Mara McAdams DeMarco

Diuretic use, increased serum urate levels, and risk of incident gout in a population‐based study of adults with hypertension: The Atherosclerosis Risk in Communities cohort study

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 Thiazide and loop diuretics were associated with increased gout risk, an association mediated by a change in serum urate levels.

Role of frailty and sarcopenia in predicting outcomes among patients undergoing gastrointestinal surgery.

According to the United States census bureau 20% of Americans will be older than 65 years in 2030 and half of them will need an operation - equating to about 36 million older surgical patients. Older adults are prone to complications during gastrointestinal cancer treatment and therefore may need to undergo special pretreatment assessments that incorporate frailty and sarcopenia assessments. A focused, structured literature review on PubMed and Google Scholar was performed to identify primary research articles, review articles, as well as practice guidelines on frailty and sarcopenia among patients undergoing gastrointestinal surgery. The initial search identified 450 articles; after eliminating duplicates, reports that did not include surgical patients, case series, as well as case reports, 42 publications on the impact of frailty and/or sarcopenia on outcome of patients undergoing gastrointestinal surgery were included. Frailty is defined as a clinically recognizable state of increased vulnerability to physiologic stressors resulting from aging. Frailty is associated with a decline in physiologic reserve and function across multiple physiologic systems. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. Unlike cachexia, which is typically associated with weight loss due to chemotherapy or a general malignancy-related cachexia syndrome, sarcopenia relates to muscle mass rather than simply weight. As such, while weight reflects nutritional status, sarcopenia - the loss of muscle mass - is a more accurate and quantitative global marker of frailty. While chronologic age is an important element in assessing a patients peri-operative risk, physiologic age is a more important determinant of outcomes. Geriatric assessment tools are important components of the pre-operative work-up and can help identify patients who suffer from frailty. Such data are important, as frailty and sarcopenia have repeatedly been demonstrated among the strongest predictors of both short- and long-term outcome following complicated surgical procedures such as esophageal, gastric, colorectal, and hepato-pancreatico-biliary resections.

The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome

Objective To determine whether the Sjögrens syndrome B (SSB)-positive/Sjögrens syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS. Methods Among registrants in the Sjögrens International Collaborative Clinical Alliance (SICCA) with possible or established SS, we compared anti-SSA/anti-SSB reactivity profiles against concurrent phenotypic features. We fitted logistic regression models to explore the association between anti-SSA/anti-SSB reactivity profile and each key SS phenotypic feature, controlling for potential confounders. Results Among 3297 participants, 2061 (63%) had negative anti-SSA/anti-SSB, 1162 (35%) had anti-SSA with or without anti-SSB, and 74 (2%) anti-SSB alone. Key SS phenotypic features were more prevalent and had measures indicative of greater disease activity in those participants with anti-SSA, either alone or with anti-SSB, than in those with anti-SSB alone or negative SSA/SSB serology. These between-group differences were highly significant and not explained by confounding by age, race/ethnicity or gender. Participants with anti-SSB alone were comparable to those with negative SSA/SSB serology in their association with these key phenotypic features. Among SICCA participants classified with SS on the basis of the American-European Consensus Group or American College of Rheumatology criteria, only 2% required the anti-SSB-alone test result to meet these criteria. Conclusions The presence of anti-SSB, without anti-SSA antibodies, had no significant association with SS phenotypic features, relative to seronegative participants. The solitary presence of anti-SSB antibodies does not provide any more support than negative serology for the diagnosis of SS. This serological profile should thus be interpreted cautiously in clinical practice and potentially eliminated from future classification criteria.

Obesity and younger age at gout onset in a community‐based cohort

Obesity is associated with gout risk. It is unclear whether obesity is associated with a younger age at gout onset. We examined whether obesity is related to age at gout onset and quantified the risk of incident gout by obesity status in the Campaign Against Cancer and Heart Disease (CLUE II) study, a longitudinal community‐based cohort.

Serum Potassium, Mortality, and Kidney Outcomes in the Atherosclerosis Risk in Communities Study

OBJECTIVES To investigate the association between serum potassium, mortality, and kidney outcomes in the general population and whether potassium-altering medications modify these associations. PATIENTS AND METHODS We studied 15,539 adults in the Atherosclerosis Risk in Communities Study. Cox proportional hazard regression was used to investigate the association of serum potassium at baseline (1987-1989), evaluated categorically (hypokalemia, <3.5 mmol/L; normokalemia, ≥3.5 and <5.5 mmol/L; hyperkalemia, ≥5.5 mmol/L) and continuously using linear spline terms (knots at 3.5 and 5.5 mmol/L), with mortality, sudden cardiac death, incident chronic kidney disease, and end-stage renal disease. The end date of follow-up for all outcomes was December 31, 2012. We also evaluated whether classes of potassium-altering medications modified the association between serum potassium and adverse outcomes. RESULTS Overall, 413 (2.7%) of the participants had hypokalemia and 321 (2.1%) had hyperkalemia. In a fully adjusted model, hyperkalemia was significantly associated with mortality (hazard ratio, 1.24; 95% CI, 1.04-1.49) but not sudden cardiac death, chronic kidney disease, or end-stage renal disease. Hypokalemia as a categorical variable was not associated with any outcome; however, associations of hypokalemia with all-cause mortality and kidney outcomes were observed among those who were not taking potassium-wasting diuretics (all P for interaction, <.001). CONCLUSIONS Higher values of serum potassium were associated with a higher risk of mortality in the general population. Lower levels of potassium were associated with adverse kidney outcomes and mortality among participants not taking potassium-wasting diuretics.

Recipient age and time spent hospitalized in the year before and after kidney transplantation

Background Kidney transplantation (KT) is a life-prolonging therapy in certain older end-stage renal disease patients, but concerns regarding peritransplantation morbidity remain. We estimate the relative increase in time spent hospitalized in the year post-KT for older versus younger end-stage renal disease patients. Methods This was a retrospective analysis of 27,247 Medicare-primary KT recipients from 2000 to 2005 using United States Renal Data System and Organ Procurement and Transplantation Network data. Time spent hospitalized was enumerated in the year pre-KT and post-KT from Medicare Part A claims. Excess inpatient days were the difference in an individual’s post-KT and pre-KT hospital and skilled nursing facility days, standardized by time spent alive in the year post-KT. Results The median excess inpatient days were similar by age group (9 in recipients 65 years or older vs. 7 in recipients younger than 65 years); however, the distribution was skewed, such that many more older adults had large increases in inpatient time (8.6% totaled >120 excess inpatient days vs. 4.2% in younger recipients). Among older recipients, risk factors for poor outcomes included recipient age, donor age, longer dialysis vintage, diabetic nephropathy, and congestive heart failure. Reasons for posttransplantation hospitalization were similar by age with the exception of rehabilitation, which was common only in the 65+ age group. Mean inpatient costs were equivalent pretransplantation by age but significantly higher posttransplantation among older KT recipients. Conclusions Posttransplantation morbidity may not be so different in most of the older individuals selected for KT; however, a minority fares much worse.

Hypertension Status, Treatment, and Control Among Spousal Pairs in a Middle-aged Adult Cohort

Hypertension status among spouses is known to be concordant, but previous studies relied on history rather than direct measurement, and few data exist on treatment and control between spouses. The goal of this study was to estimate the spousal association of hypertension status, treatment, and control in adults. The authors identified and analyzed data on 4,500 pairs from the Atherosclerosis Risk in Communities (ARIC) cohort, which sampled middle-aged adults and their spouses in 1986-1989, with 3 follow-up visits 3 years apart. Generalized estimating equations were used in logistic regression analyses to calculate the odds ratio of a spouses being hypertensive on the basis of the other spouses hypertension status across 4 visits, adjusting for age, race, body mass index, smoking status, and sodium intake in both individuals. There are marginally increased odds of hypertension for spouses married to someone with hypertension (odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.06, 1.25). Treatment was positively associated between spouses (OR = 1.35, 95% CI: 1.10, 1.67). Control was suggestive of an association, although it was not statistically significant (OR = 1.21, 95% CI: 0.93, 1.56). In middle-aged adults, hypertension status and treatment were moderately associated between spouses after controlling for shared environment. Physicians may target hypertension education and prevention to spouses as a pair rather than as 2 separate patients.

Cognitive Impairment and Graft Loss in Kidney Transplant Recipients

Background Cognitive impairment is common in end-stage renal disease patients and impairs adherence to complex treatment regimens. Given the need for post-transplant immunosuppression, we hypothesized that cognitive impairment at the time of transplant is associated with an increased risk of all-cause graft loss (ACGL) among kidney transplant (KT) recipients. Methods Using the Modified Mini-Mental State (3MS) examination, we measured global cognitive function in a prospective cohort of 864 KT candidates (8/2009-7/2016) as part of a multi-center, prospective cohort study. We estimated the association between pre-KT cognitive impairment and ACGL using Cox regression adjusting for recipient, donor, and transplant factors. We then estimated the national prevalence of cognitive impairment in US KT recipients using multiple imputation by chained equations and predictive mean matching. Results The prevalences of impairment (3MS<80) and severe impairment (3MS<60) were 6.6% and 3.3%, respectively, among living donor KT (LDKT) recipients and 12.4% and 2.6%, respectively, among deceased donor KT (DDKT) recipients. Projected nationally, 11.7% (8.5-14.9%) of all KT recipients had cognitive impairment during the study period (Table 1). LDKT recipients with impairment had higher ACGL risk than recipients without impairment (5-year ACGL: 45.5% vs. 10.6%, p<0.01; aHR impairment: 1.785.4016.34, p<0.01; aHR severe impairment: 1.295.5724.00, p=0.02) (Table 2, Figure 1). DDKT recipients with severe impairment had higher ACGL risk than recipients without severe impairment (5-year ACGL: 53.0% vs. 24.2%, p=0.04; aHR severe impairment: 1.132.927.50, p=0.03) (Figure 2). Conclusion Given the prevalence of cognitive impairment and the associated higher ACGL risk, pre-KT screening for impairment is warranted to identify higher-risk KT recipients. Figure. No caption available. Figure. No caption available. Figure. No caption available. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and the National Institute on Aging (NIA); grant numbers K01AG043501 (PI: Mara McAdams-DeMarco), R01AG055781 (PI: Mara McAdams-DeMarco), F30DK116658 (PI: Ashton Shaffer), F32AG053025? (PI: Christine Haugen), K01AG050699 (PI: Alden Gross), K24DK101828 (PI: Dorry Segev), and R01DK096008 (PI: Dorry Segev). Additionally, Jessica Ruck and Dorry Segev are supported by a Doris Duke Charitable Foundation Clinical Research Mentorship grant.

Frailty, Inflammation, and Waitlist Mortality among Patients with End-Stage Renal Disease on the Kidney Transplant Waitlist

Background Among community-dwelling older adults, frailty is associated with heightened inflammation and subsequent mortality. Although frailty is common among patients on the KT waitlist, the role of frailty and inflammation in this population remains unclear. We quantified the association between frailty, inflammation, and mortality in ESRD patients on the KT waitlist, and tested whether frailty and/or inflammation improves risk prediction beyond clinical factors available in registry-based models. Methods We studied 1,975 prevalent ESRD patients on the KT waitlist (11/1/09-2/28/17) in a multi-center cohort study of measured frailty in patients undergoing transplant evaluation; serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-a receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants. We compared the C-statistic of an established registry-based prediction model adding frailty and/or inflammation (1SD change in log IL-6, sTNFR1, CRP, or an aggregate inflammatory index). Results The mean age was 53.7 and 18.4% were frail. Frail candidates had elevated serum IL-6 (P<0.001), sTNFR1 (P=0.02), CRP (P=0.01), and a higher inflammatory index (P<0.001). The registry-based model had moderate predictive ability (C-statistic=0.655). Frailty was associated with increased waitlist mortality risk (frail HR=2.19, 95%CI:1.26-3.79) (Figure) but did not improve mortality risk prediction (C-statistic=0.646; P=0.65) (Table). Like frailty, IL-6 (HR=2.13, 95%CI:1.41-3.22), sTNFR1 (HR=1.70, 95%CI:1.12-2.59), CRP (HR=1.68, 95%CI:1.06-2.67), and the inflammatory index (HR=2.09, 95%CI:1.38-3.16) were all associated with increased waitlist mortality risk. But unlike frailty, adding IL-6 (C-statistic=0.777; P=0.02), CRP (C-statistic=0.728; P=0.02), or the inflammatory index (C-statistic=0.777; P=0.02) substantially improved mortality risk prediction. Conclusions Among adult ESRD patients on the KT waitlist, frailty and inflammation were associated with increased waitlist mortality risk, but only inflammatory markers significantly improved mortality risk prediction. Heightened inflammation may be the biological link between frailty and mortality in KT candidates. This study was supported by NIH grant R01AG042504 (PI: Dorry Segev), R01AG055781 (PI: McAdams-DeMarco) and K24DK101828 (PI: Dorry Segev). Mara McAdams-DeMarco was also supported by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center (P30AG021334), National Institute on Aging (K01AG043501). Christine Haugen was supported by the National Institute on Aging (F32AG053025). Ashton Shaffer was supported by the National Institute of General Medical Sciences (5T32GM007309). Figure. No caption available. Figure. No caption available.