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Youth with type 1 diabetes (T1D) demonstrate insulin resistance, independently of glycaemia, when compared to normoglycaemic peers. Insulin resistance increases the risk of cardiovascular disease and diabetic kidney disease, factors also associated with systemic inflammation. We evaluated the effect of metformin on markers of inflammation and diabetic kidney disease in adolescents with T1D. EMERALD, a double-blind, randomized, placebo-controlled trial of 3 months of metformin in 48 participants aged 12-21 years with T1D, included baseline and follow-up assessments of serum creatinine and cystatin C to estimate glomerular filtration rate (eGFR), aspartate aminotransferase, alanine aminotransferase, high-sensitivity C-reactive protein, white blood count, platelets, adiponectin, leptin, and urine albumin: creatinine ratio (UACR). Metformin was associated with a 13.9 mL/min/1.73 m2 (95% confidence interval 4.7-23.1 mL/min/1.73 m2 ) increase in estimated GFR by serum creatinine versus placebo (P ≤ 0.01), with a significant difference remaining after multivariable adjustments (P = 0.03). Whereas eGFR measured by serum creatinine increased significantly after metformin treatment, no differences were observed in cystatin C, UACR, or systemic inflammatory markers. Additional studies with directly measured GFR in response to metformin in T1D are needed.

Lower serum bicarbonate levels are associated with an increased risk of kidney disease progression. Whether lower serum bicarbonate levels are associated with an increased risk of developing acute kidney injury (AKI) is unclear. We included 8393 patients from the Systolic Blood Pressure Intervention Trial (SPRINT) that had baseline serum bicarbonate levels and complete data available. AKI was a predetermined adjudicated adverse event that was determined by hospital admission and discharge records with AKI as a recorded diagnosis. Serum bicarbonate was examined in clinically significant cutoffs ≤ 24, 25–28 and > 28 mEq/L, with 25–28 mEq/L as the reference group. Cox proportional hazard models were used to examine the association between serum bicarbonate and development of AKI. The mean (SD) age, estimated glomerular filtration rate (eGFR), and serum bicarbonate level at baseline were 68 (9) years, 77 (23) ml/min/1.73m2 and 26.3 (2.6) mEq/L, respectively. Participants with serum bicarbonate levels ≤ 24 mEq/L were more likely to be male and to have lower baseline eGFR. After a median follow-up time of 3.3 years, 293 participants developed AKI. More patients in the lower bicarbonate group developed AKI (6.1% vs 2.8% in the 25–28 mEq/L and 2.1% in the > 28 mEq/L). A bicarbonate level ≤ 24 mEq/L was associated with a significantly increased risk of AKI compared to those with a bicarbonate level of 25–28 mEq/L after full adjustment (HR 1.42, 95% CI 1.1–1.8). Lower serum bicarbonate levels are an independent risk factor for the development of AKI.

BACKGROUND: Children who are critically ill with AKI suffer from high morbidity and mortality rates, and lack treatment options. Emerging evidence implicates the role of complement activation in AKI pathogenesis, which could potentially be treated with complement inhibitors. The purpose of this study is to evaluate the association between complement activation fragments and severity of AKI in children who are critically ill. METHODS: A biorepository of samples from children who are critically ill from a prior multisite study was leveraged to identify children with stage 3 AKI and matched to patients without AKI on the basis of PELOD-2 (illness severity) scores. Specimens were analyzed for plasma and urine complement activation fragments of factor B, C3a, C4a, and sC5b-9. The primary outcomes were MAKE30 and severe AKI rates. RESULTS: In total, 14 patients with stage 3 AKI (five requiring RRT) were matched to 14 patients without AKI. Urine factor Ba and plasma C4a levels increased stepwise as severity of AKI increased, from no AKI to stage 3 AKI, to stage 3 AKI with RRT need. Plasma C4a levels were independently associated with increased risk of MAKE30 outcomes (OR, 3.2; IQR, 1.1–8.9), and urine Ba (OR, 1.9; IQR, 1.1–3.1), plasma Bb (OR, 2.7; IQR, 1.1–6.8), C4a (OR, 13.0; IQR, 1.6–106.6), and C3a (OR, 3.3; IQR, 1.3–8.4) were independently associated with risk of severe stage 2–3 AKI on day 3 of admission. CONCLUSIONS: Multiple complement fragments increase as magnitude of AKI severity increases. Very high levels of urine Ba or plasma C4a may identify patients at risk for severe AKI, hemodialysis, and MAKE30 outcomes. The fragments may be useful as a functional biomarker of complement activation and may identify those patients to study complement inhibition to treat or prevent AKI in children who are critically ill. These findings suggest the need for further specific investigations of the role of complement activation in children who are critically ill and at risk of AKI.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Rationale & Objective: Data suggest that exercise is beneficial for patients with chronic kidney disease (CKD) to reduce cardiovascular disease and the progression of CKD. Despite these benefits, the majority of patients with CKD remain sedentary. The purpose of this study was to identify attitudes, motivators, and barriers to exercise among individuals with CKD. Study Design: Qualitative study. Setting & Participants: 10 focus groups (41 adult participants with CKD stages 3-4 who were not currently exercising) from the Denver Metro Area. Analytical Approach: Thematic analysis. Clinics were purposively sampled. Focus groups were recorded and transcribed. Results: We identified 7 themes reflecting perceptions of exercise of patients with CKD: improvement in health and quality of life; motivation from family, friends, or peers; limitations due to comorbid conditions; challenges due to environmental factors (safety, weather, and cost concerns); lack of time; family as a barrier; and lack of provider counseling on type of exercise and the benefits. Participants recognized the benefits of exercise on health, but exercise was not viewed to have a significant impact on CKD. Having a friend, family member, or group to exercise with was viewed as a significant motivator. However, particularly in Spanish-speaking participants, family was often seen as a barrier if they were not willing to exercise with the patients. Most participants expressed receiving limited information from their kidney provider regarding how exercise affected their kidney health. Spanish-speaking participants in particular expressed frustration with their nephrologist's lack of advice regarding exercise. Limitations: Potential selection bias and inclusion of only sedentary patients with CKD. Conclusions: Barriers and motivators to exercise were similar among participating men and women with CKD. Lack of advice from kidney providers regarding exercise was a significant barrier. Exercise interventions in patients with CKD should include not only increased patient self-efficacy and social support, but also counseling and prescribing of exercise by nephrologists. Index Words: Exercise, chronic kidney disease, focus group, qualitative study, patient perspective

