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BACKGROUND: Glomerular filtration rate and albuminuria are risk factors for cardiovascular disease and markers of renal function. OBJECTIVE: To examine the contribution of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio beyond that of traditional cardiovascular risk factors to classification of patient risk for cardiovascular and renal outcomes. DESIGN: Prospective cohort study that pooled all patients of ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in Angiotensin-Converting-Enzyme-Inhibitor Intolerant Subjects with Cardiovascular Disease). PATIENTS: 27,620 patients older than 55 years with documented cardiovascular disease, who were followed for a mean of 4.6 years. MEASUREMENTS: Baseline eGFR, urinary albumin-creatinine ratio, and cardiovascular risk factors. Outcomes were all-cause mortality; a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure; long-term dialysis; and a composite of long-term dialysis and doubling of serum creatinine level. RESULTS: Lower eGFRs and higher urinary albumin-creatinine ratios were associated with the primary cardiovascular composite outcome (for example, an adjusted hazard ratio of 2.53 [95% CI, 1.61 to 3.99] for an eGFR <30 mL/min per 1.73 m(2) and a very high urinary albumin-creatinine ratio). However, adding information about eGFR and urinary albumin-creatinine ratio to the risk reclassification analyses led to no meaningful decrease in the proportion of patients assigned to the intermediate-risk category (31% without vs. 32% with renal information). In contrast, eGFR and urinary albumin-creatinine ratio were strongly associated with risk for long-term dialysis and greatly improved both model calibration and risk stratification capacity when added to traditional cardiovascular risk factors (65% assigned to intermediate-risk categories without renal information vs. 18% with renal information). LIMITATION: Creatinine levels were not standardized. CONCLUSION: In patients with high vascular risk, eGFR and urinary albumin-creatinine ratio add little to traditional cardiovascular risk factors for stratifying cardiovascular risk but greatly improve risk stratification for renal outcomes. PRIMARY FUNDING SOURCE: Boehringer Ingelheim, Population Health Research Institute, and the European Commission. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with decreased kidney function and acute ST-elevation myocardial infarction (STEMI) and non-STEMI are less likely to receive reperfusion therapy and aggressive medical treatment. This undertreatment may contribute to the poor outcome of these patients. The prognostic value of kidney function in patients with STEMI and NSTEMI treated predominantly with percutaneous coronary intervention (PCI) and aggressive medical treatment is less known. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2 academic centers in Germany; 4,701 consecutive patients with acute myocardial infarction (AMI) from 1998 to 2006. PREDICTOR: Estimated creatinine clearance (eCCr) at admission. OUTCOMES & MEASUREMENTS: The primary end point was all-cause mortality during the first year after PCI for AMI (STEMI and NSTEMI) with a prespecified landmark at 30 days (landmark analysis). Secondary end points were nonfatal myocardial infarction, stroke, and major bleeding. RESULTS: Patients were divided into quartiles according to eCCr less than 56, 56 to 76, 77 to 100, and greater than 100 mL/min. Patients had an increased risk of death with decreased eCCr both within 30 days (7.7%, 3.1%, 1.4%, and 0.7% for the 4 quartiles; P < 0.001) and after 30 days (12.1%, 4.8%, 1.9%, and 1.2%; P < 0.001). The association of eCCr with mortality was similar in patients younger and older than 70 years. Major bleeding within 30 days and incidence of stroke also were more frequent with reduced eCCr. However, recurrent myocardial infarction was not associated with eCCr. After adjustment for additional baseline characteristics, kidney function based on eCCr at admission remained a strong independent predictor of mortality at 1 year after AMI (hazard ratio, 1.21 per 10-mL/min decrease; 95% confidence interval, 1.13 to 1.30). LIMITATIONS: Single assessment of eCCr. CONCLUSIONS: In patients with AMI treated with primary PCI for STEMI and early PCI for NSTEMI, eCCr at admission remains a powerful independent predictor of short- and long-term mortality. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-receptor blockers (ARBs) blunt progression of advanced diabetic nephropathy, but their long-term renal effects in other patients are not clear.Objective: To examine the long-term renal effects of telmisartan versus placebo in adults at high vascular risk.Design: Randomized trial. Patients were randomly assigned by a central automated system between November 2001 and May 2004 and were followed until March 2008. Participants and investigators were blinded to intervention status.Setting: Multicenter, multinational study.Patients: 5927 adults with known cardiovascular disease or diabetes with end-organ damage but without macroalbuminuria or heart failure who cannot tolerate angiotensin-converting enzyme inhibitors.Intervention: Telmisartan, 80 mg/d (n = 2954), or matching placebo (n = 2972) plus standard treatment for a mean of 56 months.Measurements: Composite renal outcome of dialysis or doubling of serum creatinine, changes in estimated glomerular filtration rate (GFR), and changes in albuminuria.Results: No important difference was found in the composite renal outcome with telmisartan (58 patients [1.96%]) versus placebo (46 patients [1.55%]) (hazard ratio, 1.29 [95% CI, 0.87 to 1.89]; P = 0.20). Among the telmisartan and placebo groups, 7 and 10 patients had dialysis and 56 and 36 patients had doubling of serum creatinine, respectively (hazard ratio, 1.59 [CI, 1.04 to 2.41]; P = 0.031). Albuminuria increased less with telmisartan than with placebo (32% [CI, 23% to 41%] vs. 63% [CI, 52% to 76%]; P < 0.001). Decreases in estimated GFR were greater with telmisartan than with placebo (mean change in estimated GFR, -3.2 mL/min per 1.73 m(2) [SD, 18.3] vs. -0.26 mL/min per 1.73 m(2) [SD, 18.0]; P < 0.001).Limitation: Only 17 participants had dialysis.Conclusion: In adults with vascular disease but without macroalbuminuria, the effects of telmisartan on major renal outcomes were similar to those of placebo. [ABSTRACT FROM AUTHOR]

