Randomized Controlled-Feeding Study of Dietary Emulsifier Carboxymethylcellulose Reveals Detrimental Impacts on the Gut Microbiota and Metabolome.

BACKGROUND & AIMS: Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized. METHODS: To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days. RESULTS: Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition. CONCLUSIONS: These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).

A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn's Disease.

BACKGROUND & AIMS: This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS: Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 µg/g and reduction by >50% among those with baseline FC >250 µg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS: The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). CONCLUSIONS: The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679.

A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. STUDY DESIGN: Retrospective analysis nested in a cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). EXPOSURE: Years before ESKD. OUTCOMES: Serial FGF-23, PTH, serum phosphate, and serum calcium levels. ANALYTICAL APPROACH: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. RESULTS: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. LIMITATIONS: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. CONCLUSIONS: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease.

Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships among inflammation, FGF23, and risk of death. Therefore, we conducted a prospective investigation of 3875 participants in the Chronic Renal Insufficiency Cohort (CRIC) study with CKD stages 2 to 4 to test the associations of baseline plasma interleukin-6, high-sensitivity C-reactive protein, and FGF23 levels with all-cause mortality, censoring at the onset of end-stage renal disease. During a median follow-up of 6.9 years, 550 participants died (20.5/1000 person-years) prior to end-stage renal disease. In separate multivariable-adjusted analyses, higher levels of interleukin-6 (hazard ratio per one standard deviation increase of natural log-transformed levels) 1.35 (95% confidence interval, 1.25-1.46), C-reactive protein 1.28 (1.16-1.40), and FGF23 1.45 (1.32-1.60) were each independently associated with increased risk of death. With further adjustment for FGF23, the risks of death associated with interleukin-6 and C-reactive protein were minimally attenuated. Compared to participants in the lowest quartiles of inflammation and FGF23, the multivariable-adjusted hazard ratio of death among those in the highest quartiles of both biomarkers was 4.38 (2.65-7.23) for interleukin-6 and FGF23, and 5.54 (3.04-10.09) for C-reactive protein and FGF23. Thus, elevated levels of interleukin-6, C-reactive protein, and FGF23 are independent risk factors for mortality in CKD.

Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production.

OBJECTIVE: The consumption of an agrarian diet is associated with a reduced risk for many diseases associated with a 'Westernised' lifestyle. Studies suggest that diet affects the gut microbiota, which subsequently influences the metabolome, thereby connecting diet, microbiota and health. However, the degree to which diet influences the composition of the gut microbiota is controversial. Murine models and studies comparing the gut microbiota in humans residing in agrarian versus Western societies suggest that the influence is large. To separate global environmental influences from dietary influences, we characterised the gut microbiota and the host metabolome of individuals consuming an agrarian diet in Western society. DESIGN AND RESULTS: Using 16S rRNA-tagged sequencing as well as plasma and urinary metabolomic platforms, we compared measures of dietary intake, gut microbiota composition and the plasma metabolome between healthy human vegans and omnivores, sampled in an urban USA environment. Plasma metabolome of vegans differed markedly from omnivores but the gut microbiota was surprisingly similar. Unlike prior studies of individuals living in agrarian societies, higher consumption of fermentable substrate in vegans was not associated with higher levels of faecal short chain fatty acids, a finding confirmed in a 10-day controlled feeding experiment. Similarly, the proportion of vegans capable of producing equol, a soy-based gut microbiota metabolite, was less than that was reported in Asian societies despite the high consumption of soy-based products. CONCLUSIONS: Evidently, residence in globally distinct societies helps determine the composition of the gut microbiota that, in turn, influences the production of diet-dependent gut microbial metabolites.

Traditional and non-traditional risk factors for incident peripheral arterial disease among patients with chronic kidney disease.

