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author:("kuse, John W.")
1.  Higher Levels of Cystatin C are Associated with Worse Cognitive Function Among Older Adults with Chronic Kidney Disease: The CRIC COG Study 
Cystatin C, a measure of kidney function, has been linked to cognitive impairment, but the association between cognition and levels of cystatin C in persons with chronic kidney disease (CKD) is unknown.
We studied 821 participants from the Chronic Renal Insufficiency Cohort Cognitive Study with a baseline cognitive assessment completed at the same visit as serum cystatin C measurement.
Levels of serum cystatin C were categorized into tertiles; cognitive function was assessed with six neuropsychological tests. We compared scores on these tests across tertiles of cystatin C using linear regression and logistic regression to examine the association between cystatin C level and poor cognitive performance (1 SD difference from the mean).
The mean participant age was 64.9 years, 50.6% were male, and 48.6% were white. After multivariable adjustment for age, race, education, and medical comorbidities in linear models, higher levels of cystatin C were associated with worse cognition on the 3MS, Buschke Delayed Recall, Trails A, Trails B, and Boston Naming (p<0.05 for all). This association remained statistically significant for Buschke Delayed Recall (p=0.01) and Trails A (p=0.03) after additional adjustment for eGFR. Compared to the lowest tertile of cystatin C, the highest tertile was associated with increased likelihood of poor cognitive performance on Trails A (OR=2.17; 95% CI: 1.16-4.06), Trails B (OR=1.89; 95% CI: 1.09-3.27), and Boston Naming (OR=1.85; 95% CI: 1.07-3.19) after multivariate adjustment in logistic models.
Among patients with CKD, higher levels of serum cystatin C were associated with worse cognition and increased likelihood of poor cognitive performance on attention, executive function, and naming. Cystatin C is a marker of cognitive impairment and may be associated with cognition independent of eGFR levels.
PMCID: PMC4201363  PMID: 25125225
cystatin C; cognition; chronic kidney disease
2.  Interleukin-6 Is a Risk Factor for Atrial Fibrillation in Chronic Kidney Disease: Findings from the CRIC Study 
PLoS ONE  2016;11(2):e0148189.
Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic kidney disease (CKD). In this study, we examined the association between inflammation and AF in 3,762 adults with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. AF was determined at baseline by self-report and electrocardiogram (ECG). Plasma concentrations of interleukin(IL)-1, IL-1 Receptor antagonist, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor-β, high sensitivity C-Reactive protein, and fibrinogen, measured at baseline. At baseline, 642 subjects had history of AF, but only 44 had AF in ECG recording. During a mean follow-up of 3.7 years, 108 subjects developed new-onset AF. There was no significant association between inflammatory biomarkers and past history of AF. After adjustment for demographic characteristics, comorbid conditions, laboratory values, echocardiographic variables, and medication use, plasma IL-6 level was significantly associated with presence of AF at baseline (Odds ratio [OR], 1.61; 95% confidence interval [CI], 1.21 to 2.14; P = 0.001) and new-onset AF (OR, 1.25; 95% CI, 1.02 to 1.53; P = 0.03). To summarize, plasma IL-6 level is an independent and consistent predictor of AF in patients with CKD.
PMCID: PMC4739587  PMID: 26840403
3.  Urine Neutrophil Gelatinase-Associated Lipocalin and Risk of Cardiovascular Disease and Death in CKD: Results From the Chronic Renal Insufficiency Cohort (CRIC) Study 
Chronic kidney disease is common and associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration—based markers (such as serum creatinine or albuminuria).
Study Design
Cohort study, Chronic Renal Insufficiency Cohort (CRIC) Study.
Setting & Participants
3386 participants with estimated glomerular filtration rate of 20-70 mL/min/1.73 m2 enrolled from June 2003 through August 2008.
Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration.
Adjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke or peripheral artery disease) and death through March 2011.
Urine NGAL concentration measured at baseline with a two-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories).
There were 428 heart failure events (during 16383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16584 person-years of follow-up) and 522 deaths (during 18214 person-years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors and cardiac medications, higher urine NGAL levels remained independently associated with ischemic atherosclerotic events (adjusted HR for the highest [>49.5 ng/ml] vs. lowest [≤6.9 ng/ml] quintile, 1.83 [95% CI, 1.20-2.81]; HR, per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths.
Urine NGAL was measured only once.
