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author:("kuse, John W.")
1.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
Objectives
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.01.103
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)
2.  Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study 
PLoS ONE  2015;10(4):e0124772.
Background
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.
Methods
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.
Results
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).
Conclusion
In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.
doi:10.1371/journal.pone.0124772
PMCID: PMC4409366  PMID: 25909952
3.  Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C 
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.)
doi:10.1056/NEJMoa1114248
PMCID: PMC4398023  PMID: 22762315
4.  Inadequacy of Cardiovascular Risk Factor Management in Chronic Kidney Transplantation -- Evidence from the FAVORIT Study 
Clinical transplantation  2012;26(4):E438-E446.
Background
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.
Methods
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.
Results
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.
Conclusion
There is opportunity to improve treatment and control of traditional CVD risk factors in kidney transplant recipients.
doi:10.1111/j.1399-0012.2012.01676.x
PMCID: PMC4388027  PMID: 22775763
Kidney transplantation; cardiovascular disease; cardiovascular risk factors; medications; medical management
5.  DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC Study 
Background
Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).
Methods
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.
Results
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.
Conclusions
Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.
doi:10.1093/ndt/gft537
PMCID: PMC3967834  PMID: 24516231
chronic renal disease; chronic renal disease progression; DNA methylation; epigenetics
6.  Treatment Success of Retropubic and Transobturator Midurethral Slings at 24-months 
The Journal of urology  2012;188(6):2281-2287.
Purpose
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%.
Results
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).
Conclusions
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.
doi:10.1016/j.juro.2012.07.103
PMCID: PMC4367868  PMID: 23083653
Stress urinary incontinence; midurethral sling; surgical outcomes
7.  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.
Purpose
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.
Results
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).
Conclusions
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.
doi:10.1016/j.juro.2012.09.050
PMCID: PMC4363108  PMID: 22982425
urodynamic studies; office evaluation; stress urinary incontinence; midurethral sling; surgical outcomes; clinical diagnosis
8.  Urinary Incontinence Management Costs are Reduced Following Burch or Sling Surgery for Stress Incontinence 
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.ajog.2014.03.012
PMCID: PMC4349353  PMID: 24631433
urinary incontinence; urinary incontinence – costs; costs and cost analysis
9.  Objectives and Design of the Hemodialysis Fistula Maturation Study 
Background
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.
Predictors
Clinical, anatomical, biological, and process-of-care attributes identified pre-operatively, intra-operatively, or post-operatively.
Outcomes
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.
Measurements
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.
Results
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.
Limitations
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.
Conclusions
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.
doi:10.1053/j.ajkd.2013.06.024
PMCID: PMC4134933  PMID: 23992885
10.  5-Year Longitudinal Follow-up after Retropubic and Transobturator Midurethral Slings 
The Journal of urology  2014;193(1):203-210.
Background
Few studies have characterized longer-term outcomes after retropubic and transobturator midurethral slings.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.juro.2014.08.089
PMCID: PMC4272663  PMID: 25158274
11.  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.
Objective
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.juro.2013.10.051
PMCID: PMC4183133  PMID: 24140551
12.  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 
Aims
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00192-012-1821-0
PMCID: PMC4169424  PMID: 22669421
13.  Urological Complications of Obesity and Diabetes 
The Journal of urology  2009;182(6 0):S1.
doi:10.1016/j.juro.2009.09.031
PMCID: PMC4160045  PMID: 19846132
14.  The MAPP research network: design, patient characterization and operations 
BMC Urology  2014;14:58.
Background
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.
Methods
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.
Discussion
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
ClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”. http://clinicaltrials.gov/show/NCT01098279
doi:10.1186/1471-2490-14-58
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
15.  The MAPP research network: a novel study of urologic chronic pelvic pain syndromes 
BMC Urology  2014;14:57.
Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and “centralized” chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network’s study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network’s integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study.
