Faculty Bibliography

OBJECTIVE:Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity. METHODS:Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm. RESULTS:Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P = 0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers. CONCLUSION/CONCLUSIONS:Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.

Cardiovascular drugs are the most commonly prescribed medications. Some prior assays successfully detect cardiovascular drugs among multiple classes using a single sample. Here, we develop an assay to detect a broad range of cardiovascular drug classes to include commonly used cardiovascular drugs and evaluate the assay's analytical and statistical properties in a clinical setting. We describe a protocol for drug detection that encompasses 34 commonly prescribed cardiovascular drugs or drug metabolites with a single LC-MS/MS method using 100μL of serum or plasma. Drug classes monitored by this assay include: anticoagulants, angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta blockers, calcium channel blockers, diuretics, statins, and vasodilators, as well as digoxin, fenofibrate, and niacin. Analytical accuracy and precision for each drug were evaluated by repeating the assay on spiked samples at low, medium, and high concentrations. In 294 clinical samples obtained from hospitalized patients for whom medication administration was recorded, we evaluated the assay's statistical sensitivity, specificity, and accuracy. For the 34 drugs or drug metabolites, the assay was statistically sensitive (>0.90) for all drugs except captopril (0.25), isosorbide (0.81), and niacin (0.89). The assay was statistically specific for all drugs, with a minimum specificity of 0.94 (aspirin). To our knowledge, this method is the first method of simultaneous analysis of 34 cardiovascular drugs or drug metabolites from nine drug classes evaluated using clinical samples from hospitalized patients.

BACKGROUND:The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. OBJECTIVE:We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. METHODS:Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. RESULTS:At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ(2) test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). CONCLUSIONS:Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased.

IMPORTANCE/OBJECTIVE:Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis. OBJECTIVE:To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions. DESIGN AND PARTICIPANTS/METHODS:A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention. SETTING/METHODS:A tertiary referral dermatology center in Nashville, Tennessee. INTERVENTIONS/METHODS:Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up. MAIN OUTCOMES AND MEASURES/METHODS:Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy. OBSERVATIONS/METHODS:In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of -8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of -2.9 (2.5) mm in lesion severity compared with a decline of -0.6 (2.1) mm in the placebo group (P = .02). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov Identifier: NCT01074554.

OBJECTIVE:To test for a urate gene-by-diuretic interaction on incident gout. METHODS:The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987-1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median. RESULTS:Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney. CONCLUSIONS:Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use.

BACKGROUND:Increased serum urate levels are associated with poor outcomes including but not limited to gout. It is unclear whether serum urate levels are the sole predictor of incident hyperuricemia or whether demographic and clinical risk factors also predict the development of hyperuricemia. The goal of this study was to identify risk factors for incident hyperuricemia over 9 years in a population-based study, ARIC. METHODS:ARIC recruited individuals from 4 US communities; 8,342 participants who had urate levels <7.0 mg/dL were included in this analysis. Risk factors (including baseline, 3-year, and change in urate level over 3 years) for 9-year incident hyperuricemia (urate level of >7.0 g/dL) were identified using an AIC-based selection approach in a modified Poisson regression model. RESULTS:The 9-year cumulative incidence of hyperuricemia was 4%; men = 5%; women = 3%; African Americans = 6% and whites = 3%. The adjusted model included 9 predictors for incident hyperuricemia over 9 years: male sex (RR = 1.73 95% CI: 1.36-2.21), African-American race (RR = 1.79 95% CI: 1.37-2.33), smoking (RR = 1.27, 95% CI: 0.97-1.67), <HS education (RR = 1.27, 95% CI: 0.99-1.63), hypertension (RR = 1.65, 95% CI: 1.30-2.09), CHD (RR = 1.57, 95% CI: 0.99-2.50), obesity (class I RR = 2.37, 95% CI: 1.65-3.41 and ≥ class II RR = 3.47, 95% CI: 2.33-5.18), eGFR < 60 (RR = 2.85, 95% CI: 1.62-5.01) and triglycerides (Quartile 4 vs. Quartile 1: RR = 2.00, 95% CI: 1.38-2.89). In separate models, urate levels at baseline (RR 1 mg/dL increase = 2.33, 95% CI: 1.94-2.80) and 3 years after baseline (RR for a 1 mg/dL increase = 1.92, 95% CI: 1.78-2.07) were associated with incident hyperuricemia after accounting for demographic and clinical risk factors. CONCLUSION/CONCLUSIONS:Demographic and clinical risk factors that are routinely collected as part of regular medical care are jointly associated with the development of hyperuricemia.