BACKGROUND: The risk of peripheral arterial disease (PAD) is higher in patients with chronic kidney disease (CKD) compared with those without. However, reasons for this increased risk are not fully understood. METHODS: We studied risk factors for incident PAD among 3169 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Patients with CKD aged 21-74 years were recruited between 2003 and 2008 and followed for a median of 6.3 years. Incident PAD was defined as a new onset ankle-brachial index (ABI) of <0.9 or confirmed clinical PAD. RESULTS: In a multivariate-adjusted model, older age, female sex, non-Hispanic Black, current smoking, diabetes, higher pulse pressure, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were significantly associated with the increased risk of incident PAD. After adjustment for these traditional risk factors as well as use of medications and CRIC Study clinic sites, the following baseline novel risk factors were significantly associated with risk of incident PAD [hazard ratio and 95% confidence interval (CI) for a one standard deviation (SD) higher level]: log[C-reactive protein (CRP)] (1.16, 1.06-1.25, P < 0.001), white blood cell count (1.09, 1.01-1.18, P = 0.03), fibrinogen (1.15, 1.06-1.26, P = 0.002), log(myeloperoxidase) (1.12, 1.03-1.23, P = 0.01), uric acid (0.88, 0.80-0.97, P = 0.01), glycated hemoglobin (1.16, 1.05-1.27, P = 0.003), log(homeostatic model assessment-insulin resistance) (1.21, 1.10-1.32, P < 0.001) and alkaline phosphatase (1.15, 1.07-1.24, P < 0.001). CONCLUSIONS: Among patients with CKD, inflammation, prothrombotic state, oxidative stress, glycated hemoglobin, insulin resistance and alkaline phosphatase are associated with an increased risk of PAD, independent of traditional risk factors.

The Associations between Peripheral Artery Disease and Physical Outcome Measures in Men and Women with Chronic Kidney Disease.

BACKGROUND: Peripheral artery disease (PAD) is highly prevalent and associated with significant morbidity and mortality, but sex-based differences are incompletely understood. We sought to define the associations between PAD and physical outcome measures and to determine if these associations differed by sex in the Chronic Renal Insufficiency Cohort. METHODS: Among 3,543 participants, we assessed the cross-sectional relationship between PAD severity defined by ankle-brachial index; and (1) physical activity (metabolic equivalent [MET]-hr/wk), (2) walking pace (slow versus medium and/or fast), and (3) physical function (12-item Short Form Health Survey [SF-12]) at baseline. RESULTS: In a multivariable linear regression model, PAD severity was not associated with physical activity defined by total MET-hr per wk in men or women (P = 0.432). However, PAD severity was significantly associated with walking activity (P = 0.037), although this relationship did not differ by sex (P = 0.130). Similarly, PAD severity was significantly associated with walking pace (P < 0.001), although this relationship did not differ by sex (P = 0.086). In contrast, there was an independent association between PAD severity and SF-12 (P = 0.018), with a significant interaction by sex (P < 0.001). CONCLUSIONS: These data suggest that tools used to evaluate the functional consequences of PAD should focus on walking activity and walking pace, as well as physical function, where sex-specific associations should be accounted for.

International Network of Chronic Kidney Disease cohort studies (iNET-CKD): a global network of chronic kidney disease cohorts.

BACKGROUND: Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. METHODS: Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and 3) minimum follow-up of three years. Participating studies were surveyed regarding design, data, and biosample resources. RESULTS: Twelve prospective cohort studies and two registries covering 21 countries were included. Participants age ranges from >2 to >70 years at inclusion, CKD severity ranges from stage 2 to stage 5. Patient data and biosamples (not available in the registry studies) are measured yearly or biennially. Many studies included multiple ethnicities; cohort size ranges from 400 to more than 13,000 participants. Studies' areas of emphasis all include but are not limited to renal outcomes, such as progression to ESRD and death. CONCLUSIONS: iNET-CKD (International Network of CKD cohort studies) was established, to promote collaborative research, foster exchange of expertise, and create opportunities for research training. Participating studies have many commonalities that will facilitate comparative research; however, we also observed substantial differences. The diversity we observed across studies within this network will be able to be leveraged to identify genetic, behavioral, and health services factors associated with the course of CKD. With an emerging infrastructure to facilitate interactions among the investigators of iNET-CKD and a broadly defined research agenda, we are confident that there will be great opportunity for productive collaborative investigations involving cohorts of individuals with CKD.

Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease: Chronic Renal Insufficiency Cohort Study.

BACKGROUND AND PURPOSE: Chronic kidney disease is associated with an increased risk of cardiovascular events. However, the impact of chronic kidney disease on cerebrovascular disease is less well understood. We hypothesized that renal function severity would be predictive of stroke risk, independent of other vascular risk factors. METHODS: The study population included 3939 subjects enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective observational cohort. Stroke events were reported by participants and adjudicated by 2 vascular neurologists. Cox proportional hazard models were used to compare measures of baseline renal function with stroke events. Multivariable analysis was performed to adjust for key covariates. RESULTS: In 3939 subjects, 143 new stroke events (0.62 events per 100 person-years) occurred over a mean follow-up of 6.4 years. Stroke risk was increased in subjects who had worse baseline measurements of renal function (estimated glomerular filtration rate and total proteinuria or albuminuria). When adjusted for variables known to influence stroke risk, total proteinuria or albuminuria, but not estimated glomerular filtration rate, were associated with an increased risk of stroke. Treatment with blockers of the renin-angiotensin system did not decrease stroke risk in individuals with albuminuria. CONCLUSIONS: Proteinuria and albuminuria are better predictors of stroke risk in patients with chronic kidney disease than estimated glomerular filtration rate. The impact of therapies targeting proteinuria/albuminuria in individuals with chronic kidney disease on stroke prevention warrants further investigation.

Healthy lifestyle and risk of kidney disease progression, atherosclerotic events, and death in CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and cardiovascular events among adults with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 3,006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: 4 lifestyle factors (regular physical activity, body mass index [BMI] of 20-<25kg/m(2), nonsmoking, and "healthy diet"), individually and in combination. OUTCOMES: CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. MEASUREMENTS: Multivariable-adjusted Cox proportional hazards. RESULTS: During a median follow-up of 4 years, we observed 726 CKD progression events, 355 atherosclerotic events, and 437 deaths. BMI≥25kg/m(2) and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 [95% CI, 0.58-0.97] and 0.61 [95% CI, 0.45-0.82] for BMIs of 25 to <30 and ≥30kg/m(2), respectively, versus 20 to <25kg/m(2); HR for nonsmoking of 0.68 [95% CI, 0.55-0.84] compared to the current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 [95% CI, 0.46-0.96] for BMI of 25-<30 vs 20-<25kg/m(2) and 0.55 [95% CI, 0.40-0.75] vs current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 [95% CI, 0.52-0.79] vs inactive), BMI≥30kg/m(2) (HR, 0.64 [95% CI, 0.43-0.96] vs 20-<25kg/m(2)), and nonsmoking (HR, 0.45 [95% CI, 0.34-0.60] vs current smoker). BMI<20kg/m(2) was associated with increased all-cause mortality risk (HR, 2.11 [95% CI, 1.13-3.93] vs 20-<25kg/m(2)). Adherence to all 4 lifestyle factors was associated with a 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11-0.89). LIMITATIONS: Lifestyle factors were measured only once. CONCLUSIONS: Regular physical activity, nonsmoking, and BMI≥25kg/m(2) were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.