Among patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were independently associated with future ischemic atherosclerotic events but not with heart failure events or deaths.
PMCID: PMC4353671  PMID: 25311702
neutrophil gelatinase-associated lipocalin (NGAL); renal tubular injury; renal tubular dysfunction; biomarker; chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort (CRIC) Study; cardiovascular disease; ischemic atherosclerotic event
4.  Long-term prevalence and predictors of urinary incontinence among women in the Diabetes Prevention Program Outcomes Study 
This study examined the long-term prevalence and predictors of ≥ weekly urinary incontinence (UI) in the Diabetes Prevention Program Outcomes Study (DPPOS).
DPPOS is a follow-up study of the DPP randomized clinical trial of overweight adults with impaired glucose tolerance. This analysis included 1,778 female participants of DPPOS who had been randomly assigned during DPP to intensive lifestyle intervention [ILS; n = (582)], metformin [MET; n = 589], or placebo [PLC; n = 607)]. DPPOS participants completed semi-annual assessments after the final DPP visit and for six years until October, 2008.
At entry into DPPOS, the prevalence of weekly UI was lower in ILS compared with MET and PLC (44.2% vs. 51.8%, 48.0% UI/week, p=0.04); during the 6-year follow-up, these lower rates in ILS were maintained (46.7%, 53.1%, 49.9% UI/week; p = 0.03). Statistically adjusting for UI prevalence at the end of DPP, treatment arm no longer had a significant impact on UI during DPPOS. Independent predictors of lower UI during DPPOS included lower BMI (OR [95% CI] = 0.988 [0.982, 0.994]) and greater physical activity (OR = 0.999 [0.998, 1.000] at DPPOS entry, and greater reductions in BMI (OR = 0.75 [0.60, 0.94]) and waist circumference (OR = 0.998 [0.996, 1.0]) during DPPOS. Diabetes was not significantly related to UI.
ILS had a modest positive impact on UI that endured for years after the DPP trial and should be considered for the long-term prevention and treatment of UI in overweight/obese women with glucose intolerance.
PMCID: PMC4387889  PMID: 25352018
Diabetes Prevention Program Outcomes Study; lifestyle intervention; urinary incontinence; weight loss
5.  Anemia and risk for cognitive decline in chronic kidney disease 
BMC Nephrology  2016;17:13.
Anemia is common among patients with chronic kidney disease (CKD) but its health consequences are poorly defined. The aim of this study was to determine the relationship between anemia and cognitive decline in older adults with CKD.
We studied a subgroup of 762 adults age ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) study. Anemia was defined according to the World Health Organization criteria (hemoglobin <13 g/dL for men and <12 g/dL for women). Cognitive function was assessed annually with a battery of six tests. We used logistic regression to determine the association between anemia and baseline cognitive impairment on each test, defined as a cognitive score more than one standard deviation from the mean, and mixed effects models to determine the relation between anemia and change in cognitive function during follow-up after adjustment for demographic and clinical characteristics.
Of 762 participants with mean estimated glomerular filtration rate of 42.7 ± 16.4 ml/min/1.73 m2, 349 (46 %) had anemia. Anemia was not independently associated with baseline cognitive impairment on any test after adjustment for demographic and clinical characteristics. Over a median 2.9 (IQR 2.6–3.0) years of follow-up, there was no independent association between anemia and change in cognitive function on any of the six cognitive tests.
Among older adults with CKD, anemia was not independently associated with baseline cognitive function or decline.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-016-0226-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4730636  PMID: 26823182
Cognitive decline; CKD; Anemia
6.  Variation in Institutional Review Board (IRB) Responses to a Standard Protocol for a Multicenter Randomized Controlled Surgical Trial 
The Journal of urology  2009;181(6):2674-2679.
The primary responsibility of Institutional Review Boards (IRBs) is to protect human research subjects and therefore ensure that studies are conducted in accordance with a standard set of ethical principles. A number of studies have compared the responses from IRBs in multicenter clinical trials involving medical therapies. To date, none have been conducted in trials investigating surgical interventions. The intent of this study was to investigate the consistency of the recommendations issued from one institutional IRB to another in the Minimally Invasive Surgical Therapies (MIST) for benign prostatic hyperplasia (BPH), a multicenter trial with a uniform consent and study protocol.