BACKGROUND: Effects of dialyzer membrane characteristics on morbidity and mortality are highly controversial. METHODS: Post hoc, we analyzed data from the German Diabetes and Dialysis Study that evaluated atorvastatin in high-risk patients. Four groups were identified being constantly dialyzed with high-flux synthetic (n = 241), low-flux synthetic (n = 247), low-flux semisynthetic (n = 119), or cellulosic low-flux membranes (n = 41). Two end points were investigated: (1) a cardiovascular end point consisting of cardiac death, nonfatal myocardial infarction, and stroke and (2) death. RESULTS: After 4 years of follow-up, adjusted multivariate relative risks (RRs) were calculated. The RR to reach a cardiovascular end point was greater for patients dialyzed with cellulosic low-flux (RR, 2.33; 95% confidence interval [CI], 1.38 to 3.94; P = 0.002), low-flux semisynthetic (RR, 1.92; 95% CI, 1.35 to 2.73; P = 0.0003), or low-flux synthetic membranes (RR, 1.35; 95% CI, 0.99 to 1.85; P = 0.06) than for those treated with high-flux synthetic dialyzers. The likelihood to die was greater with cellulosic low-flux (RR, 4.14; 95% CI, 2.79 to 6.15; P < 0.0001), low-flux semisynthetic (RR, 2.24; 95% CI, 1.66 to 3.02; P < 0.0001), and low-flux synthetic membranes (RR, 1.59; 95% CI, 1.22 to 2.07; P = 0.0006) than with high-flux synthetic membranes. With respect to low-flux synthetic membranes, RRs of mortality for patients using cellulosic low-flux and low-flux semisynthetic membranes were 161% (RR, 2.61; 95% CI, 1.80 to 3.79; P < 0.0001) and 41% (RR, 1.41; 95% CI, 1.07 to 1.86; P = 0.016) greater. Cellulosic low-flux membrane use was associated with an 85% (RR, 1.85; 95% CI, 1.24 to 2.76; P = 0.0025) greater RR of death than low-flux semisynthetic membranes. CONCLUSION: These data suggest that biocompatibility and permeability may impact on death and cardiovascular events in hemodialysis patients with type 2 diabetes mellitus. Copyright © 2007 by the National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients., Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS., Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69-92.03; P < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS., Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients., (Copyright © 2020 Braunisch, Mayer, Bauer, Lorenz, Haller, Rizas, Hagmair, von Stülpnagel, Hamm, Günthner, Angermann, Matschkal, Kemmner, Hasenau, Zöllinger, Steubl, Mann, Lehnert, Scherf, Braun, Moog, Küchle, Renders, Malik, Schmidt, Wassertheurer, Heemann and Schmaderer.)