Phosphate, fibroblast growth factor 23 and retinopathy in chronic kidney disease: the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Elevated circulating concentrations of phosphate and fibroblast growth factor 23 (FGF23) contribute to the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Retinopathy is a common manifestation of microvascular disease in CKD, but its associations with phosphate and FGF23 have not been studied. We tested the hypothesis that higher serum phosphate is associated with more severe retinopathy in individuals with CKD, independent of FGF23 and known risk factors for retinopathy. METHODS: We tested the associations of serum phosphate and plasma FGF23 with retinopathy in a cross-sectional analysis of 1800 participants in the Chronic Renal Insufficiency Cohort Study who underwent fundus photography. Retinopathy severity was graded according to the Early Treatment of Diabetic Retinopathy Severity score, and retinal venous and arterial diameters were measured. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 46.5 ± 15.4 mL/min/1.73 m(2), mean serum phosphate was 3.7 ± 0.6 mg/dl and median plasma C-terminal FGF23 was 133 RU/mL (interquartile range 87.2, 217.8 RU/mL). In multivariable ordinal logistic regression models, higher serum phosphate was associated with greater retinopathy severity independent of hypertension, diabetes, CKD severity and FGF23 [adjusted odds ratio of being in one higher category of retinopathy severity: 1.19 per 1 standard deviation increase; 95% confidence interval (CI) 1.05, 1.36; P = 0.007]. Presence of diabetes or hypertension did not modify the results. Higher serum phosphate was also independently associated with greater retinal venous diameter (multivariable-adjusted 1.70 µm increase per 1 standard deviation increase in phosphate; 95% CI 0.46, 2.93; P = 0.007). FGF23 levels were not independently associated with retinopathy severity or retinal venous diameter, and neither FGF23 nor phosphate was associated with retinal arterial diameter. CONCLUSIONS: Among individuals with moderate-to-severe CKD, higher serum phosphate but not FGF23 was independently associated with more severe retinopathy and microvascular retinal venous dilatation.

Burden of chronic kidney disease in resource-limited settings from Peru: a population-based study.

BACKGROUND: The silent progression of chronic kidney diseases (CKD) and its association with other chronic diseases, and high treatment costs make it a great public health concern worldwide. The population burden of CKD in Peru has yet to be fully described. METHODS: We completed a cross sectional study of CKD prevalence among 404 participants (total study population median age 54.8 years, 50.2 % male) from two sites, highly-urbanized Lima and less urbanized Tumbes, who were enrolled in the population-based CRONICAS Cohort Study of cardiopulmonary health in Peru. Factors potentially associated with the presence of CKD were explored using Poisson regression, a statistical methodology used to determine prevalence ratios. RESULTS: In total, 68 participants (16.8 %, 95 % CI 13.5-20.9 %) met criteria for CKD: 60 (14.9%) with proteinuria, four (1%) with eGFR < 60 mL/min/1.73 m2 , and four (1%) with both. CKD prevalence was higher in Lima (20.7 %, 95 % CI 15.8-27.1) than Tumbes (12.9 %, 95 % CI 9.0-18.5). Among participants with CKD, the prevalence of diabetes and hypertension was 19.1 % and 42.7 %, respectively. After multivariable adjustment, CKD was associated with older age, female sex, greater wealth tertile (although all wealth strata were below the poverty line), residence in Lima, and presence of diabetes and hypertension. CONCLUSIONS: The high prevalence rates of CKD identified in Lima and Tumbes are similar to estimates from high-income settings. These findings highlight the need to identify occult CKD and implement strategies to prevent disease progression and secondary morbidity.

Fibroblast growth factor-23 and cardiovascular events in CKD.

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes.

IMPORTANCE: Studies suggest pioglitazone use may increase risk of cancers. OBJECTIVE: To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers. DESIGN, SETTING, AND PARTICIPANTS: Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California. EXPOSURES: Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent. MAIN OUTCOMES AND MEASURES: Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma. RESULTS: Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose. CONCLUSIONS AND RELEVANCE: Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis.

