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author:("kuse, John W.")
1.  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
2.  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
3.  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)
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Sexual activity and function in women more than 2 years after midurethral sling placement 
OBJECTIVE
The purpose of this study was to assess prospectively the effects of midurethral sling surgery on sexual function and activity.
STUDY DESIGN
Sexual activity and function was assessed in 597 women with stress urinary incontinence who were enrolled in a randomized equivalence trial of retropubic compared with transobturator midurethral slings. Repeated measures analysis of variance was used to assess changes in Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire scores over a 2-year period.
RESULTS
Significant, similar improvements in sexual function were seen in both midurethral sling groups. Mean Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire scores increased from 32.8 at baseline to 37.6 at 6 months and 37.3 at 24 months (P < .0001). Dyspareunia, incontinence during sex, and fear of incontinence during sex each significantly improved after surgery. Preoperative urge incontinence was associated with abstinence after surgery (P = .02); postoperative urge incontinence negatively impacted sexual function (P = .047).
CONCLUSION
Midurethral sling surgery for stress urinary incontinence significantly improves sexual function, although coexistent urge incontinence has a negative impact.
doi:10.1016/j.ajog.2012.06.053
PMCID: PMC3562351  PMID: 22840975
mesh; midurethral sling; sexual function; surgery; urinary incontinence
18.  Recruitment of Hispanics into an Observational Study of Chronic Kidney Disease:The Hispanic Chronic Renal Insufficiency Cohort Study Experience 
Contemporary clinical trials  2012;33(6):1238-1244.
Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21–74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community-based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD.
doi:10.1016/j.cct.2012.07.012
PMCID: PMC3594841  PMID: 22841929
19.  Pregabalin for the Treatment of Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome 
Archives of internal medicine  2010;170(17):1586-1593.
Background
Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic.
Methods
This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006–2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed.
Results
Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIHCPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo (P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and sub-scores (P < .05), a higher Global Response Assessment response rate (31.2% and 18.9%; P = .02), and improvement in total McGill Pain Questionnaire score (P = .01). Results for the other outcomes did not differ between groups.
Conclusion
Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS.
Trial Registration
clinicaltrials.gov Identifier: NCT00371033
doi:10.1001/archinternmed.2010.319
PMCID: PMC3767281  PMID: 20876412
20.  Kidney Function and Risk of Cardiovascular Disease and Mortality in Kidney Transplant Recipients: the FAVORIT Trial 
In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post-hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49±18 mL/min/1.73m2. In 3,676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73m2 higher eGFR at levels below 45 mL/min/1.73m2 was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73m2. In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than pre-existing comorbidity may lead to CVD.
doi:10.1111/j.1600-6143.2012.04101.x
PMCID: PMC3424309  PMID: 22594581
Kidney Transplant; Glomerular Filtration Rate; Cardiovascular Disease; Chronic Kidney Disease; Epidemiology; Mortality
21.  Emergency department visits, use of imaging and drugs for urolithiasis have increased in the United States 
Kidney international  2013;83(3):479-486.
The occurrence of urolithiasis in the United States has increased, however, information on long-term trends, including recurrence rates, is lacking. Here we describe national trends in rates of emergency department visits, use of imaging, and drug treatment primarily using the National Hospital Ambulatory Medical Care Surveys to describe trends and the National Health and Nutrition Examination Survey to determine the frequency of lifetime passage of kidney stones. Emergency department visit rates for urolithiasis increased from 178 to 340 visits per 100,000 individuals from 1992 to 2009. Increases in visit rates were greater in women, Caucasians and in those 25–44 years of age. The use of computed tomography in urolithiasis patients more than tripled, from 21% to 71%. Medical expulsive therapy was used in 14% of patients with a urolithiasis diagnosis in 2007–2009. Among National Health and Nutrition Examination Survey participants who reported a history of kidney stones, 22.4% had passed three or more stones. Hence, emergency department urolithiasis visit rates have increased significantly, as has the use of computed tomography in the United States. Further research is necessary to determine whether recurrent stone formers receive unnecessary radiation exposure during diagnostic evaluation in the emergency department, and allow development of corresponding evidence-based guidelines.
doi:10.1038/ki.2012.419
PMCID: PMC3587650  PMID: 23283137
Computed Tomography; Radiation; NHAMCS
22.  Decrease in Urinary Incontinence Management Costs in Women Enrolled in a Clinical Trial of Weight Loss to Treat Urinary Incontinence 
Obstetrics and Gynecology  2012;120(2 Pt 1):277-283.
Objective
To estimate the effect of a decrease in urinary incontinence frequency on urinary incontinence management costs among women enrolled in a clinical trial of a weight loss intervention and to identify factors that predict change in cost.
Methods
This is a secondary cohort analysis of 338 obese and overweight women with ≥ 10 weekly episodes of urinary incontinence enrolled in an 18-month randomized clinical trial of a weight loss intervention compared to a structured education program to treat urinary incontinence. Quantities of resources used for incontinence management, including pads, additional laundry, and dry cleaning were reported by participants. Direct costs for urinary incontinence management (“cost”) were calculated by multiplying resources used by national resource costs (in 2006 U.S. dollars). Randomized groups were combined to examine the effects of change in incontinence frequency on cost. Possible predictors of change in cost were examined using generalized estimating equations controlling for factors associated with change in cost in univariable analyses.