Background: Identifying markers of chronic kidney disease (CKD) that occur early in the disease process and are specific to loss of kidney function rather than other underlying causes of disease may allow earlier, more accurate identification of patients who will develop CKD. We therefore sought to identify diagnostic blood markers of early CKD that are caused by loss of kidney function by using an innovative "reverse Mendelian randomization" (MR) approach., Methods: We applied this technique to genetic and biomarker data from 4147 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, all with known type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance. Two-sample MR was conducted using variants associated with creatinine-based eGFR (eGFR crea ) from the CKDGen Consortium (n = 133814) to estimate the effect of genetically decreased eGFR crea on 238 serum biomarkers., Results: With reverse MR, trefoil factor 3 (TFF3) was identified as a protein that is increased owing to decreased eGFR crea (β = 1.86 SD per SD decrease eGFR crea ; 95% CI, 0.95-2.76; P = 8.0 × 10 -5 ). Reverse MR findings were consistent with epidemiological associations for incident CKD in ORIGIN (OR = 1.28 per SD increase in TFF3; 95% CI, 1.18-1.38; P = 4.58 × 10 -10 ). Addition of TFF3 significantly improved discrimination for incident CKD relative to eGFR crea alone (net reclassification improvement = 0.211; P = 9.56 × 10 -12 ) and in models including additional risk factors., Conclusions: Our results suggest TFF3 is a valuable diagnostic marker for early CKD in dysglycemic populations and acts as a proof of concept for the application of this novel MR technique to identify diagnostic biomarkers for other chronic diseases., Clinicaltrialsgov Identifier: NCT00069784., (© 2018 American Association for Clinical Chemistry.)

Background: Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV)., Method: This study cohort contains patients from the "Risk stratification in end-stage renal disease - the ISAR study," a multicenter prospective longitudinal observatory cohort study. We examined and compared the predictive value of ambulatory 24-hour PWV (24 h-PWV) and Office-PWV on mortality in a total of 344 hemodialysis patients. The endpoints of the study were all-cause and cardiovascular mortality. Survival analysis included Kaplan-Meier estimates and Cox regression analysis., Results: During a follow-up of 36 months, a total of 89 patients died, 35 patients due to cardiovascular cause. Kaplan-Meier estimates for tertiles of 24 h-PWV and Office-PWV were similarly associated with mortality. In univariate Cox regression analysis, 24 h-PWV and Office-PWV were equivalent predictors for all-cause and cardiovascular mortality. After adjustment for common risk factors, only 24 h-PWV remained solely predictive for all-cause mortality (hazard ratio 2.51 [95% CI 1.31-4.81]; p = 0.004)., Conclusions: Comparing both measurements, 24 h-PWV is an independent predictor for all-cause-mortality in hemodialysis patients beyond Office-PWV., (© 2019 S. Karger AG, Basel.)

The generation of effective levels of antigen-specific immunity at the mucosal sites of pathogen entry is a key goal for vaccinologists. We explored topical vaginal application as an approach to initiate local antigen-specific immunity, enhance previously existing systemic immunity or re-target responses to the mucosae. To deliver a protein vaccine formulation to the vaginal mucosal surface, we used a novel vaginal ring device comprising a silicone elastomer body into which three freeze-dried, rod-shaped, hydroxypropylmethylcellulose inserts were incorporated. Each rod contained recombinant HIV-1 CN54gp140 protein (167μg)±R848 (167μg) adjuvant. The inserts were loaded into cavities within each ring such that only the ends of the inserts were initially exposed. Sheep received a prime-boost vaccination regime comprising intramuscular injection of 100μg CN54gp140+200μg R848 followed by three successive ring applications of one week duration and separated by one month intervals. Other sheep received only the ring devices without intramuscular priming. Serum and vaginal mucosal fluids were sampled every two weeks and analysed by CN54gp140 ELISA and antigen-specific B cells were measured by flow cytometry at necropsy. Vaccine antigen-specific serum antibody responses were detected in both the intramuscularly-primed and vaginal mucosally-primed groups. Those animals that received only vaginal vaccinations had identical IgG but superior IgA responses. Analysis revealed that all animals exhibited mucosal antigen-specific IgG and IgA with the IgA responses 30-fold greater than systemic levels. Importantly, very high numbers of antigen-specific B cells were detected in local genital draining lymph nodes. We have elicited local genital antigen-specific immune responses after topical application of an adjuvanted antigen formulation within a novel vaginal ring vaccine release device. This regimen and delivery method elicited high levels of antigen-specific mucosal IgA and large numbers of local antigen-reactive B cells, both likely essential for effective mucosal protection., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus. This genetically modified virus (gmHIV-1 NL4-3 ) was inactivated and formulated as a killed whole-HIV vaccine, and then used for a Phase I human clinical trial (Trial Registration: Clinical Trials NCT01546818). The gmHIV-1 NL4-3 was propagated in the A3.01 human T cell line followed by virus purification and inactivation with aldrithiol-2 and γ-irradiation. Thirty-three HIV-1 positive volunteers receiving cART were recruited for this observer-blinded, placebo-controlled Phase I human clinical trial to assess the safety and immunogenicity., Results: Genetically modified and killed whole-HIV-1 vaccine, SAV001, was well tolerated with no serious adverse events. HIV-1 NL4-3 -specific PCR showed neither evidence of vaccine virus replication in the vaccine virus-infected human T lymphocytes in vitro nor in the participating volunteers receiving SAV001 vaccine. Furthermore, SAV001 with adjuvant significantly increased the pre-existing antibody response to HIV-1 proteins. Antibodies in the plasma of vaccinees were also found to recognize HIV-1 envelope protein on the surface of infected cells as well as showing an enhancement of broadly neutralizing antibodies inhibiting tier I and II of HIV-1 B, D, and A subtypes., Conclusion: The killed whole-HIV vaccine, SAV001, is safe and triggers anti-HIV immune responses. It remains to be determined through an appropriate trial whether this immune response prevents HIV infection.

