Faculty Bibliography

BACKGROUND:Estimated glomerular filtration rate (eGFR) and albuminuria are central for diagnosis, staging, and risk evaluation in chronic kidney disease (CKD). Universal thresholds regardless of age, sex, and race are recommended, but relatively little is known about how these demographic factors alter the relationship of eGFR and albuminuria to cardiovascular outcomes. STUDY DESIGN/METHODS:Observational cohort study. SETTING & PARTICIPANTS/METHODS:11,060 whites and blacks aged 52-75 years in the Atherosclerosis Risk in Communities (ARIC) Study with median follow-up of 11.2 years. PREDICTORS/METHODS:eGFR by the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation (reference, 95 mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (ACR; reference, 5 mg/g). OUTCOMES/RESULTS:Cardiovascular events (coronary disease, stroke, and heart failure) and all-cause mortality. MEASUREMENTS/METHODS:Adjusted HRs associated with eGFR and ACR in subgroups according to age, sex, and race. RESULTS:Cardiovascular risk significantly increased at eGFR <70 mL/min/1.73 m(2) in all subgroups according to age (<65 vs ≥65 years), sex, and race (P for interaction >0.2 for these subgroups; eg, at eGFR of 30 mL/min/1.73 m(2), the adjusted HR was 2.19 [95% CI, 1.10-4.35] at age 52-64 years vs 2.23 [95% CI, 1.33-3.72] at age 65-75 years). Results were similar for mortality. Log(ACR) was associated linearly with cardiovascular risk without threshold effects in all subgroups, with some quantitative interactions. HRs according to ACR tended to be lower in men versus women (eg, at ACR of 40 mg/g, 1.18 [95% CI, 0.98-1.41] vs 1.77 [95% CI, 1.45-2.15]) and in the older versus younger population (1.24 [95% CI, 1.04-1.49] vs 1.73 [95% CI, 1.42-2.12]; P for interaction <0.01 for sex and age). Less evident interactions were observed for mortality. LIMITATIONS/CONCLUSIONS:Single measurement of eGFR with creatinine and ACR and relatively narrow age range. CONCLUSIONS:The associations of eGFR and ACR with cardiovascular events were largely similar, with some quantitative interactions, in age, sex, and racial subgroups, generally supporting universal thresholds of GFR and ACR for CKD definition/staging.

BACKGROUND:Beta-trace protein (BTP), measured in serum or plasma, has potential as a novel biomarker for kidney function. Little is known about the genes influencing BTP levels. METHODS:We conducted a genome-wide association study of log-transformed plasma BTP levels in 6720 European Americans (EAs) and replicated the significant associations in 1734 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. RESULTS:We identified a genome-wide significant locus in EA upstream of Prostaglandin D2 synthase (PTGDS), the gene encoding BTP. Each copy of the A allele at rs57024841 was associated with 5% higher BTP levels (P = 1.2 × 10(-23)). The association at PTGDS was confirmed in AAs (6% higher BTP for each A allele at rs57024841, P = 1.9 × 10(-7)). The index single nucleotide polymorphisms (SNPs) in EAs and AAs explained ∼1.1% of the log(BTP) variance within each population and explained over 30% of the difference in log(BTP) levels between EAs and AAs. The index SNPs at the PTGDS locus in the two populations were not associated with the estimated glomerular filtration rate (eGFR) or the urine albumin creatinine ratio (P > 0.05). We further tested for the associations of BTP with 16 known loci of the eGFR in EA, and BTP was associated with 3 of 16 tested. CONCLUSIONS:The identification of a novel BTP-specific (non-renal related) locus and the confirmation of several genetic loci of the eGFR with BTP extend our understanding of the metabolism of BTP and inform its use as a kidney filtration biomarker.

BACKGROUND AND OBJECTIVES/OBJECTIVE:According to the cost of health care utilization systems, there may be regional differences in the relative strength of association of income and education-based socioeconomic status measures with CKD. This study investigated the relative strength of the association of income and education with CKD in a United States and a Dutch population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:This cross-sectional study examined individuals who participated in the 1999-2002 National Health and Nutritional Examination Survey (NHANES) and in Prevention of Renal and Vascular End-stage Disease (PREVEND 1997-1998), general population-based cohorts in the United States and The Netherlands, respectively. The main outcome was CKD, defined as estimated GFR <60 ml/min per 1.73 m(2) (using creatinine) or albuminuria ≥ 30 mg/24 hours or albumin-to-creatinine ratio ≥ 30 mg/g. RESULTS:In NHANES (n=6428), income was strongly associated with CKD (adjusted odds ratio, 2.34 [95% confidence interval (CI), 1.68 to 3.27]; P for trend<0.001) but education was not (adjusted odds ratio, 1.62 [95% CI, 0.87 to 2.25]; P for trend=0.05]. In contrast, in PREVEND (n=7983), low income was weakly associated with CKD whereas low education had a strong association. The fit of the logistic regression model estimating association of income and education with CKD was significantly improved only after income was added in NHANES (P<0.001) and education was added in PREVEND (P=0.01). Sensitivity analyses that used other CKD-defining variables and restricted analyses to participants <65 years of age resulted in similar findings. CONCLUSION/CONCLUSIONS:In the United States, where access to health care is traditionally income dependent, income appeared more strongly associated with CKD than in The Netherlands, where education showed a stronger association.