Materials and Methods
We obtained the IRB responses from six of the seven participating institutions after the initial submission of the MIST study protocol and classified the responses. We then re-distributed the approved protocols to an IRB at another participating institution and analyzed their review of these protocols.
We found that both the number and types of responses required for IRB approval of an identical study protocol varied significantly among the participating institutions. We also found that IRB responses were inconsistent in the second review, although all protocols were ultimately approved.
We conclude that the current system of local IRB review in the context of a multicenter surgical trial is inefficient in the review process and may not provide expertise in overseeing surgical trials. Based on these results, a central surgical IRB may be needed to improve of the ethical review process in multicenter trials.
PMCID: PMC4720253  PMID: 19375101
Institutional Review Board; Controlled Clinical Trials; Minimally Invasive Surgery
7.  Blood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the CRIC study 
Hypertension  2014;65(1):93-100.
Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease (CKD), prior to starting hemodialysis. We determined the association between SBP and mortality at advanced CKD and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort (CRIC) participants with advanced CKD followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants: 1) had an estimated glomerular filtration rate <30 ml/min/1.73m2 (N=1,705); 2) initiated hemodialysis and had dialysis-unit SBP measures (N=403) and; 3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a CRIC study visit (N=326). Cox models adjusted for demographics, cardiovascular risk factors and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced CKD, there was no association between SBP and mortality (HR 1.02 [95% CI: 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (HR 1.26 [95% CI: 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP which may merit more consideration as a target for clinical management and in interventional trials.
PMCID: PMC4268143  PMID: 25287404
CKD; hypertension; dialysis; mortality; ESRD
8.  Is it time to tip your glass to prevent CKD? 
Kidney international  2015;87(5):877-879.
Chronic kidney disease (CKD) is a major global medical and public health challenge. Based primarily on a modest number of prospective epidemiological studies it appears that alcohol consumption reduces the risk of CKD in the general population. Our understanding of the potential benefits of alcohol consumption on CKD is likely to evolve in the future and will be informed primarily from observational epidemiological studies.
PMCID: PMC4425230  PMID: 25951066
9.  Novel research approaches for interstitial cystitis/bladder pain syndrome: thinking beyond the bladder 
Despite years of basic and clinical research focused on interstitial cystitis/bladder pain syndrome (IC/BPS), including clinical trials of candidate therapies, there remains an insufficient understanding of underlying cause(s), important clinical features and a lack of effective treatments for this syndrome. Progress has been limited and is likely due to many factors, including a primary focus on the bladder and lower urinary tract as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Traditionally, there has been a lack of sufficiently diverse expertise and application of novel, integrated methods to study this syndrome. However, some important insights have been gained. For example, epidemiological studies have revealed that IC/BPS is commonly associated with other chronic pain conditions, including fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome. These observations suggest that IC/BPS may involve systemic pathophysiology, including alterations of the central nervous system in some patients. Furthermore, there may be multiple causes and contributing factors that manifest in the symptoms of IC/BPS leading to multiple patient sub-groups or phenotypes. Innovative research is necessary to allow for a more complete description of the relationship between this syndrome and other disorders with overlapping symptoms. This report provides examples of such innovative research studies and their findings which have the potential to provide fresh insights into IC/BPS and disorders associated with chronic pain through characterization of broad physiologic systems, as well as assessment of the contribution of the bladder and lower urinary tract. They may also serve as models for future investigation of symptom-based urologic and non-urologic disorders that may remain incompletely characterized by previous, more traditional research approaches. Furthermore, it is anticipated a more holistic understanding of chronic urologic pain and dysfunction will ensue from productive interactions between IC/BPS studies like those described here and broader cutting-edge research endeavors focused on potentially related chronic pain disorders. A more comprehensive vision for IC/BPS inquiry is anticipated to yield new insights into basic disease mechanisms and clinical characteristics that will inform future research studies that will lead to more effective therapies and improved clinical care for these patients.
PMCID: PMC4708560  PMID: 26813921
Interstitial cystitis (IC); bladder pain syndrome (BPS); urologic chronic pelvic pain syndrome (UCPPS); research models; translational science
10.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
11.  Time-updated systolic blood pressure and the progression of chronic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study 
Annals of internal medicine  2015;162(4):258-265.
Blood pressure (BP) is often inadequately controlled in patients with chronic kidney disease (CKD). Previous reports of the longitudinal association between achieved level of BP and end-stage renal disease (ESRD) have not incorporated time-updated BP with appropriate adjustment for known confounders.
To assess the association between baseline and time-updated systolic BP (SBP) with the progression of CKD.
Observational, prospective cohort study ( identifier: NCT00304148)
Seven US clinical centers
Participants of the Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,708) followed for a median (25th, 75th percentiles) of 5.7 (4.6, 6.7) years
The mean of three seated SBP measurements were used as the visit-specific SBP. SBP was time-updated as the mean of that visit and all prior visits. Outcomes were ESRD and the composite renal endpoint of ESRD (dialysis or transplantation) or halving of the estimated glomerular filtration rate (eGFR). Analyses investigating baseline and time-updated SBP utilized traditional Cox proportional hazards models and marginal structural models, respectively.
SBP was ≥130 mmHg at all study visits in 19.2% of participants, and ≥140 mmHg in 10.6%. The hazard ratio (95% confidence interval) for ESRD among participants with SBP 130–139 mmHg, compared to SBP <120 mmHg, was 1.46 (1.13–1.88) using only baseline data, and was 2.37 (1.48–3.80) using all available time-updated data. Among those with SBP ≥140 mmHg, corresponding hazard ratios were 1.46 (1.18–1.88) and 3.37 (2.26–5.03), respectively.
SBP was measured once annually, and the CRIC Study cohort is not a random sample.
Among participants in the CRIC Study, time-updated SBP over 130 mmHg was more strongly associated with progression of CKD than analyses based on baseline SBP.
The CRIC Study is funded under cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Translational Science Awards, and other NIH grants.
PMCID: PMC4404622  PMID: 25686166
12.  Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study 
European Heart Journal  2013;35(31):2115-2122.
Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.
Methods and results
We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13–1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio.
In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.
PMCID: PMC4132636  PMID: 24306482
Atherosclerosis; Chemokines; Myocardial infarction; CXCL12
13.  Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study 
PLoS ONE  2015;10(4):e0124772.
Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.
Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.
LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).
In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.
PMCID: PMC4409366  PMID: 25909952
14.  Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C 
Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.
Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.
Mean measured GFRs were 68 and 70 ml per minute per 1.73 m2 of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m2 with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m2 with the creatinine equation and the cystatin C equation (P = 0.07 and P = 0.05), respectively. Precision was improved with the combined equation (inter-quartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m2, respectively [P = 0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m2, the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m2 or greater than or equal to 60 ml per minute per 1.73 m2 (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 as having a GFR of 60 ml or higher per minute per 1.73 m2.
The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
PMCID: PMC4398023  PMID: 22762315
15.  Inadequacy of Cardiovascular Risk Factor Management in Chronic Kidney Transplantation -- Evidence from the FAVORIT Study 
Clinical transplantation  2012;26(4):E438-E446.
Kidney transplant recipients (KTRs) have increased risk for cardiovascular disease (CVD). Our objective is to describe the prevalence of CVD risk factors applying standard criteria and use of CVD risk factor lowering medications in contemporary KTRs.
The Folic Acid for Vascular Outcome Reduction in Transplantation study enrolled and collected medication data on 4,107 KTRs with elevated homocysteine and stable graft function an average of 5 years post-transplant.
CVD risk factors were common (hypertension or use of blood pressure lowering medication in 92%, borderline or elevated LDL or use of lipid-lowering agent in 66%, history of diabetes mellitus in 41%, and obesity in 38%); prevalent CVD was reported in 20% of study participants. National Kidney Foundation blood pressure (BP) guidelines (BP < 130/80 mm Hg) were not met by 69% of participants. Uncontrolled hypertension (BP of 140/90 mm Hg or higher) was present in 44% of those taking anti-hypertension medication; 18% of participants had borderline or elevated LDL, of which 60% were untreated, and 31% of the participants with prevalent CVD were not using an anti-platelet agent.
There is opportunity to improve treatment and control of traditional CVD risk factors in kidney transplant recipients.
PMCID: PMC4388027  PMID: 22775763
Kidney transplantation; cardiovascular disease; cardiovascular risk factors; medications; medical management
16.  DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC Study 
Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).
We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.
The mean eGFR slope was 2.2 (1.4) and −5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E−05 to 9.5E−05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E−03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD.
Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.
PMCID: PMC3967834  PMID: 24516231
chronic renal disease; chronic renal disease progression; DNA methylation; epigenetics
17.  Treatment Success of Retropubic and Transobturator Midurethral Slings at 24-months 
The Journal of urology  2012;188(6):2281-2287.