Background: Chronic kidney disease (CKD) is prevalent and associated with significant morbidity and mortality. Dietary modification may be an approach to reducing CKD., Design: In this prospective cohort study, we evaluated the association between diet quality, sodium and potassium intakes, and major renal outcomes. A total of 544,635 community-dwelling adults, aged 51 to 70 years, living in 6 states and 2 urban areas in the United States, from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Using a food frequency questionnaire completed at baseline, we assessed diet quality using the Alternate Healthy Eating Index (AHEI), Healthy Eating Index (HEI), Mediterranean Diet Score (MDS), Recommended Food Score, and Dietary Approaches to Stop Hypertension (DASH) scores. This was also used to estimate daily sodium and potassium intakes., Main Outcome Measures: Multivariable adjusted competing risks regression calculated sub-hazard ratios (sHRs) for a composite of death due to a renal cause and dialysis, with death due to a nonrenal cause as the competing event., Results: During a mean of 14.3-year follow-up, a total of 4,848 participants died from a renal cause or initiated dialysis. Four diet quality scores (AHEI, HEI, MDS, and DASH) were significantly associated with the composite renal outcome; the Recommended Food Score was not. Compared to the lowest score quintile, the highest quintiles of AHEI (sHR 0.71; 95% confidence interval [CI] 0.65-0.79), HEI (sHR 0.82; 95% CI 0.74-0.91), MDS (sHR 0.84; 95% CI 0.74-0.95), and DASH (sHR 0.85; 95% CI 0.77-0.94) were associated with a reduced hazard of the composite. The highest sodium quintile (sHR 1.17; 95% CI 1.02-1.33 for sodium intake > 3.6 g/day) was associated with an increased hazard, whereas the highest potassium quintile (sHR 0.83 [0.73-0.95]) with a reduced hazard., Conclusions: Our findings support an association between healthy dietary patterns and reduced risk of major renal outcomes and provide observational evidence to inform dietary guideline recommendations for CKD prevention., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status., Methods: In this pooled analysis, we studied 133,118 individuals (63,559 with hypertension and 69,559 without hypertension), median age of 55 years (IQR 45-63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4.2 years (IQR 3.0-5.0) and blood pressure., Findings: Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2.08 mm Hg change per g sodium increase) compared with individuals without hypertension (1.22 mm Hg change per g; pinteraction<0.0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1.23 [95% CI 1.11-1.37]; p<0.0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1.34 [1.23-1.47]; p<0.0001) were both associated with increased risk compared with sodium excretion of 4-5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4-5 g/day (18,508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥ 7 g/day in 6271 [9%] of the population without hypertension; HR 0.90 [95% CI 0.76-1.08]; p=0.2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1.26 [95% CI 1.10-1.45]; p=0.0009)., Interpretation: Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets., Funding: Full funding sources listed at end of paper (see Acknowledgments)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown., Methods: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes., Results: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group., Conclusions: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Background: We quantified the impact of lifestyle and dietary modifications on chronic kidney disease (CKD) by estimating population-attributable fractions (PAFs)., Study Design: Observational cohort study., Setting & Participants: Middle-aged adults with type 2 diabetes but without severe albuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET; n=6,916)., Factors: Modifiable lifestyle/dietary risk factors, such as physical activity, size of social network, alcohol intake, tobacco use, diet, and intake of various food items., Outcomes: The primary outcome was CKD, ascertained as moderate to severe albuminuria or ≥5% annual decline in estimated glomerular filtration rate (eGFR) after 5.5 years. The competing risk for death was considered. PAF was defined as the proportional reduction in CKD or mortality (within 5.5 years) that would occur if exposure to a risk factor was changed to an optimal level., Results: At baseline, median urinary albumin-creatinine ratio and eGFR were 6.6 (IQR, 2.9-25.0) mg/mmol and 71.5 (IQR, 58.1-85.9) mL/min/1.73m(2), respectively. After 5.5 years, 704 (32.5%) participants developed albuminuria, 1,194 (55.2%) had a ≥5% annual eGFR decline, 267 (12.3%) had both, and 1,022 (14.8%) had died. Being physically active every day has PAFs of 5.1% (95% CI, 0.5%-9.6%) for CKD and 12.3% (95% CI, 4.9%-19.1%) for death. Among food items, increasing vegetable intake would have the largest impact on population health. Considering diet, weight, physical activity, tobacco use, and size of social network, exposure to less than optimum levels gives PAFs of 13.3% (95% CI, 5.5%-20.9%) for CKD and 37.5% (95% CI, 27.8%-46.7%) for death. For the 17.8 million middle-aged Americans with diabetes, improving 1 of these lifestyle behaviors to the optimal range could reduce the incidence or progression of CKD after 5.5 years by 274,000 and the number of deaths within 5.5 years by 405,000., Limitations: Ascertainment of changes in kidney measures does not precisely match the definitions for incidence or progression of CKD., Conclusions: Healthy lifestyle and diet are associated with less CKD and mortality and may have a substantial impact on population kidney health., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The delivery of vaccines to the sublingual mucosa is an attractive prospect due to the ease and acceptability of such an approach. However, novel adjuvant and delivery approaches are required to optimally vaccinate at this site. We have previously shown that conjugation of protein antigen to the iron transport molecule, transferrin, can significantly enhance mucosal immune responses. We tested whether conjugating influenza haemagglutinin to transferrin could improve the immune response to sublingually delivered antigen. Transferrin conjugated haemagglutinin induced a significant antibody and T cell response in both naïve animals and previously immunized animals. The immune response generated was able to protect mice against influenza virus challenge. Sublingually administered antigen dispersed more widely through the gastro-intestinal tract than intranasally delivered antigen and transferrin conjugation had a more marked effect on sublingually delivered antigen than intranasal immunisation. From these studies we conclude that transferrin conjugation of antigen is effective at boosting immune responses to sublingually delivered antigen and may be an attractive approach for influenza vaccines, particularly when mass campaigns are required., (Copyright © 2016. Published by Elsevier B.V.)