Chronic kidney disease (CKD) is an increasingly common public health issue associated with substantial morbidity and mortality. Risk prediction models provide a useful clinical and research framework for forecasting the probability of adverse events and stratifying patients with CKD according to risk; however, accurate absolute risk prediction requires careful model specification. Competing events that preclude the event of interest (for example, death in studies of end-stage renal disease) must be taken into account. Functional forms of predictor variables and underlying effect modification must be accurately specified; nonlinearity and possible interactions should be evaluated. The potential effect of measurement error should also be considered. Misspecification of any of these components can dramatically affect absolute risk prediction. Evaluation of prognostic models should encompass not only traditional tests of calibration and discrimination, such as the Hosmer-Lemeshow test of 'goodness of fit' and the area under the receiver operating curve, but also newer metrics, such as risk reclassification tables and net reclassification indices. The latter two tests are particularly useful when considering the addition of novel predictors to established models. Finally, models of absolute risk prediction should be internally and externally validated as they typically generalize only to populations with similar baseline characteristics and rates of competing events.

BACKGROUND AND OBJECTIVES/OBJECTIVE:There exists gross disparity in national deceased donor kidney transplant availability and practice: waiting times exceed 6 years in some regions, but some patients receive kidneys before they require dialysis. This study aimed to quantify and characterize preemptive deceased donor kidney transplant recipients and compare their outcomes with patients transplanted shortly after dialysis initiation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:Using the Scientific Registry of Transplant Recipients database, first-time adult deceased donor kidney transplant recipients between 1995 and 2011 were classified as preemptive, early (on dialysis ≤1 year), or late recipients. Random effects logistic regression and multivariate Cox proportional hazards regression were used to identify characteristics of preemptive deceased donor kidney transplant and evaluate survival in preemptive and early recipients, respectively. RESULTS:Preemptive recipients were 9.0% of the total recipient population. Patients with private insurance (adjusted odds ratio=3.15, 95% confidence interval=3.01-3.29, P<0.001), previous (nonkidney) transplant (adjusted odds ratio=1.94, 95% confidence interval=1.67-2.26, P<0.001), and zero-antigen mismatch (adjusted odds ratio=1.45, 95% confidence interval=1.37-1.54, P<0.001; Caucasians only) were more likely to receive preemptive deceased donor kidney transplant, even after accounting for center-level clustering. African Americans were less likely to receive preemptive deceased donor kidney transplant (adjusted odds ratio=0.44, 95% confidence interval=0.41-0.47, P<0.001). Overall, patients transplanted preemptively had similar survival compared with patients transplanted within 1 year after initiating dialysis (adjusted hazard ratio=1.06, 95% confidence interval=0.99-1.12, P=0.07). CONCLUSIONS:Preemptive deceased donor kidney transplant occurs most often among Caucasians with private insurance, and survival is fairly similar to survival of recipients on dialysis for <1 year.

