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Abstract Background Serum phosphate is an independent predictor of cardiovascular morbidity and mortality in patients with chronic kidney disease and the general population. There is accumulating evidence that phosphate promotes arterial stiffening through structural vascular alterations such as medial calcification, which are already apparent in the early stages of chronic kidney disease. Aim To determine the effects of phosphate binding with sevelamer carbonate on left ventricular mass and function together with arterial stiffness in patients with stage 3 chronic kidney disease. Methods/Design A single-centre, prospective, randomised, double-blind, placebo-controlled trial of 120 subjects with stage 3 chronic kidney disease recruited from University Hospitals Birmingham NHS Foundation Trust. Baseline investigations include transthoracic echocardiography and cardiac magnetic resonance imaging to assess ventricular mass, volumes and function, applanation tonometry to determine pulse wave velocity and pulse wave analysis as surrogate measures of arterial stiffness and dual energy x-ray absorptiometry scanning to determine bone density. During an open-label run in phase, subjects will receive 1600 mg sevelamer carbonate with meals for four weeks. They will then be randomised to either continue sevelamer carbonate or receive an identical placebo (60 subjects per arm) for the remaining 36 weeks. Four-weekly monitoring of serum electrolytes and bone biochemistry will be performed. All baseline investigations will be repeated at the end of the treatment period. The primary endpoint of the study is a reduction in left ventricular mass after 40 weeks of treatment. Secondary endpoints are: i) change in aortic compliance; ii) change in arterial stiffness; iii) change in arterial elastance; iv) change in left ventricular systolic and diastolic elastance; v) change in left ventricular function; and vi) change in bone density. Trial Registration This trial is registered at ClinicalTrials.gov: NCT00806481 and Current Controlled Trials: ISRCTN35254279.

Background. Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD. Methods. Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology. Results. The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders. Conclusions. This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations. [ABSTRACT FROM AUTHOR]

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The cellular origins of vasa vasorum are ill-defined and may involve circulating or local progenitor cells. We previously discovered that murine aortic adventitia contains Sca-1+CD45+ progenitors that produce macrophages. Here we investigated whether they are also vasculogenic. In aortas of C57BL/6 mice, Sca-1+CD45+ cells were localised to adventitia and lacked surface expression of endothelial markers (<1% for CD31, CD144, TIE-2). In contrast, they did show expression of CD31, CD144, TIE-2 and VEGFR2 in atherosclerotic ApoE−/− aortas. Although Sca-1+CD45+ cells from C57BL/6 aorta did not express CD31, they formed CD31+ colonies in endothelial differentiation media and produced interconnecting vascular-like cords in Matrigel that contained both endothelial cells and a small population of macrophages, which were located at branch points. Transfer of aortic Sca-1+CD45+ cells generated endothelial cells and neovessels de novo in a hindlimb model of ischaemia and resulted in a 50% increase in perfusion compared to cell-free control. Similarly, their injection into the carotid adventitia of ApoE−/− mice produced donor-derived adventitial and peri-adventitial microvessels after atherogenic diet, suggestive of newly formed vasa vasorum. These findings show that beyond its content of macrophage progenitors, adventitial Sca-1+CD45+ cells are also vasculogenic and may be a source of vasa vasorum during atherogenesis. [ABSTRACT FROM AUTHOR]

Several letters to the editor are presented in response to articles in previous issues such as the understanding of the long term consequences of living kidney donation and the increased risk of cardiovascular disease compared with matched non-donors in the general population.