Longer-term comparative efficacy information regarding transobturator and retropubic midurethral slings (TMUS and RMUS) is needed. We report 24 month continence rates, complications and symptom outcomes from a randomized equivalence trial.
Material & Methods
Primary outcomes were objective (negative stress test, negative pad test and no retreatment for stress urinary incontinence, SUI) and subjective (no self-report of SUI symptoms, no leakage episodes on 3-day bladder diary and no retreatment for SUI) success at 24 months. Predetermined equivalence margin was ±12%.
516 of 597 (86.4%) randomized participants were assessed. Objective success rates for RMUS and TMUS were 77.3% and 72.3%, respectively (95% CI for difference of 5.1%: −2.0, 12.1%), subjective success rates were 55.7% and 48.3% (CI for difference of 7.4%: −0.7, 15.5%). Neither objective nor subjective success rates met the pre-specified criteria for equivalence.
Patient satisfaction (RMUS 86.3% vs. TMUS 88.1%, p=0.58), frequency of de novo urgency incontinence (RMUS 0% vs. TMUS 0.3%, p= 0.99), and occurrence of mesh exposure (RMUS 4.4% vs. TMUS 2.7%, p=0.26) were not significantly different. RMUS participants had higher rates of voiding dysfunction requiring surgery (3.0% vs. 0%, p=0.002) and urinary tract infections (17.1% vs. 10.7%, p=0.025) while the TMUS group had more neurologic symptoms (9.7% vs. 5.4%, p=0.045).
At 24 months, objective success rates, which met criteria for equivalence at 12 months, no longer met these criteria. Subjective success rates remained inconclusive for equivalence. Patient satisfaction remained high and symptom severity remained markedly improved. Continued surveillance is important in women undergoing MUS.
PMCID: PMC4367868  PMID: 23083653
Stress urinary incontinence; midurethral sling; surgical outcomes
18.  The Effect of Urodynamic Testing on Clinical Diagnosis, Treatment Plan and Outcomes In Women Undergoing Stress Urinary Incontinence Surgery 
The Journal of urology  2012;189(1):204-209.
To evaluate the influence of pre-operative urodynamic studies (UDS) on diagnoses, global treatment plan and outcomes in women having surgery for uncomplicated stress predominant urinary incontinence (SUI).
Materials & Methods
Secondary analysis from a multicenter, randomized trial of the value of preoperative UDS. Physicians provided pre- and post-UDS diagnoses and global treatment plans, defined as proceeding with surgery, surgery type, surgical modification, non-surgical therapy. Treatment plan changes and surgical outcomes between office evaluation (OE) and OE plus UDS were compared by McNemar’s test.
294 of 315 subjects randomized to UDS after OE had evaluable data. UDS changed the OE diagnoses in167 women (56.8%), decreasing the diagnoses of OAB-wet (41.6% to 25.2%, p<0.001), OAB-dry (31.4% to 20.8%, p=0.002) and intrinsic sphincter deficiency (ISD) (19.4% to 12.6%, p=0.003) but increasing the diagnosis of voiding dysfunction (2.2% to 11.9%, p<0.001). After UDS, physicians cancelled surgery in 4/294 (1.4%), changed the incontinence procedure in 13/294 (4.4%), and planned to modifiy the midurethral sling tension (“more or less obstructive”) in 20/294 women (6.8%). Non-surgical treatment plans changed in 40/294 (14%). UDS driven treatment plan changes were not associated with treatment success (OR, 0.96 (0.41, 2.25), p = 0.92), but were associated with increased postoperative treatment for urge UI (OR 3.23, 95% CI 1.46, 7.14), p = 0.004).
UDS significantly changed clinical diagnoses and global treatment plan but infrequently influenced surgeon decision to cancel, change or modify surgical plans. Global treatment plan changes were associated with increased treatment for post operative urgency UI.
PMCID: PMC4363108  PMID: 22982425
urodynamic studies; office evaluation; stress urinary incontinence; midurethral sling; surgical outcomes; clinical diagnosis
19.  Urinary Incontinence Management Costs are Reduced Following Burch or Sling Surgery for Stress Incontinence 
To estimate the effect of Burch and fascial sling surgery on out-of-pocket urinary incontinence (UI) management costs at 24 months post-operatively and identify predictors of change in cost among women enrolled in a randomized trial comparing these procedures.
