KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Foreword

The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD) represents a selective update of the prior guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with CKD, those on chronic dialysis therapy, or individuals with a kidney transplant. Specifically, the topic areas for which updated recommendations are issued include diagnosis of bone abnormalities in CKD-MBD; treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD; treatment of bone abnormalities by antiresorptives and other osteoporosis therapies; and evaluation and treatment of kidney transplant bone disease. Development of this guideline update followed an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant trials, and appraisal of the quality of the evidence and the strength of recommendations followed the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Limitations of the evidence are discussed, with areas of future research also presented

Statins for hemodialysis patients with diabetes? Long-term follow-up endorses the original conclusions of the 4D Study

The clinical benefits of statins in dialysis patients are unproven. New follow-up data from the 4D Study indicate no clear reduction in cardiovascular events among patients with type-2 diabetes. Assessing outcomes 7.4 years beyond the randomization period (20 mg atorvastatin versus placebo), no differences in a composite cardiovascular outcome were observed and no safety concerns emerged. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not need updating based on these new data

Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines

Objective - Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation.Methods and Results - IL-1 beta enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1 beta, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1 beta enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1 beta also caused overexpression of the sterol regulatory element binding protein ( SREBP) cleavage-activating protein ( SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression.Conclusions - These observations demonstrate that IL-1 beta disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein

Effects of the sodium–glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease

BACKGROUND: The sodium–glucose co-transporter 2 inhibitor dapagliflozin decreases haemoglobin A1c (HbA1c), body weight, blood pressure (BP) and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes. The efficacy and safety of this drug have not been properly defined in patients with type 2 diabetes and Stages 3b–4 chronic kidney disease (CKD). METHODS: In a pooled analysis of 11 phase 3 randomized controlled clinical trials, we determined least square mean changes in HbA1c, body weight, BP, estimated glomerular filtration rate (eGFR) and UACR over 102 weeks in patients with type 2 diabetes and an eGFR between 12 to less than 45 mL/min/1.73 m2 receiving placebo (n = 69) or dapagliflozin 5 or 10 mg (n = 151). Effects on UACR were determined in a subgroup of patients with baseline UACR ≥30 mg/g (n = 136). RESULTS: Placebo-corrected changes in HbA1c with dapagliflozin 5 and 10 mg were 0.03% [95% confidence interval (CI) −0.3–0.3] and 0.03% (95% CI −0.2–0.3) during the overall 102-week period. Dapagliflozin 5 and 10 mg compared with placebo reduced UACR by − 47.1% (95% CI −64.8 to − 20.6) and −38.4% (95% CI −57.6 to − 10.3), respectively. Additionally, dapagliflozin 5 and 10 mg compared with placebo reduced BP and body weight. eGFR increased with placebo during the first 4 weeks but did not change with dapagliflozin. There were no between-group differences in eGFR at the end of follow-up. Adverse events associated with renal function occurred more frequently in the dapagliflozin 10-mg group. These events were mainly asymptomatic increases in serum creatinine. CONCLUSIONS: Dapagliflozin did not decrease HbA1c in patients with type 2 diabetes and Stages 3b–4 CKD, but decreased UACR, BP and body weight to a clinically meaningful extent. These results support a large outcome trial in this population to confirm long-term safety and efficacy in reducing adverse clinical endpoints

Spectropolarimetry of Supernovae

Overwhelming evidence has accumulated in recent years that supernova explosions are intrinsically 3-dimensional phenomena with significant departures from spherical symmetry. We review the evidence derived from spectropolarimetry that has established several key results: virtually all supernovae are significantly aspherical near maximum light; core-collapse supernovae behave differently than thermonuclear (Type Ia) supernovae; the asphericity of core-collapse supernovae is stronger in the inner layers showing that the explosion process itself is strongly aspherical; core-collapse supernovae tend to establish a preferred direction of asymmetry; the asphericity is stronger in the outer layers of thermonuclear supernovae providing constraints on the burning process. We emphasize the utility of the Q/U plane as a diagnostic tool and revisit SN 1987A and SN 1993J in a contemporary context. An axially-symmetric geometry can explain many basic features of core-collapse supernovae, but significant departures from axial symmetry are needed to explain most events. We introduce a spectropolarimetry type to classify the range of behavior observed in polarized supernovae. Understanding asymmetries in supernovae is important for phenomena as diverse as the origins of gamma-ray bursts and the cosmological applications of Type Ia supernovae in studies of the dark energy content of the universe.Comment: Draft of Annual Review article prior to final copy editing; 85 pages, 13 figures, 1 tabl

Scan-rescan reproducibility of neurite microstructure estimates using NODDI

In this work we provide a preliminary assessment of the reproducibility of the Neurite Orientation Dispersion and Density Imaging (NODDI), a recent diffusion MRI technique for directly quantifying microstructural indices of neurites in vivo, in the human brain. It is important to assess the reproducibility of such a technique to verify the precision of the method, which has implications for translation to clinical studies. NODDI outputs indices which reflect the functional and computational complexity of various regions of the brain and thus can provide useful information, non-invasively, for understanding pathology of the brain. We compare the parameter maps derived from diffusion MRI data acquired using the NODDI protocol from a normal subject, at two separate imaging sessions. We show that the NODDI indices have reproducibility comparable to that of the DTI indices. We additionally show that the clinically feasible NODDI protocol maintains good reproducibility of parameter estimates, comparable to that of a more comprehensive protocol

Ranking diffusion-MRI models with in-vivo human brain data

Diffusion MRI microstructure imaging provides a unique non-invasive probe into the microstructure of biological tissue. Its analysis relies on mathematical models relating microscopic tissue features to the MR signal. This work aims to determine which compartment models of diffusion MRI are best at describing the signal from in-vivo brain white matter. Recent work shows that three compartment models, including restricted intra-axonal, glial compartments and hindered extra-cellular diffusion, explain best multi b-value data sets from fixed rat brain tissue. Here, we perform a similar experiment using in-vivo human data. We compare one, two and three compartment models, ranking them with standard model selection criteria. Results show that, as with fixed tissue, three compartment models explain the data best, although simpler models emerge for the in-vivo data. We also find that splitting the scanning into shorter sessions has little effect on the models fitting and that the results are reproducible. The full ranking assists the choice of model and imaging protocol for future microstructure imaging applications in the brain

Chlorthalidone in Advanced Chronic Kidney Disease - Have We Missed a Trick?

Control of hypertension is central to the management of chronic kidney disease, both to preserve residual kidney function and to reduce the associated high risk of cardiovascular events. International guidelines recently updated by the Kidney Disease: Improving Global Outcomes Organization recommend that patients with chronic kidney disease and hypertension be treated to reduce standardized office systolic blood pressure to less than 120 mm Hg, unless there are obvious reasons not to do so. This ambitious target is difficult to achieve with currently available antihypertensive medications, particularly in patients with more advanced chronic kidney disease (stages 4 and 5

Lessons learned from EVOLVE for the planning of future global randomized trials in chronic kidney disease

The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism (sHPT) was evaluated in the EVOLVE trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis and reporting of the trial many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting HPT), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower than predicted event rate during the trial, development of a pre-specified analytic plan that accounted for non-adherence and for co-interventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated prior to trial initiation, and interpretation of the benefits to harms ratio for individual patients. It is likely that many of these issues will arise in planning of future trials in chronic kidney disease