Faculty Bibliography

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.

Early hospital readmission (EHR) after kidney transplantation (KT) is associated with increased morbidity and higher costs. Registry-based recipient, transplant and center-level predictors of EHR are limited, and novel predictors are needed. We hypothesized that frailty, a measure of physiologic reserve initially described and validated in geriatrics and recently associated with early KT outcomes, might serve as a novel, independent predictor of EHR in KT recipients of all ages. We measured frailty in 383 KT recipients at Johns Hopkins Hospital. EHR was ascertained from medical records as ≥1 hospitalization within 30 days of initial post-KT discharge. Frail KT recipients were much more likely to experience EHR (45.8% vs. 28.0%, p = 0.005), regardless of age. After adjusting for previously described registry-based risk factors, frailty independently predicted 61% higher risk of EHR (adjusted RR = 1.61, 95% CI: 1.18-2.19, p = 0.002). In addition, frailty improved EHR risk prediction by improving the area under the receiver operating characteristic curve (p = 0.01) as well as the net reclassification index (p = 0.04). Identifying frail KT recipients for targeted outpatient monitoring and intervention may reduce EHR rates.

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.

OBJECTIVES/OBJECTIVE:To quantify the prevalence of frailty in adults of all ages undergoing chronic hemodialysis, its relationship to comorbidity and disability, and its association with adverse outcomes of mortality and hospitalization. DESIGN/METHODS:Prospective cohort study. SETTING/METHODS:Single hemodialysis center in Baltimore, Maryland. PARTICIPANTS/METHODS:One hundred forty-six individuals undergoing hemodialysis enrolled between January 2009 and March 2010 and followed through August 2012. MEASUREMENTS/METHODS:Frailty, comorbidity, and disability on enrollment in the study and subsequent mortality and hospitalizations. RESULTS:At enrollment, 50.0% of older (≥ 65) and 35.4% of younger (<65) individuals undergoing hemodialysis were frail; 35.9% and 29.3%, respectively, were intermediately frail. Three-year mortality was 16.2% for nonfrail, 34.4% for intermediately frail, and 40.2% for frail participants. Intermediate frailty and frailty were associated with a 2.7 times (95% confidence interval (CI) = 1.02-7.07, P = .046) and 2.6 times (95% CI = 1.04-6.49, P = .04) greater risk of death independent of age, sex, comorbidity, and disability. In the year after enrollment, median number of hospitalizations was 1 (interquartile range 0-3). The proportion with two or more hospitalizations was 28.2% for nonfrail, 25.5% for intermediately frail, and 42.6% for frail participants. Although intermediate frailty was not associated with number of hospitalizations (relative risk = 0.76, 95% CI = 0.49-1.16, P = .21), frailty was associated with 1.4 times (95% CI = 1.00-2.03, P = .049) more hospitalizations independent of age, sex, comorbidity, and disability. The association between frailty and mortality (interaction P = .64) and hospitalizations (P = .14) did not differ between older and younger participants. CONCLUSIONS:Adults of all ages undergoing hemodialysis have a high prevalence of frailty, more than five times as high as community-dwelling older adults. In this population, regardless of age, frailty is a strong, independent predictor of mortality and number of hospitalizations.

BACKGROUND:Patients undergoing hemodialysis are at high risk of falls, with subsequent complications including fractures, loss of independence, hospitalization, and institutionalization. Factors associated with falls are poorly understood in this population. We hypothesized that insights derived from studies of the elderly might apply to adults of all ages undergoing hemodialysis; we focused on frailty, a phenotype of physiological decline strongly associated with falls in the elderly. METHODS:In this prospective, longitudinal study of 95 patients undergoing hemodialysis (1/2009-3/2010), the association of frailty with future falls was explored using adjusted Poisson regression. Frailty was classified using the criteria established by Fried et al., as a combination of five components: shrinking, weakness, exhaustion, low activity, and slowed walking speed. RESULTS:Over a median 6.7-month period of longitudinal follow-up, 28.3% of study participants (25.9% of those under 65, 29.3% of those 65 and older) experienced a fall. After adjusting for age, sex, race, comorbidity, disability, number of medications, marital status, and education, frailty independently predicted a 3.09-fold (95% CI: 1.38-6.90, P=0.006) higher number of falls. This relationship between frailty and falls did not differ for younger and older adults (P=0.57). CONCLUSIONS:Frailty, a validated construct in the elderly, was a strong and independent predictor of falls in adults undergoing hemodialysis, regardless of age. Our results may aid in identifying frail hemodialysis patients who could be targeted for multidimensional fall prevention strategies.

OBJECTIVE:To quantify the role of diuretic use in gout development in an adult population with hypertension. METHODS:The Atherosclerosis Risk in Communities study, a prospective population-based cohort from 4 US communities, consisted of 4 visits over a 9-year period. Participants were included in this analysis if they answered a query about gout, were free of gout at baseline, and had hypertension (defined as taking medication to treat hypertension or having blood pressure of ≥140/90 mm Hg). Trained interviewers recorded use of antihypertensive drugs. Incident gout was defined as self-reported onset of gout after baseline. Using a time-dependent Cox proportional hazards model, we estimated hazard ratios (HRs; with 95% confidence intervals [95% CIs]) for incident gout by time-varying diuretic use, both adjusted for confounders and tested for mediation by serum urate level. RESULTS:There were 5,789 participants with hypertension; 37% were treated with a diuretic. Use of any diuretic (HR 1.48 [95% CI 1.11, 1.98]), a thiazide diuretic (HR 1.44 [95% CI 1.00, 2.10]), or a loop diuretic (HR 2.31 [95% CI 1.36, 3.91]) was associated with incident gout as compared with not using any diuretic, not using a thiazide diuretic, or not using a loop diuretic, respectively. After adjusting for serum urate level, the association between diuretic use and gout was null. Use of antihypertensive medication other than diuretic agents was associated with decreased gout risk (adjusted HR 0.64 [95% CI 0.49, 0.86]) compared to untreated hypertension. The longitudinal change in serum urate levels was 0.72 mg/dl (95% CI 0.57, 0.87) higher in those who began treatment with a diuretic than in those who did not (P<0.001). CONCLUSION/CONCLUSIONS:Thiazide and loop diuretics were associated with increased gout risk, an association mediated by a change in serum urate levels.

