Long-Term Outcomes of Medical Management vs Bariatric Surgery in Type 2 Diabetes.

Importance: Randomized clinical trials of bariatric surgery have been limited in size, type of surgical procedure, and follow-up duration. Objective: To determine long-term glycemic control and safety of bariatric surgery compared with medical/lifestyle management of type 2 diabetes. Design, Setting, and Participants: ARMMS-T2D (Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes) is a pooled analysis from 4 US single-center randomized trials conducted between May 2007 and August 2013, with observational follow-up through July 2022. Intervention: Participants were originally randomized to undergo either medical/lifestyle management or 1 of the following 3 bariatric surgical procedures: Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric banding. Main Outcome and Measures: The primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 7 years for all participants. Data are reported for up to 12 years. Results: A total of 262 of 305 eligible participants (86%) enrolled in long-term follow-up for this pooled analysis. The mean (SD) age of participants was 49.9 (8.3) years, mean (SD) body mass index was 36.4 (3.5), 68.3% were women, 31% were Black, and 67.2% were White. During follow-up, 25% of participants randomized to undergo medical/lifestyle management underwent bariatric surgery. The median follow-up was 11 years. At 7 years, HbA1c decreased by 0.2% (95% CI, -0.5% to 0.2%), from a baseline of 8.2%, in the medical/lifestyle group and by 1.6% (95% CI, -1.8% to -1.3%), from a baseline of 8.7%, in the bariatric surgery group. The between-group difference was -1.4% (95% CI, -1.8% to -1.0%; P < .001) at 7 years and -1.1% (95% CI, -1.7% to -0.5%; P = .002) at 12 years. Fewer antidiabetes medications were used in the bariatric surgery group. Diabetes remission was greater after bariatric surgery (6.2% in the medical/lifestyle group vs 18.2% in the bariatric surgery group; P = .02) at 7 years and at 12 years (0.0% in the medical/lifestyle group vs 12.7% in the bariatric surgery group; P < .001). There were 4 deaths (2.2%), 2 in each group, and no differences in major cardiovascular adverse events. Anemia, fractures, and gastrointestinal adverse events were more common after bariatric surgery. Conclusion and Relevance: After 7 to 12 years of follow-up, individuals originally randomized to undergo bariatric surgery compared with medical/lifestyle intervention had superior glycemic control with less diabetes medication use and higher rates of diabetes remission. Trial Registration: ClinicalTrials.gov Identifier: NCT02328599.

Association of Shear Stress with Subsequent Lumen Remodeling in Hemodialysis Arteriovenous Fistulas.

BACKGROUND: Blood flow-induced wall shear stress is a strong local regulator of vascular remodeling, but its effects on arteriovenous fistula (AVF) remodeling are unclear. METHODS: In this prospective cohort study, we used computational fluid dynamics simulations and statistical mixed-effects modeling to investigate the associations between wall shear stress and AVF remodeling in 120 participants undergoing AVF creation surgery. Postoperative magnetic resonance imaging data at 1 day, 6 weeks, and 6 months were used to derive current wall shear stress by computational fluid dynamic simulations and to quantify subsequent changes in AVF lumen cross-sectional area at 1-mm intervals along the proximal artery and AVF vein. RESULTS: Combining artery and vein data, prior mean wall shear stress was significantly associated with lumen area expansion. Mean wall shear stress at day 1 was significantly associated with change in lumen area from day 1 to week 6 (11% larger area per interquartile range [IQR] higher mean wall shear stress, 95% confidence interval [95% CI], 5% to 18%; n =101), and mean wall shear stress at 6 weeks was significantly associated with change in lumen area from 6 weeks to month 6 (14% larger area per IQR higher, 95% CI, 3% to 28%; n =52). The association of mean wall shear stress at day 1 with lumen area expansion from day 1 to week 6 differed significantly by diabetes ( P =0.009): 27% (95% CI, 17% to 37%) larger area per IQR higher mean wall shear stress without diabetes and 9% (95% CI, -1% to 19%) with diabetes. Oscillatory shear index at day 1 was significantly associated with change in lumen area from day 1 to week 6 (5% smaller area per IQR higher oscillatory shear index, 95% CI, 3% to 7%), and oscillatory shear index at 6 weeks was significantly associated with change in lumen from 6 weeks to month 6 (7% smaller area per IQR higher oscillatory shear index, 95% CI, 2% to 11%). Wall shear stress spatial gradient was not significantly associated with subsequent remodeling. In a joint model, wall shear stress and oscillatory shear index statistically significantly interacted in their associations with lumen area expansion in a complex nonlinear fashion. CONCLUSIONS: Higher wall shear stress and lower oscillatory shear index were associated with greater lumen expansion after AVF creation surgery.

Arteriovenous Fistula Maturation, Functional Patency, and Intervention Rates.

Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective: To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, Setting, and Participants: The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main Outcomes and Measures: In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results: Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and Relevance: The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

A New Panel-Estimated GFR, Including ß2-Microglobulin and ß-Trace Protein and Not Including Race, Developed in a Diverse Population.

RATIONALE AND OBJECTIVE: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. ß2-Microglobulin (B2M) and ß-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA. RESULTS: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 - P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 - P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups. LIMITATIONS: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. CONCLUSIONS: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.

BACKGROUND: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

The effect of increased frequency of hemodialysis on serum cystatin C and ß2-microglobulin concentrations: A secondary analysis of the frequent hemodialysis network (FHN) trial.

INTRODUCTION: Small molecular weight toxin clearance is the main method of assessment of hemodialysis efficiency. Middle molecules including cystatin C (CysC) and Beta-2 microglobulin (ß2-M) are understudied. We hypothesized that lowering of predialysis CysC and ß2-M serum concentrations would be affected by switching to more frequent hemodialysis. METHODS: Predialysis CysC and ß2-M serum concentrations were measured from serum samples of the Frequent Hemodialysis Network (FHN) Daily and Nocturnal Trials. The differences between predialysis concentrations at baseline (while on conventional thrice weekly dialysis) and those after 12-months of study (on more frequent dialysis) were compared separately by trial (Nocturnal, Daily). We tested the associations between predialysis serum CysC and ß2-M concentrations and outcomes. FINDINGS: Forty-nine percent and 52% of the patients from the FHN Daily and Nocturnal Trials respectively were included in this ancillary study. Predialysis serum CysC concentrations remained unchanged after intensifying hemodialysis dose by either modality. There was significant lowering of the serum ß2-M concentrations in the frequent Daily Trial hemodialysis group at 12 months in all patients and in patients without residual renal function at baseline (-3.8 ± 12.62 µg/mL, P = 0.004; -5.9 ± 12.99 µg/mL, P = 0.02, respectively). There were no significant differences between the baseline and the 12-months predialysis ß2-M serum concentrations in the two control groups (Daily 3× and Nocturnal 3× groups). No association between the changes in the two biomarkers between baseline and 12-months and in changes in left ventricular mass, physical-health composite scores, hospitalization rate, and death were found. The numbers of hospitalizations and deaths were small. DISCUSSION: ß2-M may be a better biomarker of dialysis dose than CysC. Reduction in the concentration of potentially toxic long-lived proteins of the size of ß-2M is one potential long-term benefit of more intensive dialysis that may be explored.

The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.

Body mass index, calcium supplementation and risk of colorectal adenomas.