The 4D (Die Deutsche Diabetes Dialyse) Study was a randomized, double-blind trial comparing 4 years of treatment with atorvastatin to placebo in 1255 hemodialysis patients with type 2 diabetes. The primary end point of cardiovascular events (cardiac death, myocardial infarction, and stroke) was non-significantly reduced by 8%. However, long-term effects remained uncertain. Therefore, surviving patients were invited to a follow-up survey done by questionnaire. Post-trial statin therapy was at nephrologist discretion, and outcomes were centrally adjudicated and analyzed by intention to treat and time to first event in the original treatment groups. Median overall follow-up was 11.5 years. Post-trial statin use and low-density lipoprotein cholesterol levels did not differ between groups. Statin treatment non-significantly affected the former primary outcome (relative risk, 0.91; 95% confidence interval, 0.78-1.07). The risk of all cardiac events combined and the risk of cardiac death were significantly lower in the original statin group compared to placebo (0.83, 0.70-0.97, and 0.80, 0.66-0.97). No significant effect was detected on cerebrovascular events, fatal stroke, fatal cancer, non-vascular, or all-cause death. No rhabdomyolysis was reported. Thus, after 4 years of atorvastatin treatment in diabetic hemodialysis patients, similar effects on outcomes were found after 11.5 years of follow-up as were found at the end of the original study. There was no evidence of emerging hazards in the long term, confirming current clinical practice guidelines., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: As glucagon-like peptide-1 receptor agonists lower blood pressure (BP) in type 2 diabetes mellitus (T2DM), we examined BP control in relation to targets set by international bodies prior to randomization in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial., Methods: We analyzed baseline data from LEADER (NCT01179048), an ongoing phase 3B, randomized, double-blind, placebo-controlled cardiovascular outcomes trial examining the cardiovascular safety of the glucagon-like peptide-1 receptor agonist liraglutide in 9340 people with T2DM from 32 countries [age (all mean ± SD) 64 ± 7.2 years, BMI 32.5 ± 6.3 kg/m, duration of diabetes 12.7 ± 8.0 years], all of whom were at high risk for cardiovascular disease (CVD)., Results: A total of 81% (n = 7592) of participants had prior CVD and 90% (n = 8408) had a prior history of hypertension. Despite prescription of multiple antihypertensive agents at baseline, only 51% were treated to a target BP of less than 140/85 mmHg and only 26% to the recommended baseline BP target of less than 130/80 mmHg. In univariate analyses, those with prior CVD were prescribed more agents (P < 0.001) and had lower BP than those without (137 ± 18.8/78 ± 10.6 mmHg versus 140 ± 17.7/80 ± 9.9 mmHg; P < 0.001). In logistic regression analyses, residency in North America (64% treated to <140/85 mmHg; 38% treated to <130/80 mmHg) was the strongest predictor of BP control., Conclusion: These contemporary data confirm that BP remains insufficiently controlled in a large proportion of individuals with T2DM at high cardiovascular risk, particularly outside North America. Longitudinal data from the LEADER trial may provide further insights into BP control in relation to cardiovascular outcomes in this condition.

