Search

Nephrotic-range proteinuria is associated with a several-fold increase risk of cardiovascular infarction. This increased risk is accompanied by endothelial dysfunction, which is not related to increased blood pressure and is not correctable by acute administration of L-arginine. The latter is in direct contrast to what has been found in patients with primary hypercholesterolemia, suggesting that either hypoalbuminemia itself or other aspects of the dyslipidemia characteristic of the nephrotic syndrome impair endothelial function. Lysophosphatidylcholine (lyso-PC) is formed during oxidative modification of cholesterol, and lyso-PC in oxidized low-density lipoprotein (LDL) is responsible for reduced endothelial function in vitro. However, in the circulation, lyso-PC is tightly bound to albumin. Indeed, the addition of albumin can restore endothelial function, which was previously disturbed by lyso-PC. Hypoalbuminemia induces a shift in lyso-PC to lipoproteins, notably LDL, and to erythrocytes. The latter directly induces a reduction in deformability that can also be corrected by the addition of albumin. Hypoalbuminemia may disturb endothelial function, either by directly affecting Gi-protein-dependent signal transduction or indirectly by changing the configuration of the cell membrane. Such a change in cell membrane configuration will disturb binding of ligands to receptors and of endothelial nitric oxide (NO) synthase to caveolin. However, other pathways have been suggested, such as stimulation by lyso-PC of vasoconstriction mediated by protein kinase C. It remains to be shown whether lipid-lowering and antiproteinuric strategies have independent positive effects on endothelial function in nephrotic subjects.

Chronic renal failure may occur in etiologically diverse renal diseases and can be caused by hemodynamic, immunologic and metabolic factors. Initial damage may evoke irreversible scarring, which involves production of a number of proinflammatory and fibrogenic cytokines, including platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions. We investigated CTGF mRNA expression in 65 human renal biopsy specimens of various renal diseases by in situ hybridization. In control human kidney CTFG mRNA was mainly expressed in visceral epithelial cells, parietal epithelial cells, and some interstitial cells. Connective tissue growth factor was strongly up-regulated in the extracapillary and severe mesangial proliferative lesions of crescentic glomerulonephritis, IgA nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. An increase in the number of cells expressing CTGF mRNA was observed at sites of chronic tubulointerstitial damage, which correlated with the degree of damage. in the tubulointerstitial area the majority of the CTGF mRNA positive cells coexpressed alpha-smooth muscle actin, and were negative for macrophage markers. Our results indicate that CTGF may be a common growth factor involved in renal fibrosis.

Patients with renal disease have an increased cardiovascular mortality. Hyperlipidemia, a hallmark of renal disease, is recognized as a principal cause of atherosclerosis. However, it is difficult to prove a pathogenetic role of renal dyslipidemia per se in this increased cardiovascular risk since multiple risk factors are often present in patients with progressive renal insufficiency, e.g. hypertension, diabetes and hypercoagulability. However, evidence is accumulating demonstrating detrimental effects of hyperlipidemia during both initiation and progression of the atherosclerotic process. The present review discusses this evidence in patients with renal disease, and the possible implications for treatment.

Aims Atrial fibrillation (AF) is common in dialysis patients and is associated with increased morbidity and mortality. The pathophysiology may be related to common risk factors for both AF and renal disease or to dialysis-specific factors. The purpose of this study was to determine whether and how AF onset relates to the dialysis procedure itself. Methods All dialysis patients enrolled in the implantable cardioverter defibrillator-2 (ICD-2) trial until January 2012, who were implanted with an ICD, were included in this study. Using the ICD remote monitoring function, the exact time of onset of all AF episodes was registered. Subsequently, this was linked to the timing of dialysis procedures. Results For the current study, a total of 40 patients were included, follow-up was 28±16 months, 80% male, 70±8 years old. A total of 428 episodes of AF were monitored in 14 patients. AF onset was more frequent on the days of haemodialysis (HD) (p<0.001) and specifically increased during the dialysis procedure itself ( p=0.04). Patients with AF had a larger left atrium (p<0.001) and a higher systolic blood pressure before and after HD (p<0.001). Conclusion This study provides insight in the exact timing of AF onset in relation to the dialysis procedure itself. In HD patients, AF occurred significantly more often on a dialysis day and especially during HD. These findings might help to elucidate some aspects of the pathophysiology of AF in dialysis patients and could facilitate early detection of AF in these high-risk patients. [ABSTRACT FROM AUTHOR]