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI <25 kg/m2 ; 18.5% vs. 31%). BMI appeared to modify the effect of calcium supplementation on adenomas and especially on high risk-findings: in the VCPPS, there was a 44% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.56, 95% CI = 0.26-1.23), but not among overweight (RR = 1.09, 95% CI = 0.62-1.91) or obese (RR = 1.54, 95% CI = 0.92-2.57) individuals (pinteraction = 0.03). Similarly, in the CPPS, there was a 56% reduction in high-risk findings among individuals whose BMI was normal (RR = 0.44, 95% CI = 0.26-0.74), but not among overweight (RR = 0.87, 95% CI = 0.55-1.39) or obese (RR = 1.02, 95% CI = 0.57-1.82) individuals (pinteraction = 0.02). Standardization of each trial's findings to the BMI distribution in the other attenuated calcium's protective effect on adenomas in the CPPS but enhanced it in the VCPPS. In conclusion, 1,200 mg/day calcium supplementation may reduce risk of colorectal adenomas among those with normal BMI but not in overweight or obese individuals; and differences in BMI distribution partially account for the apparent difference in calcium efficacy between the two trials.

Effect of Anti-Hypertensive Medication History on Arteriovenous Fistula Maturation Outcomes.

BACKGROUND: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs. METHODS: We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis. RESULTS: Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%-41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery. CONCLUSIONS: CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes.

Relationships Between Clinical Processes and Arteriovenous Fistula Cannulation and Maturation: A Multicenter Prospective Cohort Study.

BACKGROUND: Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation. STUDY DESIGN: Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study. SETTING & PARTICIPANTS: 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis. PREDICTORS: Postoperative care processes and complications. OUTCOMES: Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria. RESULTS: AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively). LIMITATIONS: Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution. CONCLUSIONS: Multiple processes of care and complications are associated with AVF maturation outcomes.

Histopathology of Veins Obtained at Hemodialysis Arteriovenous Fistula Creation Surgery.

Stenosis from venous neointimal hyperplasia is common in native arteriovenous fistulas (AVFs). However, the preexisting histologic characteristics of veins at fistula creation, and associations thereof with baseline patient factors, have not been well characterized. In this study, we conducted histologic analysis of a segment of the vein used for anastomosis creation, obtained during AVF creation from 554 of the 602 participants in the multicenter Hemodialysis Fistula Maturation Cohort Study. We quantified intimal and medial areas and lengths of the internal and external elastic lamina by morphometry and assessed venous wall cells by immunohistochemistry, extracellular matrix with Movat stain, and calcium deposition by alizarin red stain. We also studied a representative subset of veins for markers of monocyte/macrophage content, cell proliferation, apoptosis, and neoangiogenesis. Neointima occupied >20% of the lumen in 57% of fully circumferential vein samples, and neointimal hyperplasia associated positively with age and inversely with black race. The neointima was usually irregularly thickened, sometimes concentric, and contained α-smooth muscle actin-expressing cells of smooth muscle or myofibroblast origin. Proteoglycans admixed with lesser amounts of collagen constituted the predominant matrix in the neointima. In 82% of vein samples, the media of vessel walls contained large aggregates of collagen. A minority of veins expressed markers of inflammation, cell proliferation, cell death, calcification, or neoangiogenesis. In conclusion, we observed preexisting abnormalities, including neointimal hyperplasia and prominent accumulation of extracellular matrix, in veins used for AVF creation from a substantial proportion of this cohort.

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD.

BACKGROUND: Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, ß-trace protein (BTP), ß2-microglobulin (B2M), and cystatin C, are not well characterized. STUDY DESIGN: Pooled cross-sectional analysis of 3 studies. SETTING & PARTICIPANTS: 3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTORS: Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations. OUTCOMES: Serum creatinine, BTP, B2M, and cystatin C levels. RESULTS: In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C. LIMITATIONS: Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. CONCLUSIONS: Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

Vascular Function at Baseline in the Hemodialysis Fistula Maturation Study.