Background Interest in nephrology as a career has declined dramatically over the past several years. Only 62% of nephrology fellowship positions are filled for the upcoming 2020 appointment year. The purpose of this study was to identify perceptions, attitudes, motivators, and barriers to a career in nephrology among internal medicine residents. Methods We recruited focus groups of internal medicine residents (N=25) from the University of Colorado, and asked questions aimed at exploring perceptions, attitudes, and barriers to a career in nephrology, and ways to increase interest in nephrology. All focus groups were conducted on the University of Colorado Denver Anschutz Medical Campus. Focus group sessions were recorded and transcribed. Thematic analysis was used to identify key concepts and themes. Results Residents described many barriers to a career in nephrology, including lack of exposure, lack of advances in the field, low monetary compensation, high complexity, lack of role models/mentors, and low-prestige/noncompetitive nature of the field. Most residents had no exposure to outpatient nephrology. Lack of new therapeutics was a significant deterrent to nephrology. Nephrology teaching in medical school was described as not clinically relevant and too complicated. Several residents felt they were not smart enough for nephrology. Only three residents had a role model within nephrology. Residents used the word “stigmatized” to describe nephrology, and discussed how low prestige decreased their interest in a field. Participants expressed suggestions to increase interest in nephrology through earlier and more outpatient nephrology exposure, enhanced interactions with nephrologists, and research and advancements in the field. Conclusions Residents identified several modifiable barriers to a career in nephrology. Changing how nephrology is taught in medical school, enhancing interactions with nephrologists through increased exposure, and highlighting research and advancements in nephrology may change the perception of nephrology and increase the number of residents entering the field.

Deficiency of 25-hydroxyvitamin D (25[OH]D) is common in patients with chronic kidney disease stages 3 and 4 and is associated with poor outcomes. However, the evaluation and management of vitamin D deficiency in nephrology remains controversial. This article reports on the proceedings from a “controversies conference” on vitamin D in chronic kidney disease that was sponsored by the National Kidney Foundation. The report outlines the deliberations of the 3 work groups that participated in the conference. Until newer measurement methods are widely used, the panel agreed that clinicians should classify 25(OH)D “adequacy” as concentrations > 20 ng/mL without evidence of counter-regulatory hormone activity (ie, elevated parathyroid hormone). The panel also agreed that 25(OH)D concentrations < 15 ng/mL should be treated irrespective of parathyroid hormone level. Patients with 25(OH)D concentrations between 15 and 20 ng/mL may not require treatment if there is no evidence of counter-regulatory hormone activity. The panel agreed that nutritional vitamin D (cholecalciferol, ergocalciferol, or calcifediol) should be supplemented before giving activated vitamin D compounds. The compounds need further study evaluating important outcomes that observational studies have linked to low 25(OH)D levels, such as progression to end-stage kidney disease, infections, fracture rates, hospitalizations, and all-cause mortality. We urge further research funding in this field.

Background and objectives We examined the effect of alkali replacement for metabolic acidosis on vascular endothelial function in patients with CKD. Methods We performed a pilot, prospective, open-label 14-week crossover study examining the effect of oral sodium bicarbonate treatment on vascular function in 20 patients with an eGFR of 15–44 ml/min per 1.73 m 2 with low serum bicarbonate levels (16–21 mEq/L). Each period was 6 weeks in duration with a 2-week washout period in between. Patients were treated to goal serum bicarbonate of ≥23 mEq/L. The primary end point was change in brachial artery flow-mediated dilation (FMD) between treatment and control conditions. Secondary end points included changes in markers of inflammation, bone turnover, mineral metabolism, and calcification. Results Eighteen patients completed the study and were included in the primary efficacy analysis. The mean (SD) age and eGFR were 59 (12) years and 26 (8) ml/min per 1.73 m 2 , respectively. Serum bicarbonate increased significantly with sodium bicarbonate treatment (+2.7±2.9 mEq/L, P ≤0.001), whereas there was no change in bicarbonate levels in the control group. FMD significantly improved after sodium bicarbonate therapy (mean±SD, FMD baseline: 4.1%±4.1%; 6 weeks: 5.2%±2.9%; P =0.04) There was no significant change in FMD in the control group (mean±SD, FMD baseline: 4.6%±3.1%; 6 weeks: 4.1%±3.4%; P =0.20). Compared with control, sodium bicarbonate treatment resulted in a significant increase in FMD (mean, 1.8%; 95% confidence interval, 0.3 to 3.3; P =0.02). There was no significant change in bone markers or serum calcification propensity with treatment. Serum phosphorus and intact fibroblast growth factor 23 increased significantly during treatment. Conclusions Treatment of metabolic acidosis with sodium bicarbonate significantly improved vascular endothelial function in patients with stages 3b and 4 CKD.

Background: Only a small percentage of dialysis patients receive a transplant and this is particularly the case for racial/ethnic minorities. Our objective was to identify barriers to initial transplant evaluation in our dialysis centers. Methods: We conducted a survey of adult hemodialysis patients from 4 dialysis units in the Denver Metro area in 2016. Participants completed an 11-item survey with demographic information and questions regarding time on dialysis, if a provider ever spoke to them about transplant, and whether they had been evaluated for a transplant. Reasons for not having an evaluation were explored. Descriptive statistics, chi-square analyses, and multivariate analyses were used to examine the responses. Results: A total of 167 patients completed the survey (response rate 63.9%). The majority of participants were male and were Hispanic (49%) or Non-Hispanic black (31.7%). Of these, 140 patients (84.0%) reported discussing kidney transplantation with their doctor but only 53% reported having a transplant evaluation. After adjustment for age, gender, and time on dialysis, significantly fewer blacks reported having an evaluation than Non-Hispanic whites or Hispanics (43.4 vs. 57.7% [whites] and 59.7% [Hispanics], p = 0.03). The most frequent responses of the patients who had not been evaluated were the following: not referred by their provider (46%), did not know how to proceed (43.4%), or did not understand the benefits (39.5%) or transplant process (38.2%). Compared to Non-Hispanic whites, blacks and Hispanics reported less understanding of the benefits and process of transplant. Conclusion: Timely referral by providers and improved kidney transplantation education may reduce disparities in access to kidney transplantation.