Background: CRAd-S-pk7 is a conditionally replicative oncolytic adenoviral vector that contains a survivin promoter and a pk7 fiber modification that confer tumor-specific transcriptional targeting and preferential replication in glioma while sparing the surrounding normal brain parenchyma., Methods: This IND-enabling study performed under GLP conditions evaluated the toxicity and biodistribution of CRAd-S-pk7 administered as a single intracerebral dose to Syrian hamsters, a permissive model of adenoviral replication. Two hundred and forty animals were stereotactically administered either vehicle (n = 60) or CRAd-S-pk7 at 2.5 × 10(7), 2.5 × 10(8), or 2.5 × 10(9) viral particles (vp)/animal (each n = 60) on day 1. The animals were closely monitored for toxicology evaluation, assessment of viral distribution, and immunogenicity of CRAd-S-pk7., Results: Changes in hematology, clinical chemistry, and coagulation parameters were minor and transient, and consistent with the inflammatory changes observed microscopically. These changes were considered to be of little toxicological significance. The vector remained localized primarily in the brain and to some degree in the tissues at the incision site. Low levels of vector DNA were detected in other tissues in a few animals suggesting systemic circulation of the virus. Viral DNA was detected in brains of hamsters for up to 62 days. However, microscopic changes and virus-related toxicity to the central nervous system were considered minor and decreased in incidence and severity over time. Such changes are not uncommon in studies using adenoviral vectors., Conclusion: This study provides safety and toxicology data justifying a clinical trial of CRAd-S-pk7 loaded in FDA-approved HB1.F3.CD neural stem cell carriers administered at the tumor resection bed in humans with recurrent malignant glioma.

The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models.

Background: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain., Methods: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models., Results: The run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis., Conclusions: The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.).

Background: An effective HIV vaccine will likely require induction of both mucosal and systemic cellular and humoral immune responses. We investigated whether intramuscular (IM) delivery of electroporated plasmid DNA vaccine and simultaneous protein vaccinations by intranasal (IN) and IM routes could be combined to induce mucosal and systemic cellular and humoral immune responses to a model HIV-1 CN54 gp140 antigen in mice., Results: Co-immunisation of DNA with intranasal protein successfully elicited both serum and vaginal IgG and IgA responses, whereas DNA and IM protein co-delivery did not induce systemic or mucosal IgA responses. Cellular IFNγ responses were preserved in co-immunisation protocols compared to protein-only vaccination groups. The addition of DNA to IN protein vaccination reduced the strong Th2 bias observed with IN protein vaccination alone. Luminex analysis also revealed that co-immunisation with DNA and IN protein induced expression of cytokines that promote B-cell function, generation of TFH cells and CCR5 ligands that can reduce HIV infectivity., Significance: These data suggest that while IN inoculation alone elicits both cellular and humoral responses, co-administration with homologous DNA vaccination can tailor these towards a more balanced Th1/Th2 phenotype modulating the cellular cytokine profile while eliciting high-levels of antigen-specific antibody. This work provides insights on how to generate differential immune responses within the same vaccination visit, and supports co-immunisation with DNA and protein by a mucosal route as a potential delivery strategy for HIV vaccines.

