PubMed · 387969
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W M Cobb. 1979. The challenges ahead.. https://pubmed.ncbi.nlm.nih.gov/387969/
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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.
CONTEXT: In recent years a theory that cancer biology is different in blacks and whites has gained prominence in reaction to epidemiologic observations that blacks have poorer survival than whites, even when diagnosed with cancer of similar severity. Yet, few studies have evaluated whether lower-quality treatment and shorter overall life expectancy due to a greater burden of other illnesses may explain the survival discrepancy. OBJECTIVE: To estimate the magnitude of overall and cancer-specific survival differences between blacks and whites who receive comparable treatment for similar-stage cancer. DATA SOURCES: We searched MEDLINE for English-language articles published from 1966 to January 2002 that reported on overall survival for black and white patients treated similarly for cancer. STUDY SELECTION: The abstracts or titles for 891 citations were independently examined by 2 authors. The full text was retrieved if the abstract mentioned both black and white patients, made some comment regarding either similarity of treatment received or presented an analysis based on the treatment received, and commented on survival. Studies were included if they included data for at least 10 black and 10 white patients; specified the cohort ascertainment method and what measures were undertaken to minimize loss to follow-up; summarized survival of both blacks and whites using actuarial measures; presented outcomes within stage, adjusted for stage, or based on cohorts with balanced stage distributions; and specified that blacks and whites in the study received similar treatment. We identified 89 unique cohorts in 54 articles that met our inclusion criteria. DATA EXTRACTION: Overall survival rates and hazard ratios (HRs) for death for blacks relative to whites were calculated. These were subsequently adjusted for rates of death due to causes other than the cancer under study to determine cancer-specific survival and cancer-specific HRs. DATA SYNTHESIS: Results represent 189 877 white and 32 004 black patients with 14 different cancers. Compared with whites, blacks had an overall excess risk of death (HR, 1.16; 95% confidence interval [CI], 1.12-1.20). After correction for deaths due to other causes, the cancer-specific HR was 1.07 (95% CI, 1.02-1.13). Of the 14 cancers, blacks were at a significantly higher risk of cancer-specific death only for cancer of the breast, uterus, or bladder. CONCLUSIONS: Only modest cancer-specific survival differences are evident for blacks and whites treated comparably for similar-stage cancer. Therefore, differences in cancer biology between racial groups are unlikely to be responsible for a substantial portion of the survival discrepancy. Differences in treatment, stage at presentation, and mortality from other diseases should represent the primary targets of research and interventions designed to reduce disparities in cancer outcomes.
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