BACKGROUND:Our objective was to quantify short-term total within-person variability in standard and nontraditional kidney measures using national data. STUDY DESIGN/METHODS:Repeated examination study of serum and urine kidney measures. SETTING & PARTICIPANTS/METHODS:Participants 18 years or older in the Third National Health and Nutrition Examination Survey (NHANES III) who had repeated blood and urine samples collected during visits occurring approximately 18 days apart. MEASUREMENTS/METHODS:Standardized serum creatinine, standardized cystatin C, β-trace protein (BTP), β(2)-microglobulin (B2M), and urine albumin and creatinine. We calculated the within-person coefficient of variation (CV(w)), which includes both biological and analytical variability. We also evaluated the impact of variability on estimates of the prevalence of reduced estimated glomerular filtration rate and albuminuria. RESULTS:Serum cystatin C level demonstrated the lowest short-term within-person variability (CV(w) = 6.8%). Serum creatinine and B2M levels (CV(w) = 7.6% and 8.4%, respectively) also had low variability. BTP level had the most variability of the serum markers (CV(w) = 11.6%). As expected, urine albumin and urine creatinine measurements showed high variability (CV(w) >30% for both); however, albumin-creatinine ratio performed much better than either measure alone, with CV(w) of 11.3%. The effect of short-term variability on the prevalence of reduced estimated glomerular filtration rate was moderate, with an ~20% lower prevalence when defined based on single measurements compared to repeated application of the same test approximately 18 days apart. Repeated testing for albuminuria had a larger effect, showing a 33% lower prevalence of albuminuria when repeated testing was applied. LIMITATIONS/CONCLUSIONS:Only 2 measurements available. General population with low prevalence of kidney disease. CONCLUSIONS:Our results suggest that creatinine, cystatin C, and B2M levels have similarly low short-term variability. BTP level was more variable compared with the other serum filtration markers. Urine albumin and creatinine levels were highly variable and may benefit from repeated assessments to reduce the misclassification of albuminuria.

BACKGROUND:Sarcoidosis is an idiopathic, granulomatous disease for which molecular and immunologic studies have shown an association between it and mycobacterial antigens. Microbial antigens can reduce expression of the tyrosine kinase Lck, which has been associated with sarcoidosis severity. Here we investigate the efficacy of Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (the CLEAR regimen) for treatment of chronic, pulmonary sarcoidosis. METHODS:Fifteen chronic, pulmonary sarcoidosis patients with forced vital capacities (FVC) between 45-80% of predicted were enrolled in this open-label trial. The primary efficacy endpoint was change in absolute FVC from baseline to completion of therapy. Secondary endpoints were change in functional capacity measured by Six Minute Walk Distance (6MWD) and quality of life assessment measured by St. George's Respiratory Questionnaire (SGRQ). RESULTS:Of 15 patients enrolled, 11 completed 4 weeks of therapy, and 8 completed 8 weeks of therapy. The CLEAR regimen was associated with an increase in FVC of 0.23 liters at 4 weeks and 0.42 liters at 8 weeks (P=0.0098 and 0.016, respectively). The 6MWD increased by 87 meters from baseline to 8 weeks (p=0.0078). The mean score of the validated SGRQ was improved at 8 weeks over baseline (p=0.023). Normalized expression of Lck and NF-κB was observed in those with clinical improvement. CONCLUSIONS:The CLEAR regimen is associated with improved absolute FVC, as well as increased functional capacity and quality-of-life in selected chronic pulmonary sarcoidosis patients. Larger, randomized, controlled trials are needed to confirm these findings and to identify patients most likely to benefit from therapy. ClinicalTrials.gov number NCT01169038.

Bradykinin increases during cardiopulmonary bypass (CPB) and stimulates the release of nitric oxide, inflammatory cytokines, and tissue-type plasminogen activator (t-PA), acting through its B2 receptor. This study tested the hypothesis that endogenous bradykinin contributes to the fibrinolytic and inflammatory response to CPB and that bradykinin B2 receptor antagonism reduces fibrinolysis, inflammation, and subsequent transfusion requirements. Patients (N = 115) were prospectively randomized to placebo, ε-aminocaproic acid (EACA), or HOE 140, a bradykinin B2 receptor antagonist. Bradykinin B2 receptor antagonism decreased intraoperative fibrinolytic capacity as much as EACA, but only EACA decreased D-dimer formation and tended to decrease postoperative bleeding. Although EACA and HOE 140 decreased fibrinolysis and EACA attenuated blood loss, these treatments did not reduce the proportion of patients transfused. These data suggest that endogenous bradykinin contributes to t-PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D-dimer concentrations during EACA treatment.