BACKGROUND: End-stage renal disease is accompanied by functional and structural vascular abnormalities. The objective of this study was to characterize vascular function in a large cohort of patients with end-stage renal disease, using noninvasive physiological measurements, and to correlate function with demographic and clinical factors. METHODS AND RESULTS: We analyzed cross-sectional baseline data from the Hemodialysis Fistula Maturation Study, a multicenter prospective observational cohort study of 602 patients with end-stage renal disease from 7 centers. Brachial artery flow- and nitroglycerin-mediated dilation, carotid-femoral and -radial pulse wave velocity, and venous occlusion plethysmography were performed prior to arteriovenous fistula creation. Relationships of these vascular function measures with demographic, clinical, and laboratory factors were evaluated using linear mixed-effects models. Arterial function, as assessed by flow- and nitroglycerin-mediated dilation and carotid-femoral pulse wave velocity, worsened with increasing age and diabetes mellitus. Venous capacitance decreased with diabetes mellitus but not with age. Flow-mediated dilation was higher among patients undergoing maintenance dialysis than for those at predialysis, and a U-shaped relationship between serum phosphorus concentration and flow-mediated dilation was evident. Partial correlations among different measures of vascular function, adjusting for demographic factors, diabetes mellitus, and clinical center, were modest or essentially nonexistent. CONCLUSIONS: Multiple demographic and clinical factors were associated with the functions of vessels of different sizes and types in this large cohort of patients with end-stage renal disease. Low correlations between the different measures, controlling for demographic factors, diabetes mellitus, and center, indicated that these different types of vascular function otherwise vary heterogeneously across patients.

GFR Estimation Using ß-Trace Protein and ß2-Microglobulin in CKD.

BACKGROUND: ß-Trace protein (BTP) and ß2-microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M to creatinine and cystatin C are limited by the absence of rigorously developed glomerular filtration rate (GFR) estimating equations for the novel markers. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: Pooled database of 3 populations with chronic kidney disease (CKD) with mean measured GFR of 48 mL/min/1.73 m2 (N=3,551; MDRD [Modification of Diet in Renal Disease] Study, AASK [African American Study of Kidney Disease and Hypertension], and CRIC [Chronic Renal Insufficiency Cohort] Study). INDEX TESTS: GFR estimated using creatinine, cystatin C, BTP, or B2M level. REFERENCE TEST: GFR measured as the urinary clearance of iothalamate. RESULTS: For BTP and B2M, coefficients for age, sex, and race were smaller than for creatinine and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age, and race were smaller than for creatinine and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age, and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine-cystatin C equation was not more accurate than the CKD-EPI creatinine-cystatin C equation. LIMITATIONS: No external validation population, study population was restricted to CKD, few participants older than 65 years, or nonblack nonwhite race. CONCLUSIONS: BTP and B2M are less influenced by age, sex, and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas.

BACKGROUND: Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS: We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS: Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).

The effect of location and configuration on forearm and upper arm hemodialysis arteriovenous grafts.

OBJECTIVE: The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG. METHODS: Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted. RESULTS: A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P < .001), and receiving dialysis at the time of surgery (62% vs 80%; P < .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P < .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16). CONCLUSIONS: Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft.

Changes in dietary protein intake has no effect on serum cystatin C levels independent of the glomerular filtration rate.

Cystatin C is being considered as a replacement for serum creatinine in the estimation of the glomerular filtration rate (GFR); however, its plasma levels might be affected by factors other than the GFR, such as protein intake. We performed a post hoc analysis of the data in the Modification of Diet in Renal Disease study, in which we compared serum creatinine and cystatin C levels in 741 patients with available estimates of protein intake at baseline prior to their randomization to diets containing various amounts of protein, and at 2 years of follow-up in 426 of these patients in whom a cystatin C measurement was available. The 503 patients in study A (GFR 25-55 ml/min per 1.73 m(2)) had been assigned a low (0.58 g/kg per day) or a usual (1.3 g/kg per day) protein intake, and the 238 participants in study B (GFR 13-24 ml/min per 1.73 m(2)) were assigned a very low (0.28 g/kg per day) or the low protein intake. In either study group, lowering the dietary protein intake reduced the change in creatinine, but did not have a significant change in cystatin C. Thus, in patients with moderate-to-severe chronic kidney disease, serum cystatin C unlike serum creatinine was not affected by dietary protein intake independent of changes in GFR. Hence, cystatin C may allow more accurate estimates of GFR than creatinine for patients with reduced protein intake. Further study of other non-GFR determinants of cystatin C is needed before the widespread adoption.

