PubMed · 11632866
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F Iglesias. 1980. [Not Available].. https://pubmed.ncbi.nlm.nih.gov/11632866/
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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.
BACKGROUND: Guidelines are increasingly recommending preventive services starting at 50 years of age, and policymakers are considering such a recommendation for pneumococcal polysaccharide vaccination. The finding that pneumococcal vaccination is cost-saving for people 65 years of age or older raises the question of the vaccination's implications for other older adults, especially black people, whose disease incidence exceeds that of nonblack people, and those with high-risk conditions. OBJECTIVE: To assess the implications of vaccinating black and nonblack people 50 through 64 years of age against invasive pneumococcal disease. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Published literature for vaccination effectiveness and cost estimates; data on disease incidence and case-fatality rates from the Centers for Disease Control and Prevention. TARGET POPULATION: Hypothetical cohort 50 through 64 years of age with the 1995 U.S. age distribution. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Pneumococcal polysaccharide vaccination compared with no vaccination. OUTCOME MEASURES: Incremental medical costs and health effects, in quality-adjusted life-years per vaccinee. RESULTS OF BASE-CASE ANALYSIS: Vaccination saved medical costs and improved health among high-risk black people (27.55 dollars savings per vaccinee) and nonblack people (5.92 dollars savings per vaccinee), excluding survivors' future costs. For low-risk black and nonblack people and the overall general population, vaccination cost 2477 dollars, 8195 dollars, and 3434 dollars, respectively, to gain 1 year of healthy life. RESULTS OF SENSITIVITY ANALYSIS: Excluding survivors' future costs, in the general immunocompetent population, cost per quality-adjusted life-year in global worst-case results ranged from 21 513 dollars for black people to 68 871 dollars for nonblack people; in the high-risk population, cost ranged from 11 548 dollars for black people to 39 000 dollars for nonblack people. In the global best case, vaccination was cost-saving for black and nonblack people in the general immunocompetent and high-risk populations, excluding survivors' future costs. The cost-effectiveness range was narrower in probabilistic sensitivity analyses, with 95% probabilistic intervals ranging from cost-saving to 1594 dollars for black people and from cost-saving to 12 273 dollars for nonblack people in the general immunocompetent population. Costs per quality-adjusted life-year for low-risk people with case-fatality rates from 1998 were 2477 dollars for black people and 8195 dollars for nonblack people, excluding survivors' medical costs. CONCLUSIONS: These results support the current recommendation to vaccinate high-risk people and provide useful information for considering extending the recommendation to the general population 50 through 64 years of age. Lack of evidence about the effectiveness of revaccination for people 65 years of age or older, when disease risks are higher, argues for further research to guide vaccination policy.
CONTEXT: Blacks are disproportionately affected by stroke, and they are about 2 times more likely than most other individuals in the United States to die of or experience stroke. OBJECTIVE: To determine the efficacy and safety of aspirin and ticlopidine to prevent recurrent stroke in black patients. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, investigator-initiated, multicenter trial of 1809 black men and women who recently had a noncardioembolic ischemic stroke and who were recruited between December 1992 and October 2001 from 62 academic and community hospitals in the United States and followed up for up to 2 years. INTERVENTION: A total of 902 patients received 500 mg/d of ticlopidine and 907 received 650 mg/d of aspirin. MAIN OUTCOME MEASURES: Recurrent stroke, myocardial infarction, or vascular death was the composite primary end point (according to intention-to-treat analysis). The secondary outcome was fatal or nonfatal stroke. RESULTS: The blinded phase of the study was halted after about 6.5 years when futility analyses revealed a less than 1% probability of ticlopidine being shown superior to aspirin in the prevention of the primary outcome end point. The primary outcome of recurrent stroke, myocardial infarction, or vascular death was reached by 133 (14.7%) of 902 patients assigned to ticlopidine and 112 (12.3%) of 907 patients assigned to aspirin (hazard ratio, 1.22; 95% confidence interval, 0.94-1.57). Kaplan-Meier curves for time to event for the primary outcome did not differ significantly (P =.12 by log-rank test). Kaplan-Meier curves for time to the secondary outcome of fatal or nonfatal stroke approached a statistically significant reduction favoring aspirin over ticlopidine (P =.08 by log-rank test). The frequency of laboratory-determined serious neutropenia was 3.4% for patients receiving ticlopdine vs 2.2% for patients receiving aspirin (P =.12) and 0.3% vs 0.2% for thrombocytopenia, respectively (P =.69). One ticlopidine-treated patient developed thrombocytopenia, which was thought to be a case of possible thrombotic thrombocytopenia purpura, and recovered after therapy with plasmapheresis. CONCLUSIONS: During a 2-year follow-up, we found no statistically significant difference between ticlopidine and aspirin in the prevention of recurrent stroke, myocardial infarction, or vascular death. However, there was a nonsignificant trend for reduction of fatal or nonfatal stroke among those in the aspirin group. Based on these data and the risk of serious adverse events with ticlopidine, we regard aspirin as a better treatment for aspirin-tolerant black patients with noncardioembolic ischemic stroke.