Background Few quantitative nephrology-specific simulations assess fellow competency. We describe the development and initial validation of a formative objective structured clinical examination (OSCE) assessing fellow competence in ordering acute dialysis. Methods The three test scenarios were acute continuous renal replacement therapy, chronic dialysis initiation in moderate uremia and acute dialysis in end-stage renal disease-associated hyperkalemia. The test committee included five academic nephrologists and four clinically practicing nephrologists outside of academia. There were 49 test items (58 points). A passing score was 46/58 points. No item had median relevance less than ‘important’. The content validity index was 0.91. Ninety-five percent of positive-point items were easy–medium difficulty. Preliminary validation was by 10 board-certified volunteers, not test committee members, a median of 3.5 years from graduation. The mean score was 49 [95% confidence interval (CI) 46–51], κ = 0.68 (95% CI 0.59–0.77), Cronbach’s α = 0.84. Results We subsequently administered the test to 25 fellows. The mean score was 44 (95% CI 43–45); 36% passed the test. Fellows scored significantly less than validators (P

OBJECTIVE:The high pill burden of many phosphate binders (PBs) may contribute to increased prevalence of hyperphosphatemia and poor nutritional status observed among patients undergoing maintenance hemodialysis therapy. We examined the real-world effectiveness of sucroferric oxyhydroxide (SO), a PB with low pill burden, in managing serum phosphorus in patients with prevalent hemodialysis over a 1-year period. DESIGN:Historical cohort analyses of de-identified electronic medical records. SUBJECTS:In-center hemodialysis patients switched from another PB to SO therapy as part of routine care with 12months of uninterrupted SO prescriptions recorded, and documented serum phosphorus levels were eligible for inclusion. Clinical data were extracted from a pharmacy service, FreseniusRx, database and Fresenius Kidney Care clinical data warehouse. MAIN OUTCOME MEASURES:Comparisons were made between the 91-day period before SO initiation (i.e., baseline) and the 4 consecutive 91-day intervals of SO treatment (Q1-Q4). Clinical measures included achievement of target phosphorus levels (≤5.5mg/dL) and mean number of PB pills/day. RESULTS:Among 530 analyzed patients, the proportion achieving target serum phosphorus levels increased by >100% 1year after switching to SO therapy, that is, from 17.7% at baseline to 24.5%, 30.5%, 36.4%, and 36.0% at Q1 through Q4, respectively (P&nbsp

Maintenance of calcium levels within a narrow physiological range is essential to life. Calcium homeostasis is complex and tightly regulated and depends on regulation of calcium fluxes within the intestine, kidney, and bones. Calcium metabolism is controlled by calcium itself through a calcium receptor and several hormones, the major ones of which are parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2D). PTH and 1,25(OH)2D exert their effects on the gastrointestinal tract, kidney, and bone in order to maintain normal levels of calcium. Hypercalcemia and hypocalcemia indicate critical disruptions of calcium homeostasis. This chapter reviews the regulation of calcium homeostasis and the diagnosis and management of disorders of calcium metabolism.

Background: Low serum bicarbonate concentrations are associated with mortality and kidney disease progression. Data regarding associations between bicarbonate and cardiovascular disease (CVD) are scarce. Methods: We performed a cohort study of 6,229 adult participants from the Multi-Ethnic Study of Atherosclerosis, a community-based cohort free of CVD at baseline. Serum bicarbonate was measured at baseline. Cardiovascular outcomes were defined as: (1) subclinical CVD (left ventricular mass [LVM] and aortic pulse pressure [PP] measured at baseline), (2) incident atherosclerotic cardiovascular events (CVE; composite of myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease death, and stroke death), and (3) incident heart failure. Results: During a median (interquartile range) follow-up of 8.5 (7.7-8.6) years, 331 (5.3%) participants had an incident CVE and 174 (2.8%) developed incident heart failure. We stratified analyses by use of diuretics because we observed a significant interaction between diuretic use and bicarbonate with study outcomes. Among diuretic nonusers, with adjustment, bicarbonate ≥25 mEq/L was associated with an estimated 3.0 g greater LVM (95% CI 0.5-5.0) and 1.0 mm Hg higher aortic PP (95% CI 0.4-2.0) compared to bicarbonate 23-24 mEq/L. Each 1 mEq/L of bicarbonate increase was associated with a 13% higher risk of incident heart failure (hazards ratio 1.13, 95% CI 1.01-2.11). Among diuretic users, higher bicarbonate was not associated with CVD. Bicarbonate was not associated with incident atherosclerotic CVE irrespective of diuretic use. Conclusion: Among nonusers of diuretics in a large community-based study, higher serum bicarbonate concentrations are associated with subclinical CVD and new heart failure.

Background: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. Objectives: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. Methods: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. Results: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI ­0.41–0.91) compared to the elevated stable trajectory group. Conclusions: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.

CKD mineral and bone disorder (CKD-MBD) is characterized by several inter-related abnormalities in circulating vitamin D metabolites and related regulatory hormones ([1][1]). Reduced kidney function leads to reduced circulating concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active

Objective To evaluate the attitudes and perceptions of primary care providers (PCPs) regarding the presence and underlying sources of racial/ethnic and socioeconomic disparities in hypertension control. Methods We conducted a survey of 115 PCPs from 2 large academic centers in Colorado. We included physicians, nurse practitioners, and physician assistants. The survey assessed provider recognition and perceived contributors of disparities in hypertension control. Results Respondents were primarily female (66%), non-Hispanic White (84%), and physicians (80%). Among respondents, 67% and 73% supported the collection of data on the patients' race/ethnicity and socioeconomic status (SES), respectively. Eighty-six percent and 89% agreed that disparities in race/ethnicity and SES existed in hypertension care within the US health system. However, only 33% and 44% thought racial/ethnic and socioeconomic disparities existed in the care of their own patients. Providers were more likely to perceive patient factors rather than provider or health system factors as mediators of disparities. However, most supported interventions such as improving provider communication skills (87%) and cultural competency training (89%) to reduce disparities in hypertension control. Conclusions Most providers acknowledged that racial/ethnic and socioeconomic disparities in hypertension control exist in the US health system, but only a minority reported disparities in care among patients they personally treat. Our study highlights the need for testing an intervention aimed at increasing provider awareness of disparities within the local health setting to improve hypertension control for minority patients.

Background: Evidence suggests that the renin-angiotensin-aldosterone system (RAAS) interacts with the vitamin D-fibroblast growth factor 23-Klotho axis. We investigated whether circulating mineral metabolism markers modify outcomes in response to RAAS inhibition in subjects with advanced chronic kidney disease (CKD). Methods: In this retrospective cohort study, we analyzed the association of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use with all-cause mortality and dialysis initiation among 1,753 subjects (1,099 CKD, estimated glomerular filtration rate 18 ± 6 ml/min/1.73 m2 and 654 end-stage renal disease [ESRD]) from the Homocysteine in Kidney and End Stage Renal Disease (HOST) study. A propensity score analysis accounted for indication bias and Cox regression models adjusted for mineral metabolism markers. Results: Mean follow-up was 3.2 years; 714 (41%) subjects died and 615 (56%) initiated dialysis. In adjusted analyses, all subjects treated with ACEI/ARB had a significantly lower hazard of death (hazards ratio (HR) 0.81, 95% CI 0.70-0.95, p = 0.007). Those with CKD not on dialysis and treated with ACEI/ARB trended toward a lower hazard of dialysis initiation (HR 0.86, 95% CI 0.73-1.01, p = 0.06). The association with mortality did not differ by level of mineral metabolism marker (p for interaction >0.16); however, the relationship with dialysis initiation differed according to the median serum phosphorus level (p for interaction Conclusions: RAAS inhibition was associated with decreased all-cause mortality independent of disordered mineral metabolism among mostly male HOST subjects with advanced CKD and ESRD. However, among those with CKD not requiring dialysis, the renoprotection associated with RAAS inhibition was attenuated by higher serum phosphorus levels. Further studies are needed to confirm this association.

Background and objectives High circulating vitamin D levels are associated with lower cardiovascular mortality in CKD, possibly by modifying endothelial function. We examined the effect of calcitriol versus cholecalciferol supplementation on vascular endothelial function in patients with CKD. Design, setting, participants, & measurements We performed a prospective, double-blind, randomized trial of 128 adult patients with eGFR=15–44 ml/min per 1.73 m2and serum 25-hydroxyvitamin D level Results One hundred and fifteen patients completed the study. The mean (SD) age and eGFR of participants were 58±12 years old and 33.0±10.2 ml/min per 1.73 m2, respectively. There were no significant differences between groups at baseline. After 6 months, neither calcitriol nor cholecalciferol treatment resulted in a significant improvement in flow-mediated dilation (mean±SD percentage flow-mediated dilation; calcitriol: baseline 4.8±3.1%, end of study 5.1±3.6%; cholecalciferol: baseline 5.2±5.2%, end of study 4.7±3.6%); 25-hydroxyvitamin D levels increased significantly in the cholecalciferol group compared with the calcitriol group (cholecalciferol: 11.0±9.5 ng/ml; calcitriol: −0.8±4.8 ng/ml; P Conclusions Six months of therapy with calcitriol or cholecalciferol did not improve vascular endothelial function or improve inflammation in patients with CKD.

Cognitive impairment is common in advanced chronic kidney disease (CKD), but little is known about its relation with abnormalities in mineral metabolism. Methods: The longitudinal association between plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF-23) levels and cognitive function was assessed in 605 patients (67 ± 12 years) with advanced CKD not requiring dialysis (n = 247) or end-stage renal disease (ESRD; n = 358) who participated in the Homocysteine Study Cognitive Function Substudy (HOSTCOG)). Cognitive function was assessed using the Telephone Interview for Cognitive Status-modified (TICSm; mean follow-up 3.1 years) and associated with baseline mineral metabolite levels using linear regression analyses. Results: In unadjusted analyses, increasing log 1,25(OH)2D and decreasing log iPTH and FGF-23 levels were associated with worse cognitive status (p < 0.05). In fully adjusted multivariate analyses, the associations were no longer significant. Log 25(OH)D levels were not associated with cognitive function in unadjusted or adjusted analyses. Results were similar when analyzed by tertile or separately within CKD and ESRD groups. Conclusions: These results suggest that mineral metabolism dysregulation does not mediate the impairment in cognitive function common in advanced CKD.

Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels

The relationship between dietary sodium and potassium intake with elevated blood pressure (BP) levels is unclear. The authors examined the association between dietary sodium and potassium intake and BP levels in 6985 adults aged 18 years and older with no prior history of hypertension who participated in the National Health and Nutrition Examination Survey (2001-2006). After adjustment for age, sex, race, body mass index, diabetes, and estimated glomerular filtration rate, there was no association between higher quartiles of sodium or potassium intake with the risk of a BP >140/90 mm Hg or >130/80 mm Hg. There was also no relationship between dietary sodium and potassium intake with BP when systolic and diastolic BP were measured as continuous outcomes (P=.68 and P=.74, respectively). Furthermore, no association was found between combinations of sodium and potassium intake with elevated BP. In the US adult population without hypertension, increased dietary sodium or low potassium intake was not associated with elevated BP levels.

In patients with chronic kidney disease (CKD), vascular calcification is associated with significant morbidity and mortality. The prevalence of vascular calcification increases as glomerular filtration rate (GFR) declines and calcification occurs years earlier in CKD patients than in the general population. The mechanisms of vascular calcification in CKD patients are complex and not completely understood but likely involve non-traditional risk factors, which may be unique to patients with CKD. These unique risk factors may predispose patients to early and more accelerated calcification. Experimental and clinical studies show that disorders in mineral metabolisms including calcium and phosphorus homeostasis initiate and promote vascular calcification in patients with CKD. It is currently unknown if vascular calcification can be prevented or reversed with therapies aimed at maintaining calcium and phosphorus homeostasis. This review focuses on the potential mechanisms by which disordered mineral metabolism may promote vascular calcification in patients with CKD.

Aims: The concentration of fibroblast growth factor 23 (FGF-23) is elevated in patients on dialysis. FGF receptors have been implicated in the pathogenesis of left ventricular (LV) hypertrophy. The objective of this study was to examine the associations between high plasma FGF-23 concentration and LV systolic dysfunction. Methods: We tested the hypothesis that high plasma FGF-23 concentration is associated with LV dysfunction in 110 chronic dialysis patients from the Homocysteine study who had paired echocardiograms performed for clinical indications. C-terminal FGF-23 concentrations were measured in stored plasma samples. Multivariate regression analyses were performed to evaluate the association of FGF-23 concentration with LV dysfunction. Results: Participants had a mean age of 60 ± 11 years. Median FGF-23 level and mean ejection fraction (EF) at baseline were 4,632 (1,384 – 14,997) RU/ml and 50 ± 13%, respectively. Median follow-up time was 1.9 years. Higher FGF-23 concentration was directly associated with decreases in EF during follow-up. After adjustment for demographics, baseline EF, hypertension, diabetes, cardiovascular disease, body mass index, systolic blood pressure, hemoglobin and markers of mineral metabolism, participants with FGF-23 in the highest tertile had an 8% decrease in EF compared to participants in the lowest tertile (β –8.0, 95% CI –15.5 to –0.53; p = 0.04). When FGF-23 was evaluated as a continuous variable, for every log10 increase in FGF-23, EF decreased during follow-up by 6.5% (β –6.5, 95% CI –11.3 to –1.73; p = 0.01). Conclusion: In conclusion, higher FGF-23 concentration is independently associated with LV systolic dysfunction in chronic dialysis patients.

We sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S.Six hundred and seven NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75 ± 17 vs. 85 ± 20 nmol/L [30 ± 7 vs. 34 ± 8 ng/mL], P0.001). Inadequate 25(OH)D status progressively increased the odds of NAFLD when classified categorically as sufficient (25(OH)D 75 nmol/L [30 ng/mL], reference group), insufficient (37-75 nmol/L [15-30 ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90-6.34) or deficient (37 nmol/L [15 ng/mL]; adjusted OR: 2.56, 95% CI: 1.27-5.19). When modeled as a continuous variable, increased log10 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064-0.96, P=0.02).Compared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.

Neuromuscular complications are almost universal in CKD by the time that a patient commences dialysis. Recent studies have indicated that chronic hyperkalemia may contribute to the development of neuropathy in CKD. This study was undertaken to determine whether dietary restriction of potassium intake may be a neuroprotective factor in CKD.A 24-month prospective, single-blind, randomized, controlled trial was undertaken in 47 consecutively recruited patients with stages 3 and 4 CKD. The intervention arm (There was a greater increase in total neuropathy score from baseline to final assessment in the control arm compared with the intervention arm (6.1±6.2-8.6±7.9 controls; 7.8±7.4-8.2±7.5 intervention; change 2.8±3.3-0.4±2.2, respectively;Our results provide important preliminary evidence that dietary potassium restriction confers neuroprotection in CKD and should be confirmed in a larger multicenter trial.

Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to patients with CKD, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance the progression of vascular calcification, including (1) transition of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters, (2) induction of VSMC apoptosis, (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells, (4) elevation of fibroblast growth factor 23 levels, and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis presently is unknown. This review discusses these mechanisms in depth, exploring the interplay among vascular calcification promoters, inhibitors, and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.

Background Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is a systemic disorder that leads to vascular calcification and accelerated atherosclerosis. Uric acid has been shown to associate with vascular calcification and with carotid intima-media thickness (CIMT) and to suppress the 1 α-hydroxylase enzyme leading to lower 1,25-dihydroxyvitamin D (1,25(OH)2D) and higher intact parathyroid hormone (iPTH) levels. We hypothesized that lowering serum uric acid would reduce CIMT, calcification propensity, and circulating markers of CKD-MBD in CKD. Methods This is a post-hoc analysis of a randomized, double-blind study of 80 patients with stage 3 CKD and hyperuricemia who received allopurinol or placebo for 12 weeks. CIMT and T50 were measured as markers of vascular disease and serum calcification propensity, respectively. The following markers of CKD-MBD were measured: serum calcium, phosphorus, vitamin D metabolites, iPTH, and fibroblast growth factor-23 (FGF-23). Expression of extra-renal 1α-hydroxylase was evaluated in endothelial cells of study participants. Findings Allopurinol successfully lowered serum uric acid levels compared to placebo with an estimate of -3.3 mg/dL (95% C.I. -4.1,-2.5; p < 0.0001). After 12 weeks, however, we found no significant change in CIMT or serum T50. There was not a significant change in vitamin D metabolites, iPTH, FGF-23, or the expression of endothelial 1α-hydroxylase. Conclusion These data suggest that factors other than uric acid may play a more important role in the regulation of CKD- MBD including vascular calcification and vitamin D metabolism in patients with CKD.

Elevated serum levels of gamma-glutamyltransferase (GGT) are a marker of liver injury, but may also be associated with other diseases and death. Currently, the association of serum GGT concentrations with chronic kidney disease has not been established in the U.S. general population.We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey 2001 through 2006 and examined the association between serum GGT concentrations and chronic kidney disease in a nationally representative sample of 13,188 adults aged 20 years or older. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease formula. The prevalence of chronic kidney disease defined as eGFR60 ml/min/1.73 m(2) or abnormal albuminuria in those with eGFR ≥60 ml/min/1.73 m(2) was 13.9% (n = 1842). Serum GGT elevation was associated with an increased odds of chronic kidney disease (odds ratio 2.38, 95% confidence intervals 2.02-2.80, p0.0001). After adjustment for demographics, comorbidities, daily alcohol consumption, lipid-lowering medications, viral hepatitis status and laboratory measures, the odds ratio of chronic kidney disease per log serum GGT increase was 1.79 (1.41, 2.27; p0.0001).These results show a strong, independent, relationship of increased serum GGT concentrations with chronic kidney disease in the US adult population.

To examine the relationship between systolic blood pressure and progression of carotid intima-media thickness in patients with chronic kidney disease (CKD), we studied 3364 patients from a community-based cohort of elderly individuals of whom 724 had CKD defined as creatinine clearances of stage 3 or less. The contribution of systolic blood pressure was evaluated in four ranges (120, 120-129, 130-139, andor = 140 mm Hg). All multiple linear regression analyses were adjusted for traditional and nontraditional cardiovascular risk factors. The higher ranges of systolic blood pressure at baseline were associated with a greater carotid intima-media thickness at the initiation of the study in patients with or without CKD. Covariate-adjusted averages of carotid intima-media thickness at the initiation of the study in patients with CKD significantly increased across the four strata of systolic blood pressure. Higher systolic blood pressure at baseline was associated with a significantly greater yearly change in covariate-adjusted mean carotid intima-media thickness and vascular events in patients with CKD over a 4-year follow-up period.