Trial registration
ClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.
doi:10.1186/1471-2490-14-57
PMCID: PMC4134515  PMID: 25085007
Urological chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Translational research; Multi-disciplinary
16.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
BACKGROUND
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
METHODS
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
RESULTS
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
CONCLUSIONS
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
doi:10.1056/NEJMoa1310345
PMCID: PMC3969022  PMID: 24206458
17.  Retinopathy and Cognitive Impairment in Adults With CKD 
Background
Retinal microvascular abnormalities have been associated with cognitive impairment, possibly serving as a marker of cerebral small vessel disease. This relationship has not been evaluated among persons with chronic kidney disease (CKD), a condition associated with increased risk of both retinal pathology and cognitive impairment.
Study Design
Cross-sectional study
Setting & Participants
588 participants ≥ 52 years old with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study
Predictor
Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels.
Outcomes
Neuropsychological battery of six cognitive tests
Measurements
Logistic regression models were used to evaluate the association of retinopathy, individual retinopathy features, and retinal vessel diameters with cognitive impairment (≤1 SD from the mean), and linear regression models were used to compare cognitive test scores across levels of retinopathy adjusting for age, race, sex, education, and medical comorbidities.
Results
The mean age of the cohort was 65.3 +/− 5.6 (SD) years; 51.9% were non-White, and 52.6% were male. The prevalence of retinopathy was 30.1% and 14.3% for cognitive impairment. Compared to those without retinopathy, participants with retinopathy had increased likelihood of cognitive impairment on executive function (35.1% vs. 11.5%; OR, 3.4; 95% CI, 2.0-6.0), attention (26.7% vs. 7.3%; OR, 3.0; 95% CI, 1.8-4.9), and naming (26.0% vs. 10.0%; OR, 2.1; 95% CI, 1.2-3.4) after multivariable adjustment. Increased level of retinopathy was also associated with lower cognitive performance on executive function and attention. Microaneurysms were associated with cognitive impairment on some domains, but there were no significant associations with other retinal measures after multivariable adjustment.
Limitations
Unknown temporal relationship between retinopathy and impairment.
Conclusions
In adults with CKD, retinopathy is associated with poor performance on several cognitive domains including executive function and attention. Evaluation of retinal microvascular abnormalities may be a promising tool for identifying patients with CKD who are at increased risk of cognitive impairment.
doi:10.1053/j.ajkd.2012.10.006
PMCID: PMC4030670  PMID: 23206534
18.  Limited health literacy is associated with low glomerular filtration in the Chronic Renal Insufficiency Cohort (CRIC) study 
Clinical nephrology  2014;81(1):30-37.
Background
Low health literacy in the general population is associated with increased risk of death and hospitalization. The evaluation of health literacy in individuals with predialysis chronic kidney disease (CKD) is limited.
Methods
We conducted a cross-sectional study to evaluate the associations of limited health literacy with kidney function and cardiovascular disease (CVD) risk factors in 2,340 non-Hispanic (NH) Whites and Blacks aged 21 – 74 years with mild-to-moderate CKD. Limited health literacy was defined as a Short Test of Functional Health Literacy in Adults (STOFHLA) score ≤ 22. Outcomes evaluated included estimated glomerular filtration rate (eGFR), 24-hour urine protein excretion, and CVD risk factors.
Results
The prevalence of limited health literacy was 28% in NH-Blacks and 5% in NH-Whites. Compared with participants with adequate health literacy, those with limited health literacy were more likely to have lower eGFR (34 vs. 42 mL/min/1.73 m2); higher urine protein/24-hours (0.31 vs. 0.15 g); and higher self-reported CVD (61 vs. 37%); and were less likely to have BP < 130/80 mmHg (51 vs. 58%); p ≤ 0.01 for each comparison. After adjustment, limited health literacy was associated with self-reported CVD (OR 1.51, 95% CI 1.13 – 2.03) and lower eGFR (β − 2.47, p = 0.03).
Conclusion
In this CKD cohort, limited health literacy was highly prevalent, especially among NH-Blacks, and it was associated with lower eGFR and a less favorable CVD risk factor profile. Further studies are needed to better understand these associations and inform the development of health literacy interventions among individuals with CKD.
doi:10.5414/CN108062
PMCID: PMC3951206  PMID: 24219913
chronic kidney disease; health literacy
19.  Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency 
The New England journal of medicine  2009;360(21):2191-2201.
BACKGROUND
Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.
RESULTS
At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole–aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.