INTRODUCTION/BACKGROUND:There is a growing prevalence of gout in the US and worldwide. Gout is a recognized risk factor for cardiovascular disease (CVD). It is unclear whether other risk factors for CVD are also associated with increased risk of gout. Anemia is one such CVD risk factor. No studies have evaluated the relationship between anemia and gout. We tested whether anemia was associated with incident gout independent of comorbid conditions in Atherosclerosis Risk in the Communities. METHODS:This population-based cohort recruited 15,792 individuals in 1987 to 1989 from four US communities and contained nine years of follow-up. Anemia was defined as hemoglobin <13.5 g/dL for men and <12 g/dL for women. Using a Cox Proportional Hazards model, we estimated the hazard ratio (HR) and confidence intervals (CI) of incident gout by baseline anemia, adjusted for confounders (sex, race, estimated glomerular filtration rate, body mass index and alcohol intake) and clinical factors (coronary heart disease, congestive heart failure, diabetes, hypertension, diuretic use and serum urate level). RESULTS:Among the 10,791 participants, 10% had anemia at baseline. There were 271 cases of incident gout. Patients with anemia had a two-fold increased risk of developing gout over nine years (HR = 2.01, 95% CI: 1.46, 2.76). Anemia was associated with incident gout independent of known gout risk factors, confounders and clinical risk factors (HR = 1.73, 95% CI: 1.24, 2.41). This association persisted after additionally adjusting for serum urate level (HR = 1.83, 95% CI: 1.30, 2.57). CONCLUSION/CONCLUSIONS:We identified anemia as a novel risk factor for gout. Anemia was associated with an approximately two-fold increased risk of gout-independent kidney function and serum urate. These findings suggest that anemia is a risk factor for gout on par with other chronic conditions such as obesity and diabetes. The biological mechanism linking anemia to gout remains unclear.

BACKGROUND:We hypothesized that women with early- and mid-adult life obesity, as well as high mid-adult life waist-to-hip ratios, and high weight gain during adulthood, experience a greater incidence of gout. METHODS:We examined the incidence of gout in the Atherosclerosis Risk in Communities Study, a population-based biracial cohort comprised of individuals aged 45-65 years at baseline (1987-1989). A total of 6263 women without prior history of gout were identified. We examined the association of body mass index (BMI) and obesity at cohort entry and at age 25 years, waist-to-hip ratio, and weight change with gout incidence (1996-1998). RESULTS:Over 9 years of follow-up, 106 women developed gout. The cumulative incidence of gout, by age 70 years, according to BMI category at baseline of <25, 25-29.9, 30-34.9, and ≥35 kg/m(2), was 1.9, 3.6, 7.9, and 11.8%, respectively (P <.001). Obese women (BMI ≥30) at baseline had an adjusted 2.4-fold greater risk of developing gout than nonobese women (95% confidence interval [CI], 1.53-3.68). This association was attenuated after further adjustment for urate levels. Further, early adult obesity in women was associated with a 2.8-fold increased risk of gout compared with nonobese women (95% CI, 1.33-6.09), which remained statistically significant after baseline urate adjustment. There was a graded association between each anthropometric measure, including weight gain, with incident gout (each P for trend <.001). The results were similar in black and white women. CONCLUSIONS:In a large cohort of black and white women, obesity in early- and mid-adulthood, and weight gain during this interval, were each independent risk factors for incident gout in women.

The authors quantified the impact of hypertension on gout incidence in middle-aged white and African American men and women. The Atherosclerosis Risk in Communities Study (ARIC) was a prospective population-based cohort that recruited patients between 1987 and 1989 from 4 US communities. Using a time-dependent Cox proportional hazards model, the authors estimated the adjusted hazard ratio (HR) of incident gout by time-varying hypertension and tested for mediation by serum urate level. There were 10,872 participants among whom 45% had hypertension during follow-up; 43% were men and 21% were African American. Over 9 years, 274 (2.5%) participants developed gout (1.8% of women and 3.5% of men). The unadjusted HR of incident gout was approximately 3 times (HR, 2.87; 95% confidence interval [CI], 2.24-3.78) greater for those with hypertension. Adjusting for confounders resulted in an attenuated but still significant association between hypertension and gout (HR, 2.00; 95% CI, 1.54-2.61). Adjustment for serum urate level further attenuated but did not abrogate the association (HR, 1.36, 95% CI, 1.04-1.79). There was no evidence of effect modification by sex (P=.35), race (P=.99), or obesity at baseline (P=.82). Hypertension was independently associated with increased gout risk in middle-aged African American and white adults. Serum urate level may be a partial intermediate on the pathway between hypertension and gout.