The development of renal ischemia has been postulated to be a main cause of the progressive nature of kidney diseases. In recent years, it has become clear that inappropriate and sustained activation of the endothelium could mediate this phenomenon. Endothelial activation will result in leucostasis and can compromise peritubular flow. The associated sustained redox signaling will also accelerate the development of endothelial senescence. In addition, risk factors for renal disease progression can reduce endothelial repair. In the course of these events, loss of capillary structure and rarefaction develops, which drives the further development of nephron loss. In this mini review, the evidence for this pathophysiological concept as well as the possibility to detect such endothelial activation in the clinical arena is summarized.Kidney International (2007) 72, 926–930; doi:10.1038/sj.ki.5002414; published online 4 July 2007 [ABSTRACT FROM AUTHOR]

This ISN-sponsored Forefront in Nephrology meeting, which has brought together 120 scientists from 21 countries, has been concerned with various aspects of endothelial function and dysfunction and their contribution to progression of chronic kidney disease and/or its cardiovascular complications. The following themes were discussed in great depth: (1) phenotypical changes in the vascular endothelium – permeability, senescence, and apoptosis; (2) regulation of endothelial nitric oxide (NO) synthase function – caveolar and shear stress mechanisms, epigenetic regulation, S-nitrosylation, and Rho-kinase regulation; (3) oxidative stress and hypoxia-induced changes; (4) organellar dysfunction – lysosomes, mitochondria, and endoplasmic reticulum; (5) NO-independent mechanisms of vasomotion – epoxides, heme oxygenase-1 and carbon monoxide, thromboxane, tumor necrosis factor-alpha, and uric acid; (6) endothelial crosstalk with podocytes, monocytes, smooth muscle cells, and platelets; (7) candidate clinical biomarkers of endothelial dysfunction – functional testing of macro- and micro-vascular functions, surrogate markers, circulating detached endothelial cells, and endothelial precursor cells; and culminated in Round Table discussion on the diagnosis of endothelial dysfunction and its treatment options. In conclusion, this meeting has focused on several key problems of endothelial cell pathobiology relevant to chronic kidney disease.Kidney International (2006) 70, 258–264. doi:10.1038/sj.ki.5001559; published online 14 June 2006 [ABSTRACT FROM AUTHOR]

Micro-vascular and renal complications in diabetic patients are a considerable clinical challenge. In a previous study, we found a significant decrease in vascular endothelial growth factor A (VEGF-A) mRNA levels in glomeruli from patients with diabetic nephropathy (DN). We now set out to investigate the relationship between reduced VEGF-A and connective tissue growth factor (CTGF) expression levels, the number of podocytes, and the extent of interstitial fibrosis. Laser capture microdissection was applied to obtain glomerular RNA from 28 patients with DN and 22 controls. mRNA levels of VEGF-A, CTGF, nephrin, podocin, and Wilms tumor1 (WT1) were measured using real-time polymerase chain reaction. Protein expression was evaluated using immuno-stainings for VEGF-A and CTGF, as well as markers for podocytes (WT1) and endothelial cells (CD31). We found a significant decrease in glomerular mRNA levels for VEGF-A (2.5 times), CTGF (1.6), nephrin (2.8), podocin (3.3), and WT1 (1.7) in patients with DN. There was a significant correlation between expression of podocyte markers and VEGF-A mRNA levels, and an inverse correlation between podocin message and the extent of interstitial fibrosis. CD31-positive area was significantly decreased (3.2 times) in patients with DN. Reduction of angiogenic factors correlated with the extent of interstitial fibrosis. This downregulation was related to a reduction of podocytes in DN. The results may suggest that downregulation of VEGF-A and CTGF in DN is a result of podocyte loss.Kidney International (2007) 71, 637–645. doi:10.1038/sj.ki.5002101; published online 31 January 2007 [ABSTRACT FROM AUTHOR]