CONCLUSIONS
Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)
doi:10.1056/NEJMoa0805840
PMCID: PMC3929400  PMID: 19458364
20.  A TRIAL OF TWO STRATEGIES TO REDUCE NOCTURNAL BLOOD PRESSURE IN AFRICAN AMERICANS WITH CHRONIC KIDNEY DISEASE 
Hypertension  2012;61(1):82-88.
The objective of our study was to determine the effects of two antihypertensive drug dose schedules (‘PM dose’ and ‘Add on dose’) on nocturnal blood pressure (BP) in comparison to usual therapy (‘AM dose’) in African Americans with hypertensive chronic kidney disease (CKD) and controlled office BP. In a three period, cross-over trial, former participants of the African American Study of Kidney Disease were assigned to receive the following three regimens, each lasting 6 weeks, presented in random order: AM dose (once daily antihypertensive medications taken in the morning), PM dose (once daily antihypertensives taken at bedtime) and ‘Add on dose’ (once daily antihypertensives taken in the morning and an additional antihypertensive medication before bedtime [diltiazem 60–120 mg, hydralazine 25 mg, or additional ramipril 5 mg]). Ambulatory BP monitoring was performed at the end of each period. The primary outcome was nocturnal systolic BP. Mean age of the study population (n=147) was 65.4 years, 64% were male, mean estimated GFR was 44.9 ml/min/1.73 m2. At the end of each period, mean (SE) nocturnal systolic BP was 125.6 (1.2) mm Hg in the AM dose, 123.9 (1.2) mm Hg in the PM dose, and 123.5(1.2) mm Hg in the Add-on dose. None of the pairwise differences in nocturnal, 24-hour and daytime systolic BP were statistically significant. Among African Americans with hypertensive CKD, neither PM (bedtime) dosing of once daily antihypertensive nor the addition of drugs taken at bedtime significantly reduced nocturnal BP compared to morning dosing of anti-hypertensive medications.
doi:10.1161/HYPERTENSIONAHA.112.200477
PMCID: PMC3523681  PMID: 23172931
Nocturnal blood pressure; chronic kidney disease; hypertension
21.  Limited health literacy is associated with low glomerular filtration in the Chronic Renal Insufficiency Cohort (CRIC) study 
Clinical Nephrology  2013;81(1):30-37.
Background: Low health literacy in the general population is associated with increased risk of death and hospitalization. The evaluation of health literacy in individuals with predialysis chronic kidney disease (CKD) is limited. Methods: We conducted a cross-sectional study to evaluate the associations of limited health literacy with kidney function and cardiovascular disease (CVD) risk factors in 2,340 non-Hispanic (NH) Whites and Blacks aged 21 – 74 years with mild-to-moderate CKD. Limited health literacy was defined as a Short Test of Functional Health Literacy in Adults (STOFHLA) score ≤ 22. Outcomes evaluated included estimated glomerular filtration rate (eGFR), 24-hour urine protein excretion, and CVD risk factors. Results: The prevalence of limited health literacy was 28% in NH-Blacks and 5% in NH-Whites. Compared with participants with adequate health literacy, those with limited health literacy were more likely to have lower eGFR (34 vs. 42 mL/min/1.73 m2); higher urine protein/24-hours (0.31 vs. 0.15 g); and higher self-reported CVD (61 vs. 37%); and were less likely to have BP < 130/80 mmHg (51 vs. 58%); p ≤ 0.01 for each comparison. After adjustment, limited health literacy was associated with self-reported CVD (OR 1.51, 95% CI 1.13 – 2.03) and lower eGFR (β –2.47, p = 0.03). Conclusion: In this CKD cohort, limited health literacy was highly prevalent, especially among NH-Blacks, and it was associated with lower eGFR and a less favorable CVD risk factor profile. Further studies are needed to better understand these associations and inform the development of health literacy interventions among individuals with CKD.
doi:10.5414/CN108062
PMCID: PMC3951206  PMID: 24219913
chronic kidney disease; health literacy
22.  Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans 
Archives of internal medicine  2008;168(8):10.1001/archinte.168.8.832.
Background
Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD.
Methods
Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20–65 mL/min/1.73 m2). Following a 3×2-factorial trial (1995–2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and β-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002–2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death.
Results
During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2).
