Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease

This study compared the molecular lipidomic profi le of LDL in patients with nondiabetic advanced renal disease and no evidence of CVD to that of age-matched controls, with the hypothesis that it would reveal proatherogenic lipid alterations. LDL was isolated from 10 normocholesterolemic patients with stage 4/5 renal disease and 10 controls, and lipids were analyzed by accurate mass LC/MS. Top-down lipidomics analysis and manual examination of the data identifi ed 352 lipid species, and automated comparative analysis demonstrated alterations in lipid profi le in disease. The total lipid and cholesterol content was unchanged, but levels of triacylglycerides and N -acyltaurines were signifi cantly increased, while phosphatidylcholines, plasmenyl ethanolamines, sulfatides, ceramides, and cholesterol sulfate were signifi cantly decreased in chronic kidney disease (CKD) patients. Chemometric analysis of individual lipid species showed very good discrimination of control and disease sample despite the small cohorts and identifi ed individual unsaturated phospholipids and triglycerides mainly responsible for the discrimination. These fi ndings illustrate the point that although the clinical biochemistry parameters may not appear abnormal, there may be important underlying lipidomic changes that contribute to disease pathology. The lipidomic profi le of CKD LDL offers potential for new biomarkers and novel insights into lipid metabolism and cardiovascular risk in this disease. -Reis, A., A. Rudnitskaya, P. Chariyavilaskul, N. Dhaun, V. Melville, J. Goddard, D. J. Webb, A. R. Pitt, and C. M. Spickett. Topdown lipidomics of low density lipoprotein reveal altered lipid profi les in advanced chronic kidney disease. J. Lipid Res. 2015

Are rare diseases still orphans or happily adopted? The challenges of developing and using orphan medicinal products

Orphan medicinal products (OMPs) are targeted at the diagnosis, prevention or treatment of rare diseases and have a special status in European law. This status brings incentives for pharmaceutical companies to invest in OMP development. The goal of the legislation is to encourage the development of more treatments for life-threatening rare disorders, but increased availability of OMPs raises important issues surrounding the public funding of very expensive treatments by national health services. In this article we review OMPs and the incentives for their development and discuss the challenges presented by funding these treatments

Renal Dysfunction Does Not Affect the Peripheral-to-Central Arterial Pressure Transfer Function

Arterial generalized transfer functions (GTFs) are increasingly used to estimate central pressure from peripheral measurements. Analysis of derived central waveforms may be valuable in the assessment of patients with chronic kidney disease. The aim of this study was to assess whether the GTF is affected by renal disease. Ninety-four subjects with varying degrees of renal function (Kidney Disease Outcomes Quality Initiative stages 1 to 5; 14 controls) had simultaneous measurements of carotid and radial waveforms made by applanation tonometry. GTFs were calculated by Fourier analysis for each subject group. Derived carotid waveforms were obtained by applying an independently generated GTF to the radial waveform. Glomerular filtration rate inversely correlated with central systolic (R = -0.42; P &lt; 0.001), mean (R = -0.34; P &lt; 0.01) and diastolic (R = --0.27, P &lt; 0.01) blood pressures, as well as central augmentation index (R = -0.30; P&lt; 0.01) and carotid-femoral pulse wave velocity (R = -0.33; P &lt; 0.001). Derived waveforms were not significantly different from measured waveforms in terms of systolic blood pressure, augmentation index, maximum slope, or the delay between the incident and reflected waves, although the derived waveforms slightly underestimated the systolic ejection period (-4.4 ± 0.9 ms; P &lt; 0.001). Overall root-mean-square error was 2.4 ± 0.1 mm Hg. No significant relationship existed between the degree of bias of any derived waveform measure and glomerular filtration rate or chronic kidney disease stage (P &gt; 0.16). No significant differences between chronic kidney disease stages were observed in transfer function gain or phase (P &gt; 0.05). We conclude that the peripheral-to-central GTF is not affected by degree of renal dysfunction and can be used with equivalence in patients with varying degrees of chronic kidney disease.</p

Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupus nephritis

Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 ± 2.7%, 10.0 ± 3.0 pg/μmol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 ± 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal