Faculty Bibliography
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Department/Unit:Population Health
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13249
Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies
BACKGROUND:The primary biomarkers used to define CKD are serum creatinine and albuminuria. These biomarkers have directed focus on the filtration and barrier functions of the kidney glomerulus even though albuminuria results from tubule dysfunction as well. Given that proximal tubules make up ∼90% of kidney cortical mass, we evaluated whether a sensitive and specific marker of proximal tubule injury, urinary kidney injury molecule-1 (KIM-1), is elevated in individuals with CKD or with risk factors for CKD. METHODS:We measured urinary KIM-1 in participants of five cohort studies from the USA and Sweden. Participants had a wide range of kidney function and were racially and ethnically diverse. Multivariable linear regression models were used to test the association of urinary KIM-1 with demographic, clinical and laboratory values. RESULTS:In pooled, multivariable-adjusted analyses, log-transformed, creatinine-normalized urinary KIM-1 levels were higher in those with lower eGFR {β = -0.03 per 10 mL/min/1.73 m(2) [95% confidence interval (CI) -0.05 to -0.02]} and greater albuminuria [β = 0.16 per unit of log albumin:creatinine ratio (95% CI 0.15-0.17)]. Urinary KIM-1 levels were higher in current smokers, lower in blacks than nonblacks and lower in users versus nonusers of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. CONCLUSION:Proximal tubule injury appears to be an integral and measurable element of multiple stages of CKD.
PMCID:5009290
PMID: 27270293
ISSN: 1460-2385
CID: 5584222
Risk of end-stage renal disease in Japanese patients with chronic kidney disease increases proportionately to decline in estimated glomerular filtration rate
Predominantly based on North American and European studies, 30% to 40% declines in estimated glomerular filtration rate (eGFR) over a few years are strongly associated with the risk of end-stage renal disease (ESRD) and have been proposed as surrogate endpoints of ESRD for clinical research. However, this association has not been systematically quantified in Asian populations. To do this we studied adult Japanese patients with baseline eGFR 10-59 ml/min/1.73m2. Changes in eGFR from baseline measured by centrally assessed serum creatinine were linked to subsequent ESRD in 2410 patients after one year and in 2079 patients after year 2. After year 1, 1.4% experienced a 53% decrease in eGFR (equivalent to doubling of serum creatinine), whereas 4.3% and 9.7% had eGFR decrease of 40% or 30% or more, respectively. The corresponding numbers after 2 years were 4.2%, 10.9%, and 19.3%, respectively. After year 1 baseline period, 498 patients developed ESRD over a median follow-up of 2.9 years (365 ESRD cases over a median follow-up of 2 years after year 2). In year 1, after accounting for potential confounders, a strong linear association was found between eGFR declines and subsequent ESRD, with adjusted hazard ratios of 20.7 (95% confidence interval 14.3-30.1) for a 53% decrease, 9.6 (7.4-12.5) for a 40% decrease, and 5.3 (4.1-6.9) for a 30% decrease compared to no change. Corresponding hazard ratios for year two analysis were 17.3 (11.8-25.3), 6.5 (4.7-9.1), and 3.1 (2.2-4.4), respectively. The associations were consistent across demographics and kidney diseases. Thus, 30% to 40% declines in eGFR are strongly associated with the risk of ESRD in Japanese patients with reduced eGFR, broadening global implications as a surrogate endpoint in clinical research.
PMID: 27666758
ISSN: 1523-1755
CID: 5584332
Persistent but not Paroxysmal Atrial Fibrillation Is Independently Associated With Lower Cognitive Function: ARIC Study [Letter]
PMCID:4955949
PMID: 26988962
ISSN: 1558-3597
CID: 5584152
Determinants of minimal elevation in high-sensitivity cardiac troponin T in the general population
OBJECTIVES/OBJECTIVE:To study the relationship between cardiovascular risk factors and detectable cardiac troponin-T using a highly sensitive assay (hs-cTnT) among persons without a history of cardiovascular disease. DESIGN AND METHODS/METHODS:We examined the cross-sectional associations between cardiovascular risk factors and hs-cTnT in 9593 participants (mean age 65.6 (SD, 5.6), 41% female, 22% black) free of cardiovascular disease in a community-based cohort, through the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to characterize the association between cardiovascular risk factors and detectable (≥3.0 to 13.9ng/L) and elevated (≥14.0ng/L) hs-cTnT. RESULTS:hs-cTnT was detectable in 59% and elevated in 7% of the study population. Among persons with ideal cardiovascular health, hs-cTnT was detectable in 44%. In models adjusting for significant determinants of hs-cTnT concentration, detectable hs-cTnT was more frequent among males, blacks and persons with diabetes and hypertension and less frequent among statin users, current smokers and drinkers. Other risk factors associated with detectable hs-cTnT were older age, lower kidney function and higher body mass index. These risk factors were associated with elevated hs-cTnT in a similar pattern. CONCLUSION/CONCLUSIONS:In a community-based sample without cardiovascular disease hs-cTnT is detectable in most adults, even among those with ideal cardiovascular health. Although most traditional cardiovascular risk factors were significant determinants of detectable and elevated hs-cTnT, the associations were particularly robust for sex, age, race, hypertension and diabetes.
PMCID:4889514
PMID: 26975902
ISSN: 1873-2933
CID: 5584142
An Empirical Approach to Signature Peptide Choice for Selected Reaction Monitoring: Quantification of Uromodulin in Urine
BACKGROUND:Many avenues have been proposed for a seamless transition between biomarker discovery data and selected reaction monitoring (SRM) assays for biomarker validation. Unfortunately, studies with the abundant urinary protein uromodulin have shown that these methods do not converge on a consistent set of surrogate peptides for targeted mass spectrometry. As an alternative, we present an empirical peptide selection work flow for robust protein quantification. METHODS:We compared the relative SRM signal intensity of 12 uromodulin-derived peptides between tryptic digests of 9 urine samples. Pairwise CVs between the 12 peptides were 0.19-0.99. We used a correlation matrix to identify peptides that reproducibly tracked the amount of uromodulin protein and selected 4 peptides with robust and highly correlated SRM signals. Absolute quantification was performed with stable isotope-labeled versions of these peptides as internal standards and a standard curve prepared from a tryptic digest of purified uromodulin. RESULTS:Absolute quantification of uromodulin in 40 clinical urine samples yielded interpeptide correlations of ≥0.984 and correlations of ≥0.912 with ELISA data. The SRM assays were linear over >3 orders of magnitude and had typical interdigest CVs of <10%, interinjection CVs of <7%, and intertransition CVs of <7%. CONCLUSIONS:Comparing the apparent abundance of a plurality of peptides derived from the same target protein makes it possible to select signature peptides that are unaffected by the unpredictable confounding factors inevitably present in biological samples.
PMID: 26589548
ISSN: 1530-8561
CID: 5584012
Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
PMCID:4764151
PMID: 26631737
ISSN: 1939-327x
CID: 5584022
Managing Chronic Kidney Disease in Older People--Reply [Comment]
PMID: 26784787
ISSN: 1538-3598
CID: 5584052
The George W. Comstock Center for Public Health Research and Prevention: A Century of Collaboration, Innovation, and Translation [Historical Article]
The Johns Hopkins Bloomberg School of Public Health has been engaged in public health research and practice in Washington County, Maryland, nearly since its inception a century ago. In 2005, the center housing this work was renamed the George W. Comstock Center for Public Health Research and Prevention to honor its pioneering leader. Principles that guided innovation and translation well in the past included: research synergies and opportunities for translation realized through longstanding connection with the community; integration of training with public health research; lifelong learning, mentorship, and teamwork; and efficiency through economies of scale. These principles are useful to consider as we face the challenges of improving the health of the population over the next 100 years.
PMCID:4772436
PMID: 26872712
ISSN: 1476-6256
CID: 5584072
Temporal Trends in Hospitalization for Acute Decompensated Heart Failure in the United States, 1998-2011
Estimates of the numbers and rates of acute decompensated heart failure (ADHF) hospitalization are central to understanding health-care utilization and efforts to improve patient care. We comprehensively estimated the frequency, rate, and trends of ADHF hospitalization in the United States. Based on Atherosclerosis Risk in Communities (ARIC) Study surveillance adjudicating 12,450 eligible hospitalizations during 2005-2010, we developed prediction models for ADHF separately for 3 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 428 discharge diagnosis groups: 428 primary, 428 nonprimary, or 428 absent. We applied the models to data from the National Inpatient Sample (11.5 million hospitalizations of persons aged ≥55 years with eligible ICD-9-CM codes), an all-payer, 20% probability sample of US community hospitals. The average estimated number of ADHF hospitalizations per year was 1.76 million (428 primary, 0.80 million; 428 nonprimary, 0.83 million; 428 absent, 0.13 million). During 1998-2004, the rate of ADHF hospitalization increased by 2.0%/year (95% confidence interval (CI): 1.8, 2.5) versus a 1.4%/year (95% CI: 0.8, 2.1) increase in code 428 primary hospitalizations (P < 0.001). In contrast, during 2005-2011, numbers of ADHF hospitalizations were stable (-0.5%/year; 95% CI: -1.4, 0.3), while the numbers of 428-primary hospitalizations decreased by -1.5%/year (95% CI: -2.2, -0.8) (P for contrast = 0.03). In conclusion, the estimated number of hospitalizations with ADHF is approximately 2 times higher than the number of hospitalizations with ICD-9-CM code 428 in the primary position. The trend increased more steeply prior to 2005 and was relatively flat after 2005.
PMCID:4772439
PMID: 26895710
ISSN: 1476-6256
CID: 5584082
Spousal Influence on Physical Activity in Middle-Aged and Older Adults: The ARIC Study
Low physical activity levels are a public health concern. Few studies have assessed the concordance of physical activity change among spouses. We studied this concordance during a 6-year period (baseline: 1987-1989; follow-up: 1993-1995) in 3,261 spousal pairs from the US-based Atherosclerosis Risk in Communities (ARIC) Study. Linear regression was used to examine the association between change in individuals' sport/exercise and leisure physical activity indices (ranging from 1 (low) to 5 (high)) and change in his or her spouse's indices. The association between individual and spousal changes in meeting physical activity recommendations was assessed with logistic regression. Individual changes in the sport/exercise and leisure indices were positively associated with spousal changes. For every standard deviation increase in their wives' sport/exercise index, men's exercise index increased by 0.09 (95% confidence interval: 0.05, 0.12) standard deviation; for every standard deviation increase in their wives' leisure index, men's leisure index increased by 0.08 standard deviation. Results were similar for women. Individuals had higher odds of meeting physical activity recommendations if their spouse met recommendations at both visits or just follow-up. In conclusion, changes in an individual's physical activity are positively associated with changes in his or her spouse's physical activity. Physical activity promotion efforts should consider targeting couples.
PMCID:4772433
PMID: 26337074
ISSN: 1476-6256
CID: 5583922
