0.04). In multivariate analysis, hysterectomy with bilateral oophorectomy was an independent predictor of Framingham risk (p = 0.04), whereas hysterectomy with ovarian preservation was not.