BACKGROUND:Lifetime risk estimates of chronic kidney disease (CKD) can motivate preventative behaviors at the individual level and forecast disease burden and health care use at the population level. STUDY DESIGN/METHODS:Markov Monte Carlo model simulation study. SETTING & POPULATION/METHODS:Current US black and white population. MODEL, PERSPECTIVE, & TIMEFRAME/METHODS:Markov models simulating kidney disease development, using an individual perspective and lifetime horizon. OUTCOMES/RESULTS:Age-, sex-, and race-specific residual lifetime risks of CKD stages 3a+ (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²), 3b+ (eGFR <45 mL/min/1.73 m²), 4+ (eGFR <30 mL/min/1.73 m²), and end-stage renal disease (ESRD). MEASUREMENTS/METHODS:State transition probabilities of developing CKD and of dying prior to its development were modeled using: (1) mortality rates from the National Vital Statistics Report, (2) mortality risk estimates from a 2-million person meta-analysis, and (3) CKD prevalence from National Health and Nutrition Examination Surveys. Incidence, prevalence, and mortality related to ESRD were supplied by the US Renal Data System. RESULTS:At birth, the overall lifetime risks of CKD stages 3a+, 3b+, 4+, and ESRD were 59.1%, 33.6%, 11.5%, and 3.6%, respectively. Women experienced greater CKD risk yet lower ESRD risk than men; blacks of both sexes had markedly higher CKD stage 4+ and ESRD risks (lifetime risks for white men, white women, black men, and black women, respectively: CKD stage 3a+, 53.6%, 64.9%, 51.8%, and 63.6%; CKD stage 3b+, 29.0%, 36.7%, 33.7%, and 40.2%; CKD stage 4+, 9.3%, 11.4%, 15.8%, and 18.5%; and ESRD, 3.3%, 2.2%, 8.5%, and 7.8%). Risk of CKD increased with age, with approximately one-half the CKD stage 3a+ cases developing after 70 years of age. LIMITATIONS/CONCLUSIONS:CKD incidence was modeled from prevalence estimates in the US population. CONCLUSIONS:In the United States, the lifetime risk of developing CKD stage 3a+ is high, emphasizing the importance of primary prevention and effective therapy to reduce CKD-related morbidity and mortality.

BACKGROUND:The US prevalence of reduced estimated glomerular filtration rate (eGFR) based on serum creatinine level increased during the decade ending in 2002. National Health and Nutrition Examination Survey (NHANES) cystatin C measurements recently were calibrated to the international standard, allowing for an independent test of the trend in prevalence of reduced eGFR using cystatin C level. STUDY DESIGN/METHODS:Cross-sectional surveys performed during 2 periods. SETTING & PARTICIPANTS/METHODS:Nationally representative subsamples of adult participants from NHANES III (1988-1994) and the NHANES 1999-2002 surveys. PREDICTOR/METHODS:Survey period. OUTCOMES/RESULTS:Prevalence of reduced GFR, defined as eGFR <60 mL/min/1.73 m² based on levels of serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys), using estimating equations developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). MEASUREMENTS/METHODS:Serum cystatin C level, measured from stored samples in 2006, calibrated to the international standard in 2012. RESULTS:Between 1988-1994 and 1999-2002, the prevalence of reduced eGFRcr, eGFRcys, and eGFRcr-cys increased from 4.7% (95% CI, 4.1%-5.3%) to 6.5% (95% CI, 5.9%-7.1%) (P < 0.001), from 5.5% (95% CI, 4.6%-6.5%) to 8.7% (95% CI, 7.5%-10.0%) (P < 0.001), and from 4.4% (95% CI, 3.7%-5.2%) to 7.1% (95% CI, 6.2%-8.0%) (P < 0.001), respectively. The higher prevalence of reduced GFR in the later period was observed in all subgroups of age, race, sex, and GFR categories. After adjusting for changes in the US population by age, sex, race, diabetes, hypertension, and body mass index, prevalence ratios of reduced GFR in the later versus earlier survey were 1.24 (95% CI, 1.09-1.45), 1.34 (95% CI, 1.15-1.67), and 1.33 (95% CI, 1.17-1.65) using eGFRcr, eGFRcys, and eGFRcr-cys, respectively. LIMITATIONS/CONCLUSIONS:Likely underascertainment of persons with GFR <15 mL/min/1.73 m²; GFR was estimated and not measured; comparability of laboratory assays based on a calibration subsample. CONCLUSIONS:The prevalence of reduced eGFRcys in the US civilian noninstitutionalized population increased between 1988-1994 and 1999-2002, confirming the increase observed in the prevalence of reduced eGFRcr.