Undocumented immigrants with end-stage renal disease have variable access to hemodialysis in the United States despite evidence-based standards for frequency of dialysis care.To determine whether mortality and health care use differs among undocumented immigrants who receive emergency-only hemodialysis vs standard hemodialysis (3 times weekly at a health care center).A retrospective cohort study was conducted of undocumented immigrants with incident end-stage renal disease who initiated emergency-only hemodialysis (Denver Health, Denver, Colorado, and Harris Health, Houston, Texas) or standard (Zuckerberg San Francisco General Hospital, San Francisco, California) hemodialysis between January 1, 2007, and July 15, 2014.Access to emergency-only hemodialysis vs standard hemodialysis.The primary outcome was mortality. Secondary outcomes were health care use (acute care days and ambulatory care visits) and rates of bacteremia. Outcomes were adjusted for propensity to undergo emergency hemodialysis vs standard hemodialysis.A total of 211 undocumented patients (86 women and 125 men; mean [SD] age, 46.5 [14.6] years; 42 from the standard hemodialysis group and 169 from the emergency-only hemodialysis group) initiated hemodialysis during the study period. Patients receiving standard hemodialysis were more likely to initiate hemodialysis with an arteriovenous fistula or graft and had higher albumin and hemoglobin levels than patients receiving emergency-only hemodialysis. Adjusting for propensity score, the mean 3-year relative hazard of mortality among patients who received emergency-only hemodialysis was nearly 5-fold (hazard ratio, 4.96; 95% CI, 0.93-26.45; P = .06) greater compared with patients who received standard hemodialysis. Mean 5-year relative hazard of mortality for patients who received emergency-only hemodialysis was more than 14-fold (hazard ratio, 14.13; 95% CI, 1.24-161.00; P = .03) higher than for those who received standard hemodialysis after adjustment for propensity score. The number of acute care days for patients who received emergency-only hemodialysis was 9.81 times (95% CI, 6.27-15.35; P .001) the expected number of days for patients who had standard hemodialysis after adjustment for propensity score. Ambulatory care visits for patients who received emergency-only hemodialysis were 0.31 (95% CI, 0.21-0.46; P .001) times less than the expected number of days for patients who received standard hemodialysis.Undocumented immigrants with end-stage renal disease treated with emergency-only hemodialysis have higher mortality and spend more days in the hospital than those receiving standard hemodialysis. States and cities should consider offering standard hemodialysis to undocumented immigrants.

Background Chronic kidney disease (CKD) is associated with an increased risk of incident cardiovascular disease (CVD); however, the role of statins for the primary prevention of acute cardiovascular events in patients with CKD and the effect of statins on kidney function loss in persons without prevalent CVD have not been studied. Study Design Post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. Setting & Participants Multicenter, randomized, double-blind, placebo-controlled trial of 5,608 men and 997 women without CVD randomly assigned to treatment with lovastatin or placebo. Intervention Placebo or lovastatin, 20 mg/d. Outcomes & Measurements First major acute cardiovascular event in participants with mild CKD and kidney function loss in persons with or without CKD. Estimated glomerular filtration rate was calculated using the 4-variable Modification of Diet in Renal Disease Study equation. Results At baseline, mean estimated glomerular filtration rate in participants with CKD (n = 304) was 53.0 ± 6.0 mL/min/1.73 m 2 . After an average follow-up of 5.3 ± 0.8 years, the incidence of a fatal and nonfatal CVD event was lower in participants with CKD receiving lovastatin than in those receiving placebo (adjusted relative risk [RR], 0.31; 95% CI, 0.13-0.72; P = 0.01). Tests for interaction suggested that the benefit of lovastatin was independent of the presence of CKD. Lovastatin did not reduce the annualized mean decrease in estimated glomerular filtration rate (−1.3 ± 0.07 vs −1.4 ± 0.07 mL/min/1.73 m 2 /y, respectively; P = 0.1) or the frequency of a ≥ 25% decrease in kidney function (adjusted RR, 1.10; 95% CI, 0.96-1.28; P = 0.2) or incident CKD (adjusted RR, 1.04; 95% CI, 0.86-1.27; P = 0.6). Limitations Unable to determine the cause and duration of kidney disease, and information regarding proteinuria was not available. Conclusions Lovastatin is effective for the primary prevention of CVD in patients with CKD, but is not effective in decreasing kidney function loss in persons with no CVD.

Objective Statins have been hypothesized to slow loss of kidney function, however, data is conflicting. This study assessed whether simvastatin reduces rates of kidney function loss in participants with coronary heart disease (CHD). Methods We performed a post hoc analysis from the Scandinavian Simvastatin Survival Study, a randomized trial of simvastatin vs . placebo in 4444 men and women with CHD. Kidney disease progression defined as the occurrence of a ≥25% reduction in estimated glomerular filtration rate (GFR) from baseline or development of chronic kidney disease (CKD), defined as estimated GFR 2 . The annual rate of change in estimated GFR was also evaluated. Estimated GFR was determined by the Modified Diet and Renal Disease Study equation. Results Change in kidney function could be calculated in 3842 subjects, of whom 409 had CKD at baseline. In the whole population, simvastatin significantly reduced the frequency of a ≥25% decline in kidney function [adjusted odds ratio (OR) 0.68, 95% confidence interval (CI), 0.50–0.92; p =0.01] during 5.5 years of follow-up. The adjusted annualized least-square mean decline in estimated GFR in the simvastatin group was lower than that in the placebo group (0.34mL/min/1.73m 2 /year vs . 0.41mL/min/1.73m 2 /year, respectively; p =0.02). There was no significant effect of simvastatin on kidney function in the subgroup of participants ( n =363), who developed incident CKD at the end of follow-up [adjusted OR: 0.89 (95% CI 0.70–1.14; p =0.36)]. Conclusion Simvastatin was associated with a moderate protective effect on the rate of kidney function loss in participants with CHD.

Serum 25-hydroxyvitamin D [25(OH)D] levels are inversely associated with important cardiovascular disease (CVD) risk factors. However, the association between 25(OH)D levels and prevalent CVD has not been extensively examined in the general population.We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) and examined the association between serum 25(OH)D levels and prevalence of CVD in a representative population-based sample of 16,603 men and women aged 18 years or older. Prevalence of CVD was defined as a composite measure inclusive of self-reported angina, myocardial infarction or stroke.In the whole population, there were 1308 (8%) subjects with self-reported CVD. Participants with CVD had a greater frequency of 25(OH)D deficiency [defined as serum 25(OH)D levels20 ng/mL] than those without (29.3% vs. 21.4%; p0.0001). After adjustment for age, gender, race/ethnicity, season of measurement, physical activity, body mass index, smoking status, hypertension, diabetes, elevated low-density lipoprotein cholesterol, hypertriglyceridemia, low high-density lipoprotein cholesterol, chronic kidney disease and vitamin D use, participants with 25(OH)D deficiency had an increased risk of prevalent CVD (odds ratio 1.20 [95% confidence interval (CI) 1.01-1.36; p=0.03]).These results indicate a strong and independent relationship of 25(OH)D deficiency with prevalent CVD in a large sample representative of the US adult population.

Patients with chronic kidney disease (CKD) have a reduced lifespan, and a substantial proportion of these individuals die from cardiovascular disease. Although a large percentage of patients with CKD have traditional cardiac risk factors such as diabetes, hypertension and abnormalities in cholesterol, interventions to address these factors--which have significantly decreased cardiovascular mortality in the general population--have not shown such benefit in the CKD population. In addition, the severity and extent of cardiovascular complications in patients with CKD is disproportionate to the number and severity of traditional risk factors. This realization has focused attention on nontraditional cardiac risk factors that are particularly relevant to patients with CKD, including decreased hemoglobin levels, microalbuminuria, increased inflammation and oxidative stress, and abnormalities in bone and mineral metabolism. However, large prospective trials in patients with advanced CKD or in those requiring chronic dialysis have not shown that normalization of these nontraditional risk factors improves survival. Moreover, the mechanisms by which these nontraditional risk factors contribute to cardiovascular disease are unknown. Therefore, although current treatment of patients with CKD includes management of traditional and nontraditional risk factors, the value of modifying some nontraditional risk factors remains unclear.

Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.

Background and objective The optimal BP target to reduce adverse clinical outcomes in patients with CKD is unclear. This study examined the relationship between BP and death, cardiovascular events (CVEs), and kidney disease progression in patients with advanced kidney disease. Design, setting, participants, & measurements The relationship of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) with death, CVE, and progression to long-term dialysis was examined in 1099 patients with advanced CKD (eGFR≤30 ml/min per 1.7 3m 2 ; not receiving dialysis) who participated in the Homocysteine in Kidney and ESRD study. That study enrolled participants from 2001 to 2003. Cox proportional hazard models were used to examine the association between BP and adverse outcomes. Results The mean±SD baseline eGFR was 18±7 ml/min per 1.73 m 2 . During a median follow-up of 2.9 years, 453 patients died, 215 had a CVE, and 615 initiated long-term dialysis. After adjustment for demographic characteristics and confounders, SBP, DBP, and PP were not associated with a higher risk of death. SBP and DBP were also not associated with CVE. The highest quartile of PP was associated with a substantial higher risk of CVE compared with the lowest quartile (hazard ratio [HR], 1.67; 95% confidence interval [95% CI], 1.10 to 2.52). The highest quartiles of SBP (HR, 1.28; 95% CI, 1.01 to 1.61) and DBP (HR, 1.36; 95% CI, 1.07 to 1.73), but not PP, were associated with a higher risk of progression to long-term dialysis compared with the lowest quartile. Conclusions In patients with advanced kidney disease not undergoing dialysis, higher PP was strongly associated with CVE whereas higher SBP and DBP were associated with progression to long-term dialysis. These results suggest that SBP and DBP should not be the only factors considered in determining antihypertensive therapy; elevated PP should also be considered.

Smyth et al. examined the association between urinary sodium and potassium excretion and adverse renal outcomes in adults at high cardiovascular risk. They found no association between urinary sodium excretion and adverse renal outcomes, but a reduced odds of adverse renal outcomes with higher urinary potassium excretion. It will be important to ascertain whether this finding holds true in individuals free from vascular disease and diabetes, as well as in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.

Background Cardiovascular diseases such as atherosclerosis and vascular calcification are a major cause of death in patients with chronic kidney disease ( CKD ). Recently, the long‐awaited results of the Study of Heart and Renal Protection trial were reported. This large randomized clinical trial found that an extensive cholesterol‐lowering therapy through the combination of simvastatin and ezetimibe significantly reduced cardiovascular diseases in a wide range of patients with CKD . However, the mechanism by which this cholesterol‐lowering therapy reduces CKD ‐dependent vascular diseases remains elusive. The objective of the present study was to determine the contribution of the oxysterol‐induced pro‐apoptotic transcription factor CCAAT/enhancer‐binding protein homologous protein ( CHOP ) on the pathogenesis of CKD ‐dependent cardiovascular diseases through endoplasmic reticulum stress signaling. Methods and Results CKD increased levels of serum oxysterols such as 7‐ketocholesterol in human patients and ApoE −/− mice. Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD ‐dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction. This therapy also reduced aortic endoplasmic reticulum stress induced by CKD . The short hairpin RNA ‐mediated knockdown of CHOP and activating transcription factor‐4 in vascular smooth muscle cells attenuated oxysterol‐induced mineralization, osteogenic differentiation, and endoplasmic reticulum stress. In addition, CHOP deficiency protected ApoE −/− mice from CKD ‐dependent vascular calcification, cardiac dysfunction, and vascular cell death. Conclusions These data reveal that the cholesterol‐lowering therapy of simvastatin plus ezetimibe attenuates CKD ‐dependent vascular diseases through a reduction of oxysterol‐mediated endoplasmic reticulum stress. CHOP plays a crucial role in the pathogenesis of CKD ‐dependent vascular calcification.

Escherichia coli Ol57:H7 infection ranges from mild diarrheal illness to severe hemorrhagic colitis but may rarely be complicated by pseudomembranous colitis and/or necrosis. Herein, we report a sporadic case of ischemic E. coli Ol57:H7 pseudomembranous colitis in an adult that occurred during a national outbreak of E. coli Ol57:H7 in the United States.

Background/Aims: Clinical guidelines recommend a diet low in sodium and high in potassium to reduce blood pressure and cardiovascular events. Little is known about the relationship between dietary sodium and potassium intake and chronic kidney disease (CKD). Methods: 13,917 participants from the National Health and Nutrition Examination Survey (2001-2006) were examined. Sodium and potassium intake were calculated from 24-hour recall and evaluated in quartiles. CKD was defined as estimated glomerular filtration rate (eGFR) 2 or eGFR ≥60 ml/min/1.73 m2 with albuminuria (>30 mg/g creatinine). Results: The mean (SE) age and eGFR of participants were 45.0 ± 0.4 years and 88.0 ± 0.60 ml/min/1.73 m2, respectively. 2,333 (14.2%) had CKD: 1,146 (7.3%) had an eGFR 2 and 1,514 (8.4%) had an eGFR ≥60 ml/min/1.73 m2 and albuminuria. After adjustment for age, sex, race, BMI, diabetes, hypertension, cardiovascular disease and congestive heart failure, subjects in the highest quartile of sodium intake had lower odds of CKD compared to subjects in the lowest quartile (adjusted OR: 0.79; 95% CI: 0.66-0.96; p < 0.016). Compared to the highest quartile, the odds of CKD increased 44% for participants in the lowest quartile of potassium intake (adjusted OR: 1.44; 95% CI: 1.16-1.79; p = 0.0011). Conclusions: Higher intake of sodium and potassium is associated with lower odds of CKD among US adults. These results should be corroborated through longitudinal studies and clinical trials designed specifically to examine the effects of dietary sodium and potassium intake on kidney disease and its progression.

Background: Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19 subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index (BMI). Methods: This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with BMI, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides. Cox proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality. Results: Participants had a mean age of 60 ± 11 years and a median (IQR) FGF23 concentration of 4,212 (1,411-13,816) RU/ml. An increase per SD in log10 FGF23 was associated with lower BMI (β = -1.11; p = 0.008), TC (β = -6.46; p = 0.02), LDL-C (β = -4.73; p = 0.04) and HDL-C (β = -2.14; p = 0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid-lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile). Conclusion: These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.