BACKGROUND & AIMS: Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. METHODS: We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC <50 µg/g. Secondary outcomes were continued remission with FC <100 µg/g or <200 µg/g (among patients with pre-randomization values above these levels). RESULTS: The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P = .0496). More patients in the dose escalation group reduced FC to below 100 µg/g (P = .04) and 200 µg/g (P = .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 µg/g compared with those with FC <200 µg/g (P = .01). CONCLUSIONS: Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: Various indicators of progression of chronic kidney disease (CKD) have been used as outcomes in clinical research studies. The effect of using varying measures on the association of risk factors with CKD progression has not been well characterized. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,939) enrolled men and women with mild to moderate CKD, 48% of whom had diabetes and 42% were self-reported black race. PREDICTORS: Age, race, sex, diabetes, baseline estimated glomerular filtration rate (eGFR), proteinuria, and other established CKD risk factors. OUTCOMES: Death, end-stage renal disease (ESRD), and eGFR events, including: (1) eGFR halving, (2) eGFR<15mL/min/1.73m(2), (3) eGFR halving and <15mL/min/1.73m(2), (4) eGFR decrease of 20mL/min/1.73m(2), (5) eGFR halving or decrease of 20mL/min/1.73m(2), and (6) eGFR decrease of 25% and change in CKD stage. RESULTS: Mean entry eGFR was 44.9mL/min/1.73m(2). Annual rates of death, ESRD, and eGFR halving were 2.5%, 4.0%, and 6.1%, respectively, during an average follow-up of 5.4 years. Associations between risk factors and ESRD and eGFR events were similar across different definitions. However, these associations were substantially different from those with death. HRs for ESRD, eGFR halving, and death in the highest compared to the lowest proteinuria category were 11.83 (95% CI, 8.40-16.65), 11.19 (95% CI, 8.53-14.68), and 1.47 (95% CI, 1.10-1.96), respectively. LIMITATIONS: Participants may not be representative of the entire CKD population. CONCLUSIONS: Using ESRD or eGFR events, but not death, in the definition of kidney disease outcomes is appropriate in follow-up studies to identify risk factors for CKD progression.

Proteinuria testing among patients with diabetes mellitus is associated with bladder cancer diagnosis: potential for unmeasured confounding in studies of pioglitazone and bladder cancer.

BACKGROUND: The observed association between pioglitazone and bladder cancer could be causal or because of bias in the design of prior studies. We hypothesize that proteinuria testing may lead to detection bias if routine test results for proteinuria lead to a full urinalysis. METHODS: We reanalyzed patients with diabetes mellitus within Kaiser Permanente Northern California. Logistic and Cox regression adjusted for age, sex, race, and smoking were used to assess the association of proteinuria testing with pioglitazone use, subsequent full urinalysis, and diagnosis with bladder cancer. RESULTS: Patients treated with pioglitazone were more likely than others with diabetes to undergo testing for proteinuria (p < 0.001). The odds of positive tests for proteinuria were higher among pioglitazone-treated patients (OR = 1.41, 95%CI 1.36-1.46). A positive proteinuria test was associated with increased odds of completing a urinalysis in the following 6 months (OR = 1.78, 95%CI 1.73-1.85). Negative and positive proteinuria test results were inversely (hazard ratio (HR) 0.63, 95%CI 0.52-0.75) and positively associated (HR 2.45, 95%CI 2.12-2.82) with bladder cancer risk, respectively. Adjustment for negative and positive proteinuria testing reduced the magnitude of association between pioglitazone and bladder cancer by only 5 to 10% (ever-exposed HR: from 1.06 to 1.01 and >4 years exposure HR: from 1.38 to 1.28). CONCLUSIONS: Proteinuria testing may be a confounder in studies of pioglitazone and bladder cancer but does not fully explain the association between pioglitazone and bladder cancer in this cohort. Optimal adjustment for proteinuria testing likely requires knowledge of the test result.

Limited health literacy is associated with low glomerular filtration in the Chronic Renal Insufficiency Cohort (CRIC) study.

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 (ß -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.

Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.

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 331-420 days) of baseline. Baseline plasma FGF23 was not associated with the 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 coreceptor, 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.