Conclusion
Despite the benefits of renin-angiotensin system–blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.
doi:10.1001/archinte.168.8.832
PMCID: PMC3870204  PMID: 18443258
23.  A New Equation to Estimate Glomerular Filtration Rate 
Annals of internal medicine  2009;150(9):604-612.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
Objective
To develop a new estimating equation (CKD-EPI creatinine equation).
Design
Cross-sectional analysis. Separate pooled databases for equation development and validation. Representative U.S. population for prevalence estimates.
Setting
Research studies and clinical populations (“studies”) with measured GFR. National Health and Nutrition Examination Survey (NHANES) 1999-2006.
Patients
Equation development in 10 studies (8254 people) and validation in 16 studies (3896 people). Prevalence estimates based on 16,032 people.
Measurements
GFR measured as the clearance of exogenous filtration markers (iothalamate in the development dataset; iothalamate and other markers in the validation dataset). Linear regression to estimate the logarithm of measured GFR from standardized creatinine, sex, race and age.
Results
In the validation dataset, the CKD-EPI performed better than the MDRD Study equation (p<0.001 for all subsequent comparisons), especially at higher GFR: lesser bias (median difference between measured and estimated GFR of 2.5 vs. 5.5 mL/min/1.73 m2, respectively); improved precision (interquartile range of the differences of 16.6 vs. 18.3 mL/min/1.73 m2, respectively); and greater accuracy (percent of estimated GFR within 30% of measured GFR of 84.1 vs. 80.6%, respectively. In NHANES, median (interquartile range) estimated GFR was 94.5 (79.7 – 108.1) vs. 85.0 (72.9 – 98.5) mL/min/1.73 m2, and the prevalence (95% confidence interval) of CKD was 11.5 (10.6, 12.4) % vs. 13.1 (12.1, 14.0) %, respectively.
Limitations
Limited number of elderly people and racial and ethnic minorities with measured GFR.
Conclusions
The CKD-EPI creatinine equation is more accurate than the MDRD Study equation and could replace it for routine clinical use.
PMCID: PMC2763564  PMID: 19414839
24.  The effect of weight loss on changes in health-related quality of life among overweight and obese women with urinary incontinence 
OBJECTIVE
To estimate the effect of change in weight and change in urinary incontinence (UI) frequency on changes in preference-based measures of health-related quality of life (HRQL) among overweight and obese women with UI participating in a weight loss trial.
METHODS
We conducted a longitudinal cohort analysis of 338 overweight and obese women with UI enrolled in a randomized clinical trial comparing a behavioral weight loss intervention to an educational control condition. At baseline, 6, and 18 months, health utilities were estimated using the Health Utilities Index Mark 3 (HUI3), a transformation of the SF-36 to the preference-based SF-6D, and the estimated Quality of Well-Being (eQWB) score (a summary calculated from the SF-36 physical functioning, mental health, bodily pain, general health perceptions, and role limitations-physical subscale scores). Potential predictors of changes in these outcomes were examined using generalized estimating equations.
RESULTS
In adjusted multivariable models, weight loss was associated with improvement in HUI3, SF-6D, and eQWB at 6 and 18 months (p<.05). Increases in physical activity also were independently associated with improvement in HUI3 (p=.01) and SF-6D (p=.006) scores at 18 months. In contrast, reduction in UI frequency did not predict improvements in HRQL at 6 or 18 months.
CONCLUSION
Weight loss and increased physical activity, but not reduction in UI frequency, were strongly associated with improvements in health utilities measured by the HUI3, SF-6D, and eQWB. These findings provide important information that can be used to inform cost-utility analyses of weight loss interventions.
doi:10.1007/s11136-011-0086-2
PMCID: PMC3375350  PMID: 22161726
quality of life; weight loss; urinary incontinence; HUI; eQWB; SF-6D
25.  Fibroblast growth factor 23 is not associated with and does not induce arterial calcification 
Kidney international  2013;83(6):1159-1168.
Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331 to 420 days) of baseline. Baseline plasma FGF23 was not associated with prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its co-receptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.
doi:10.1038/ki.2013.3
PMCID: PMC3672330  PMID: 23389416
phosphate; fibroblast growth factor 23; vascular calcification; vascular smooth muscle; chronic kidney disease

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