Background: Patients with chronic kidney disease (CKD) not requiring dialysis have a high prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency but the relationship between 25(OH)D levels and metabolic syndrome is unknown in this population. Methods: This study analyzed stored plasma samples from 495 non-diabetic subjects with severe kidney disease, not yet on dialysis, who participated in the homocysteine in kidney and end stage renal disease study. Metabolic syndrome was defined as the presence of all three of the following: (1) Serum triglycerides ≥ 150 mg/dl or drug treatment for hypertriglyceridemia; (2) serum high density lipoprotein-cholesterol (HDL-C) 30 ng/ml after adjustment for multiple confounders (OR 2.25, 95% CI 1.25 – 4.07). Plasma 25(OH)D levels were inversely associated with diastolic blood pressure (R = –0.10, p = 0.029) and serum triglyceride levels (R = –0.14, p = 0.002). Conclusion: 25(OH)D deficiency is strongly associated with an increased risk of metabolic syndrome in non-diabetic patients with severe CKD not yet on dialysis, independent of cardiometabolic risk factors and other important regulators of mineral metabolism.

Background Low vitamin D concentrations are prevalent in patients with chronic kidney disease (CKD). We investigated the relationship between plasma 25-hydroxyvitamin D (25[OH]D) or 1,25-dihydroxyvitamin D (1,25[OH] 2 D) concentrations with death, cardiovascular events, and dialysis therapy initiation in patients with advanced CKD. Study Design The HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD (stages 4 and 5 not yet on dialysis therapy). 25(OH)D and 1,25(OH) 2 D were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs ( 30 ng/mL) and tertiles ( 22 pg/mL), respectively. Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes. Setting & Participants 1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers. Predictors 25(OH)D and 1,25(OH) 2 D concentrations. Outcomes Death, cardiovascular events, and time to initiation of long-term dialysis therapy. Results After a median follow-up of 2.9 years, 41% (n = 453) died, whereas 56% (n = 615) initiated dialysis therapy. Mean 25(OH)D and 1,25(OH) 2 D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH) 2 D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of long-term dialysis therapy (HR, 1.78; 95% CI, 1.40-2.26) compared with the highest tertile. The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 (FGF-23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared with highest tertile). There was no association between 25(OH)D concentrations and outcomes. Limitations Participants were mostly men. Conclusions Low plasma 1,25(OH) 2 D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD. FGF-23 level may attentuate this relationship.

Aims: To examine the effect of combined calcium and vitamin D3 supplementation on bone mineral density (BMD) in patients with chronic kidney disease (CKD). Methods: We performed a post-hoc analysis of the DECALYOS II, a 2-year randomized, double-blind, placebo-controlled study of 610 women randomized to: calcium-vitamin D3 fixed combination, calcium plus vitamin D3 separate combination, or placebo. Both active treatment groups received the same daily amount of calcium (1,200 mg) and vitamin D3 (800 IU). BMD of the distal radius was measured by single X-ray absorptiometry at baseline, 12 and 24 months. Results: At baseline 47.2%, 36.4% and 16.4% of the study population had an eGFR ≥ 60, 45 – 59, and < 45 ml/min/1.73 m2, respectively. Both active regimens vs. placebo markedly increased serum 25-hydroxyvitamin D levels from baseline in all eGFR groups (p < 0.0001). Analysis of variance demonstrated an overall treatment effect on distal radius BMD (p = 0.005), with the active treatment groups showing a lower rate of BMD loss when compared to the placebo group. The effects of the intervention on BMD did not differ significantly according to baseline eGFR (interaction p > 0.22 for all time points). Conclusion: Combined calcium and vitamin D3 supplementation was effective in reducing rate of BMD loss in women with moderate CKD.

Summary Background and objectives This study examined differences in the concentration of markers of mineral metabolism across race in patients with advanced CKD not requiring dialysis and ESRD. Design, setting, participants, & measurements Concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25dihydroxyvitamin D (1,25(OH)2D), intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF-23) were measured in stored plasmasamples of 1497 patients with advanced CKD not yet on dialysis and ESRD who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Linear regression models were used to examine the relationship between race and 25(OH)D, 1,25(OH)2D, iPTH, and FGF-23 concentrations. ResultsNon-Hispanic white patients comprised 58% of the cohort, whereas non-Hispanic blacks comprised 42%. Median (interquartile range) FGF-23 concentrations were lower in blacks compared with whites with CKD (323 [181–655] versus 431 [232–1026] RU/ml; P,0.001) but not in ESRD. In adjusted linear regression models, blacks with CKD not requiring dialysis had significantly lower plasma FGF-23 concentrations (difference, 2159; 95% confidence interval, 2205 to 2106; P,0.001) compared with whites, independent of plasma 25(OH)D, 1,25(OH)2D, and iPTH concentrations. This difference was not observed in the ESRD group. The magnitude of correlation for the relationships between 1,25(OH)2D with iPTH, FGF-23 with 1,25(OH)2D, and FGF-23 with iPTH were stronger among blacks than whites with CKD not requiring dialysis. Conclusions In advanced CKD not requiring dialysis, blacks have lower FGF-23 concentrations than whites. Blacks with CKD and ESRD have lower 25(OH)D and higher iPTH compared with whites, independent of FGF-23 concentrations. Clin J Am Soc Nephrol 7: 640–647, 2012. doi: 10.2215/CJN.07020711

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.

Cardiovascular diseases (CVD) and infectious diseases represent the two most important causes of death in patients with chronic kidney disease (CKD). The traditional risk factors of CVD do not appear to account sufficiently for the increased risk of CVD in patients with CKD, and vitamin D deficiency appears to be an important non-traditional, and potentially modifiable, CVD risk factor in this patient population. 25-Hydroxyvitamin D (25(OH)D) is converted to its biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), by the enzyme 1 α-hydroxylase in the kidneys. The recent discovery that many extrarenal tissues also possess both the 1 α-hydroxylase enzyme and the vitamin D receptors has provided new insights into the important physiologic autocrine and paracrine roles of vitamin D in various tissues and organs that are mainly dependent on the availability of 25(OH)D from the circulating plasma. Accordingly, the present review focuses on the rapidly expanding body of clinical and experimental evidence that supports a strong association between 25(OH)D deficiency/insufficiency and the risk of adverse CVD outcomes and infectious diseases as well as on the non-calcemic autocrine and paracrine actions of vitamin D both in the general population and in patients with CKD.