Factors other than glomerular filtration rate affect serum cystatin C levels.

Cystatin C is an endogenous glomerular filtration marker hence its serum level is affected by the glomerular filtration rate (GFR). To study what other factors might affect it blood level we performed a cross-sectional analysis of 3418 patients which included a pooled dataset of clinical trial participants and a clinical population with chronic kidney disease. The serum cystatin C and creatinine levels were related to clinical and biochemical parameters and errors-in-variables models were used to account for errors in GFR measurements. The GFR was measured as the urinary clearance of 125I-iothalamate and 51Cr-EDTA. Cystatin C was determined at a single laboratory while creatinine was standardized to reference methods and these were 2.1+/-1.1 mg/dL and 1.8+/-0.8 mg/L, respectively. After adjustment for GFR, cystatin C was 4.3% lower for every 20 years of age, 9.2% lower for female gender but only 1.9% lower in blacks. Diabetes was associated with 8.5% higher levels of cystatin C and 3.9% lower levels of creatinine. Higher C-reactive protein and white blood cell count and lower serum albumin were associated with higher levels of cystatin C and lower levels of creatinine. Adjustment for age, gender and race had a greater effect on the association of factors with creatinine than cystatin C. Hence, we found that cystatin C is affected by factors other than GFR which should be considered when the GFR is estimated using serum levels of cystatin C.

Cystatin C as a risk factor for outcomes in chronic kidney disease.

BACKGROUND: No study has compared cystatin C level, serum creatinine concentration, and estimated glomerular filtration rate (GFR) as risk factors for outcomes in chronic kidney disease (CKD), and none has compared measured GFR with CKD in any population. OBJECTIVE: To compare cystatin C level with serum creatinine concentration and iothalamate GFR as risk factors for death and kidney failure. DESIGN: Observational study using serum cystatin C assayed from baseline samples of the Modification of Diet in Renal Disease Study (1989-1993). SETTING: 15 clinical centers in the United States that participated in the Modification of Diet in Renal Disease Study. PARTICIPANTS: 825 trial participants with stage 3 or 4 nondiabetic CKD who had measurements of serum cystatin C. MEASUREMENTS: All-cause mortality, cardiovascular (CVD) mortality, and kidney failure until December 2000. RESULTS: Mean cystatin C level, creatinine concentration, and GFR were 2.2 mg/L (SD, 0.7), 212.16 micromol/L (SD, 88.4) (2.4 mg/dL [SD, 1.0]), and 33 mL/min per 1.73 m2 (SD, 12), respectively. Median follow-up was 10 years. Twenty-five percent of patients (n = 203) died of any cause, 15% (n = 123) died of CVD, and 66% (n = 548) reached kidney failure. In multivariate-adjusted models, 1-SD decreases in 1/creatinine, GFR, and 1/cystatin C were associated with increased risks for all-cause mortality of 1.27 (95% CI, 1.06 to 1.49), 1.27 (CI, 1.08 to 1.49), and 1.41 (CI, 1.18 to 1.67), respectively. For CVD mortality, the increased risks were 1.32 (CI, 1.05 to 1.64), 1.28 (CI, 1.04 to 1.59), and 1.64 (CI, 1.28 to 2.08), respectively. For kidney failure, the increased risks were 2.81 (CI, 2.48 to 3.18), 2.41 (CI, 2.15 to 2.70), and 2.36 (CI, 2.10 to 2.66), respectively. LIMITATION: The Modification of Diet in Renal Disease Study cohort may not be representative of all patients with nondiabetic CKD because participants were more likely to reach kidney failure than death in follow-up. CONCLUSION: The association of cystatin C level with all-cause and CVD mortality was as strong as or perhaps stronger than that of iothalamate GFR with these outcomes in stage 3 or 4 CKD.

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

CONTEXT: Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. OBJECTIVE: To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later). MAIN OUTCOME MEASURES: The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas). RESULTS: During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. CONCLUSIONS: Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00272324.