Aims: No intraprocedural assessment is currently available to evaluate the extent of nerve ablation by renal denervation (RDN). We prospectively evaluated the association of intraprocedural reduction of renal veno-arterial norepinephrine gradient with blood pressure (BP) response after RDN., Methods and Results: In 46 consecutive RDN patients, the periprocedural norepinephrine veno-arterial difference was defined as veno-arterial norepinephrine gradient. We observed a reduction of the office systolic BP from 176±19 mmHg to 165±24 mmHg (p=0.02) at three months and 163±22 mmHg (p=0.02) at six months. The mean and maximum systolic ABP decreased by 5 mmHg (p=0.03) and 9 mmHg (p=0.02), respectively. There was a decrease of the norepinephrine RV-RA difference from pre- to post-procedural levels (median 186 pg/ml [54;466] vs. 81 pg/ml [0;182], p=0.02). OBP responders (office systolic BP reduction ≥10 mmHg) showed a greater reduction of the norepinephrine gradient compared to non-responders (-290±450 pg/ml vs. -4±106 pg/ml, p=0.01). Patients with a reduction of norepinephrine gradient in both kidneys showed the most pronounced decrease of the systolic OBP (-24±14 mmHg) compared to patients with a reduction of norepinephrine gradient in only one kidney (-7±15 mmHg) or patients without a norepinephrine reduction (-3±19 mmHg, p=0.03 vs. bilateral reduction)., Conclusions: Measuring renal norepinephrine gradient during RDN may be a method to gauge the extent of renal nerve ablation.

Background and Objectives: Quantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained., Design, Setting, Participants, & Measurements: Baseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged ≥55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models., Results: Of the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R(2) value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R(2) value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors., Conclusions: Albuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance., (Copyright © 2015 by the American Society of Nephrology.)

Chronic kidney disease (CKD) affects 10-13% of the general population and diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). In addition to known demographic, biochemical and lifestyle risk factors, genetics is also contributing to CKD risk. In recent years, genome-wide association studies (GWAS) have provided a hypothesis-free approach to identify common genetic variants that could account for the genetic risk component of common diseases such as CKD. The identification of these variants might reveal the biological processes underlying renal impairment and could aid in improving risk estimates for CKD. This review aims to describe the methods as well as strengths and limitations of GWAS in CKD and to summarize the findings of recent GWAS in DN. Several loci and SNPs have been found to be associated with distinct CKD traits such as eGFR and albuminuria. For diabetic kidney disease, several loci were identified in different populations. Subsequent functional studies provided insights into the mechanism of action of some of these variants, such as UMOD or CERS2. However, overall, the results were ambiguous, and a few of the variants were not consistently replicated. In addition, the slow progression from albuminuria to ESRD could limit the power of longitudinal studies. The typically small effect size associated with genetic variants as well as the small portion of the variability of the phenotype explained by these variants limits the utility of genetic variants in improving risk prediction. Nevertheless, identifying these variants could give a deeper understanding of the molecular pathways underlying CKD, which in turn, could potentially lead to the development of new diagnostic and therapeutic tools., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Renal disease is prevalent in patients with diabetes mellitus type 2. Aggressive metabolic control and lowering of systemic and/or intraglomerular blood pressure are effective interventions but not without side effects. Thus a better, early identification of patients at risk for incidence or progression to end-stage renal failure by the use of new, validated biomarkers is highly desirable. In the majority of patients, hypertension and hyperglycaemia are pathogenetically important pathways for the progression of renal disease. Nonetheless even aggressive therapy targeting these factors does not eliminate the risk of end-stage renal failure and experimental evidence suggests that many other pathways (e.g. tubulointerstitial hypoxia or inflammation etc.) also contribute. As their individual importance might vary from patient to patient, interventions which interfere are likely not to be therapeutically effective in all subjects. In this situation, an option to preserve the statistical power of clinical trials is to rely on biomarkers that reflect individual pathophysiology. In current clinical practice, albuminuria is the biomarker that has been best evaluated to guide stratified/personalized therapy but there is a clear need to expand our diagnostic abilities., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Although the prevalence of chronic kidney disease (CKD) is ∼ 30% in the group of people with diabetes, data on interventions in the very early stage of the disease are still missing. Furthermore, the effects of modifiable lifestyle factors such as nutrition on incidence and progression of CKD in patients with diabetes in Europe remain elusive., Methods: We analyzed whether diet quality and adherence to dietary guidelines using the modified Alternate Healthy Eating Index (mAHEI) score was associated with CKD incidence or progression after 5.5 years in 3088 European participants of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) with type 2 diabetes and baseline normo- or micro-albuminuria. Death was considered as a competing risk in the multinomial logit regression models, which were adjusted for age, gender, duration of diabetes, ONTARGET randomization, baseline albuminuria and glomerular filtration rate (GFR). We also estimated the potential impact on population health of improvement in diet quality., Results: At study end, 450 (14.6%) participants had died and 926 (30%) had experienced the renal endpoint of incidence or progression of CKD, of which 422 (13.7%) participants had progressed to micro- or macro-albuminuria, 596 (19.3%) had a GFR-decline of >5% per year and 18 (0.6%) had developed end-stage renal disease. Participants in the healthiest tertile of the mAHEI score had a decreased risk of incidence or progression of CKD (odds ratio 0.8, 95% confidence interval 0.68-0.94) and death (0.65, 0.52-0.81) compared with participants in the least healthy tertile. If individuals with a suboptimal dietary quality (e.g. mAHEI < 28) were able to improve their diet to an mAHEI of 28, 3.2% of CKD incidence or progression and 10.0% of deaths might be avoided in 5.5 years., Conclusions: If the association between diet and these endpoints is causal, then optimizing diet quality in individuals with diabetes who have no CKD or very early CKD would have substantial population benefits in terms of prevention of CKD incidence or progression and mortality in this high-risk population., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Purpose of Review: Inhibition of the renin-angiotensin system (RASi) lowers blood pressure, reduces cardiovascular outcomes and blunts the progressive course of heart failure and of chronic kidney disease. This narrative article summarizes why the hypothesis came up that more complete RASi with two different agents should be more beneficial compared with one agent and how this hypothesis was deflated in randomized clinical trials (RCTs)., Recent Findings: The hypothesis was based on experimental findings and surrogate endpoints in patients, namely lowering of blood pressure and reduction of proteinuria. Three large RCTs in patients with atherosclerotic vascular disease or in diabetic kidney disease randomized almost 40, 000 patients. RASi with one agent was compared with RASi with two agents. All three RCTs ruled out benefits of dual RASi on major cardiovascular outcomes and reported substantial adverse effects of dual RASi. The latter included hyperkalemia, acute kidney injury, symptomatic hypotension and syncope. There was also no substantial advantage of dual over monotherapy on decline in kidney function. In one RCT, there was a hint of nonsustained, early benefit on kidney outcomes with dual therapy., Summary: Outside heart failure, RASi with two agents is not indicated to treat hypertension because of substantial safety concerns and lack of benefit on major cardiovascular and kidney outcomes.

Background: Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP)., Methods: We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end., Results: Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR ≥80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to ≥150 mmHg, with the lowest risk at a SBP of 130-140 mmHg., Conclusion: Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Background: Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study., Methods: In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0 g/day (2-6 tablets/day; n = 710) or sevelamer 2.4-14.4 g/day (3-18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study., Results: Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 ± 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 ± 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13-1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 ± 1.5) versus sevelamer (10.1 ± 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time., Conclusions: The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Aims: To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization., Methods: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤ 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥ 20 ng/l., Results: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men., Conclusions: In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations., (© 2015 The Authors. Diabetes, Obesity and Metabolism published by JohnWiley & Sons Ltd.)

Purpose: Data from an ongoing European pharmacoepidemiological study (MONITOR-CKD5) were used to examine congruence between physician-reported risk-based individualisation of target haemoglobin (Hb) and the actual Hb targets set by these physicians for their patients, as well as actual Hb levels in their patients., Methods: Physician investigators participating in the study completed a questionnaire about their anaemia practice patterns and attitudes post-TREAT at the start of the study (T1) and in summer 2013 (T2). These data were compared with the Hb targets identified at baseline for actual patients (n = 1197) enrolled in the study. Risk groups included presence/absence of hypertension, diabetes, cardiovascular complications, history of stroke, history of cancer, and age/activity level (elderly/inactive or young/active)., Results: At each time point, more than three quarters of physicians responded that results from the TREAT study, in patients not on dialysis, have influenced their use of erythropoiesis-stimulating agents in patients on haemodialysis. At T1, there was a clear difference in physician-reported (theoretical) target Hb levels for patients across the different risk groups, but there was no difference in patients' actual Hb levels across the risk groups. A similar disparity was noted at T2., Conclusions: Physicians' theoretical attitudes to anaemia management in patients on haemodialysis appear to have been influenced by the results of the TREAT study, which involved patients not on dialysis. Physicians claim to use risk-based target Hb levels to guide renal anaemia care. However, there is discrepancy between these declared risk-based target Hb levels and actual target Hb levels for patients with variable risk factors.

This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.