Resources used for UI management (supplies, laundry, dry cleaning) were self-reported by 491 women at baseline and 24 months post-surgery and total out-of-pocket costs for UI management (in 2012 US dollars) were estimated. Data from the two surgical groups were combined to examine change in cost for UI management over 24 months. Univariate and bivariate changes in cost were analyzed using Wilcoxon signed rank test. Predictors of change in cost were examined using multivariate mixed models.
At baseline mean (±SD) age of participants was 53±10 years, and frequency of weekly UI episodes was 23±21. Weekly UI episodes decreased by 86% at 24 months (P<0.001). Mean weekly cost was $16.60±$27 (median $9.39) at baseline and $4.57±$15 (median $0.10) at 24 months (P<0.001), a decrease of 72%. In multivariate analyses, cost decreased by $3.38±$0.77 per week for each decrease of 1 UI episode per day (P<0.001) and was strongly associated with greater improvement in UDI and IIQ scores (P<0.001) and decreased 24-hour pad weight (P<0.02).
Following Burch or fascial sling surgery, UI management cost at 24 months decreased by 72% ($625 per woman per year) and was strongly associated with decreasing UI frequency. Reduced out-of-pocket expenses may be a benefit of these established urinary incontinence procedures.
PMCID: PMC4349353  PMID: 24631433
urinary incontinence; urinary incontinence – costs; costs and cost analysis
20.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes.
Study Design
Multicenter prospective cohort study.
Setting & Participants
Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years.
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
The primary outcome is unassisted clinical maturation defined as successful use of the fistula for dialysis for four weeks without any maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use.
Pre-operative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intra-operative vein tissue collection for histopathological and molecular analyses; post-operative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation.
Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively.
Exclusion of two-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation.
The HFM Study will be of sufficient size and scope to 1) evaluate a broad range of mechanistic hypotheses, 2) identify clinical practices associated with maturation outcomes, 3) assess the predictive utility of early indicators of fistula outcome, and 4) establish targets for novel therapeutic interventions to improve fistula maturation.
PMCID: PMC4134933  PMID: 23992885
21.  5-Year Longitudinal Follow-up after Retropubic and Transobturator Midurethral Slings 
The Journal of urology  2014;193(1):203-210.
Few studies have characterized longer-term outcomes after retropubic and transobturator midurethral slings.
Women completing 2-year participation in a randomized equivalence trial who had not received surgical retreatment for stress urinary incontinence were invited to participate in a 5-year observational cohort. The primary outcome, treatment success, was defined as no retreatment or self-reported stress incontinence symptoms. Secondary outcomes included urinary symptoms and quality of life, satisfaction, sexual function and adverse events.
404 of 597 (68%) women from the original trial enrolled. Five-years after surgical treatment, success was 7.9% greater in women assigned to retropubic-sling compared to transobturator-sling (51.3% vs 43.4%, 95% CI −1.4%, 17.2%) not meeting pre-specified criteria for equivalence. Satisfaction decreased over 5-years, but remained high and similar between arms (79%, retropubic-sling vs 85%, transobturator-sling groups, p=0.15). Urinary symptoms and quality of life worsened over time (p<0.001), and women with retropubic-sling reported greater urinary urgency (P=0.001), more negative quality of life impact (p=0.02), and worse sexual function (P=0.001). There was no difference in proportion of women experiencing at least 1 adverse event (p=0.17). Seven new mesh erosions were noted (retropubic-sling-3, transobturator-sling-4).
Treatment success declined over 5-years for retropubic and transobturator-slings and did not meet pre-specified criteria for equivalence with retropubic demonstrating a slight benefit. However, satisfaction remained high in both arms. Women undergoing transobturator-sling reported more sustained improvement in urinary symptoms and sexual function. New mesh erosions occurred in both arms over time, although at a similarly low rate.
PMCID: PMC4272663  PMID: 25158274
22.  Inflammatory and Tissue Remodeling Urinary Biomarkers Before and After Midurethral Sling Surgery for Stress Urinary Incontinence 
The Journal of urology  2013;191(3):703-709.
Urinary biomarkers were measured from women at baseline and 1 post-surgery for stress urinary incontinence (SUI) and associations with clinicodemographic covariates and outcomes were analyzed.
Pre- and post-surgery urine specimens from 150 women were assayed for inflammatory biomarkers (TNF-α, IFN-γ, IL-1β, IL6, IL10, IL12p70, IL17, NGF) and tissue remodeling biomarkers (collagenase activity, MMPs-1, 2, 9, 13, N-telopeptide cross-linked collagen (NTx), EGF, HB-EGF). Paired t-tests compared changes in biomarker over 1 year (significance p<0.05). Linear regression models correlated baseline and changes in biomarker levels with covariates (significance p≤0.001). Logistic regression models, controlling for age, analyzed associations of baseline and changes in biomarker levels with surgical failure (significance p<0.05).
Over one year, IL12p70 decreased (0.53±1.4 to 0.28±.62 pg/mg Cr, p=0.04) and NGF increased (0.034 ± 0.046 to 0.044 ± 0.060 pg/ml/mOsm, p=0.03). Baseline NTx level/mg Cr was positively associated with age and post-menopausal status (p=0.001), and negatively associated with current estrogen use (p=0.0001). Baseline collagenase activity/mg Cr was positively associated with age (p=0.001). EGF/mOsm, NTx/mOsm and IFN-γ/mOsm were negatively correlated with age, current estrogen use, and UDI-irritative score, respectively (p≤0.001). Subjects with lower baseline NTx/mg Cr were less likely to experience surgical failure (OR 0.49, 95% CI 0.26, 0.93, p=0.03). Changes in biomarker levels were neither associated with any covariates nor surgical failure.
Women with lower baseline NTx levels were significantly less likely to fail SUI surgery. Studies are needed to validate NTx as a possible independent biomarker for SUI surgery outcomes.
PMCID: PMC4183133  PMID: 24140551
23.  Pre-operative Clinical, Demographic and Urodynamic Measures Associated with Failure to Demonstrate Urodynamic Stress Incontinence in Women Enrolled in Two Randomized Clinical Trials of Surgery for Stress Urinary Incontinence 
The unexpected absence of urodynamic stress incontinence (USI) in women planning surgery for stress urinary incontinence (SUI) is a challenge to surgeons. We examined the prevalence and clinical and demographic factors associated at baseline (pre-operatively) with the unexpected absence of USI among study participants of two multi-center randomized clinical trials of surgery for treatment of SUI.
Women with stress incontinence symptoms and positive stress tests on physical examination enrolled in two separate clinical trials comparing the autologous fascial sling with the Burch suspension (SISTEr trial), and the retropubic mid urethral sling compared to the transobturator mid urethral sling (TOMUS), were evaluated for USI preoperatively. The association of clinical, demographic and urodynamic parameters was examined in women without USI in univariable and multivariable analyses.
Overall, 144 of 1233 women (11.7%) enrolled in the two studies did not show USI. These women had a significantly lower mean volume at maximum cystometric capacity than those with USI (347.5 vs. 395.8 in SISTEr, p = 0.012), (315.2 vs. 358.2 in TOMUS, p = 0.003), and a lower mean number of daily accidents reported on a three day diary (2.2 vs 2.7 in SISTEr, p = 0.030) (1.7 vs 2.7 in TOMUS, p < 0.001). Additionally, those without demonstrable USI were more likely to have POPQ stage III/IV (31.7% vs 14.4% in SISTEr, p = 0.002), (15.5% vs 6.9% in TOMUS, p = 0.025). Severity of SUI as recorded on Urogenital Distress Inventory correlated strongly with the presence of USI in both studies.
We observed that about one of out eight women planning surgery for SUI does not show USI. Severity of stress incontinence and Stage 3/4 pelvic organ prolapse were strongly associated with the unexpected absence of USI. A diminished urodynamic bladder capacity among women who did not display USI may reflect an inability to reach the limits of capacity during urodynamics, at which these women normally leak.
PMCID: PMC4169424  PMID: 22669421
24.  Urological Complications of Obesity and Diabetes 
The Journal of urology  2009;182(6 0):S1.
PMCID: PMC4160045  PMID: 19846132
25.  The MAPP research network: design, patient characterization and operations 
BMC Urology  2014;14:58.
The “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network’s central study and common data elements are described.
The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as “positive” controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.
The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.
Trial registration identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.
PMCID: PMC4126395  PMID: 25085119
Urologic chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Urine biomarkers; Plasma biomarkers; Non-urologic associated syndromes; Quantitative sensory testing (QST); Neuroimaging

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