Results
Mean (±SD) age was 53±10 years and baseline weight was 97+17 kg. Mean weekly urinary incontinence frequency was 24+18 at baseline and decreased by 37% at 6 months and 60% at 18 months follow-up (both P<0.001). At baseline, adjusted mean cost was $7.76±$14 per week, with costs increasing significantly with greater incontinence frequency. Mean cost decreased by 54% at 6 months and 81% at 18 months (both P<0.001). In multivariable analyses, cost independently decreased by 23% for each decrease of seven urinary incontinence episodes per week and 21% for each 5 kg of weight lost (P<0.001 for both).
Conclusion
In obese and overweight women enrolled in a clinical trial of weight loss for urinary incontinence, incontinence management cost decreased by 81% at 18 months ($327 per woman per year) and was strongly and independently associated with decreasing incontinence frequency.
doi:10.1097/AOG.0b013e31825dd268
PMCID: PMC3404427  PMID: 22825085
23.  Patient Related Factors Associated with Long-Term Urinary Continence After Burch Colposuspension and Pubovaginal Fascial Sling Surgeries 
The Journal of urology  2012;188(2):485-489.
Purpose
To examine pre-and post-operative patient-related factors associated with continence status up to 7 years post-surgery for stress urinary incontinence (SUI).
Materials and Methods
Women randomized to Burch colposuspension or fascial sling surgery and assessed for the primary outcome of urinary continence two years post-procedure were eligible to enroll in a prospective observational study. Survival analysis was used to investigate baseline and post-surgery factors on subsequent risk of SUI defined as self-report of SUI symptoms, incontinence episodes on a 3-day diary or surgical retreatment.
Results
Seventy four percent (482/655) of women who participated in the randomized trial were enrolled in the follow-up study. Urinary continence rates decreased over a period of two to seven years post-operatively from 42% to 13% in the Burch group and from 52% to 27%, in the sling group, respectively. Among the baseline factors included in the first multivariable model age (p=0.03) prior SUI surgery (p=0.02), menopausal status (0.005), urge index (0.006), assigned surgery (p=0.01) and recruiting site (p=0.02) were independently associated with increased risk of incontinence. In the final multivariable model including baseline and post-operative factors, Burch surgery (p=0.01), baseline variables of prior UI surgery (p=0.04), menopausal status (p=0.03) and post-surgery urge index (p<0.001), were each significantly associated with greater risk of recurrent urinary incontinence.
Conclusion
Pre- and postoperative urgency incontinence symptoms, Burch urethropexy, prior SUI surgery and menopausal status were negatively associated with long-term continence rates. More effective treatment of urgency UI in patients who undergo SUI surgery may improve long-term overall continence status.
doi:10.1016/j.juro.2012.04.010
PMCID: PMC3560926  PMID: 22704099
Stress urinary incontinence; urgency urinary incontinence; surgical outcomes
24.  Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study 
Background
Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.
Study Design
Cross-sectional study of 1,433 participants from the Chronic Renal Insufficiency Cohort (CRIC) Study (i.e., the GFR subcohort) to derive an internal GFR estimating equation using a split sample approach.
Setting & Participants
Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.
Index Test
CRIC GFR estimating equation
Reference Test or Outcome
Urinary 125I-iothalamate clearance testing (measured GFR)
Other Measurements
Laboratory measures including serum creatinine and cystatin C, and anthropometrics
Results
In the validation dataset, the model that included serum creatinine, serum cystatin C, age, gender, and race was the most parsimonious and similarly predictive of mGFR compared to a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, the root mean square errors for the separate model were 0.207 vs. 0.202, respectively. The performance of the CRIC GFR estimating equation was most accurate among the subgroups of younger participants, men, non-blacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower levels of high-sensitivity C-reactive protein, and those with higher mGFR.
Limitations
Urinary clearance of 125I-iothalamate is an imperfect measure of true GFR; cystatin C is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.
Conclusions
The CRIC GFR estimating equation predicts measured GFR accurately in the CRIC cohort using serum creatinine and cystatin C, age, gender, and race. Its performance was best among younger and healthier participants.
doi:10.1053/j.ajkd.2012.04.012
PMCID: PMC3565578  PMID: 22658574
glomerular filtration rate (GFR); kidney function; GFR estimation
25.  Retinopathy and Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort Study (CRIC) 
Archives of ophthalmology  2012;130(9):1136-1144.
Objectives
Retinal vascular and anatomic abnormalities caused by diabetes, hypertension, and other conditions can be observed directly in the ocular fundus and may reflect severity of chronic renal insufficiency. The purpose of this study was to investigate the association between retinopathy and chronic kidney disease (CKD).
Methods
In this observational, cross-sectional study, 2605 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, a multi-center study of CKD, were offered participation. Non-mydriatic fundus photographs of the disc and macula in both eyes were obtained in 1936 of these subjects.
Photographs were reviewed in a masked fashion at a central photograph reading center using standard protocols. Presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter caliber were assessed by trained graders and a retinal specialist using protocols developed for large epidemiologic studies. Kidney function measurements and information on traditional and non-traditional risk factors for decreased kidney function were obtained from the CRIC study.
Results
Greater severity of retinopathy was associated with lower estimated glomerular filtration rate (eGFR) after adjustment for traditional and non-traditional risk factors. Presence of vascular abnormalities usually associated with hypertension was also associated with lower eGFR. We found no strong direct relationship between eGFR and average arteriolar or venular calibers.
Conclusions
Our findings show a strong association between severity of retinopathy and its features and level of kidney function after adjustment for traditional and non-traditional risk factors for CKD, suggesting that retinovascular pathology reflects renal disease.
doi:10.1001/archophthalmol.2012.1800
PMCID: PMC3719171  PMID: 22965589
Retinopathy; Retinal Vascular Diameter; Chronic Kidney Disease

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