Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy.

Proteinuria in diabetic nephropathy predicts the progressive loss of glomerular filtration rate (GFR) and serves as independent predictor for mortality. We performed the present study (ClinicalTrials.gov identifier: NCT 00324675) to clarify whether the activation of PPARγ receptor by thiazolidinediones was able to improve proteinuria and preserve renal function in advanced diabetic nephropathy. A total of 28 type 2 diabetic patients (4 women and 24 men, mean age 66.1±9.1 years) with urinary albumin excretion >300 mg/24 h and an estimated GFR <60 ml/min were included into this prospective double blind trial to receive either rosiglitazone (RSG) 4 mg b.i.d or matching placebo (PLC) for 52 weeks in addition to their concomitant antidiabetic background therapy. At baseline and after 26 and 52 weeks, renal plasma flow (RPF) and GFR were determined before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine acetate. RSG treatment resulted in a significant reduction of proteinuria (2.4±1.1; 1.2±0.6; 1.5±0.7 g/d at baseline, 26 weeks and 52 weeks; respectively, p<0.05) whereas PLC did not influence proteinuria (1.6±0.6; 1.6±0.8; 1.7±0.8 g/d). GFR and RPF did not change significantly during the study, however, RSG improved the intrarenal NO bioavailability. RSG treatment was generally well tolerated and the major adverse event - development of edema - could be controlled by dose adjustment of the study drug and diuretic agents. In conclusion, we demonstrated a possible renoprotective effect of RSG in patients with advanced diabetic nephropathy.

Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients.

Activation of rho-kinase (ROK) is involved in the development of hypertension as it is a potent regulator of vascular smooth muscle cell (VSMC) contractility. Here we evaluated whether activation of ROK is present in hypertensive kidney transplant recipients (NTX). We tested the effect of the ROK-inhibitor fasudil on the regulation of forearm blood flow (FBF) in NTX and in healthy control subjects (CTL). In addition potential modulating effects of ROK-inhibition on local vascular nitric oxide (NO) release were studied. The effect of intra-arterial infusion of fasudil on FBF was studied by venous-occlusion plethysmography in NTX and CTL. To unmask the role of NO fasudil was infused with/without clamping of vascular NO in NTX and CTL. To unravel the basal NO-mediated tone the NO-synthase inhibitor l-NMMA was infused. Fasudil markedly but comparably increased FBF in NTX and CTL. The vascular response to fasudil was blunted during NO-clamp in CTL (104+/-18% vs. 244+/-48% for NO-clamp+fasudil vs. fasudil alone; baseline=0%, P<0.05) but not in NTX. The l-NMMA-induced vasoconstriction was impaired in NTX compared to CTL. In NTX and CTL basal vascular tone equally depends on ROK. Fasudil-induced vasodilatation is partly mediated by vascular NO in CTL but not in NTX. The greater NO-insensitive fasudil-induced increase in FBF in NTX suggests an increased ROK-mediated VSMC constrictor tone in these patients. Basal NO-mediated tone is attenuated in hypertensive NTX.

A single lipid apheresis does not modulate pulse wave reflection in hypercholesterolemic patients.

BACKGROUND: Lipid apheresis (LA) is instituted to increase life expectancy in patients with previous cardiovascular events and severe and otherwise untreatable hypercholesterolemia. Studies have demonstrated that even a single LA markedly improves endothelial and micro-vascular function in patients. It is unknown whether these changes also impact pulse wave reflection and established parameters of arterial stiffness. METHODS: In 20 patients on regular LA (8 treated by immunoadsorption, 7 by lipid filtration, 5 by direct adsorption of lipids) we measured peripheral blood pressure, heart rate, central systolic pressure (CSP), central pulse pressure (CPP), augmentation index (AIX) and pulse wave velocity by applanation tonometry (SphygmoCor, Atcor Medical) before and after a single treatment. RESULTS: Peripheral blood pressure and heart rate were comparable pre- and post treatment. CSP, CPP, AIX and PWV did not significantly change during LA independent of treatment modality although LDL-cholesterol levels were markedly reduced (in average from 3.5+/-0.9 to 0.9+/-0.3 mmol/L). CONCLUSION: The well-documented effects of a single LA on microvascular function are not associated with measurable changes in pulse wave reflection. Future studies are required in order to evaluate long-term effects of LA in this context.

Kidney transplantation substantially improves endothelial progenitor cell dysfunction in patients with end-stage renal disease.

Endothelial progenitor cells (EPC) are involved in endothelial repair and maintenance. Dysfunction of EPC may contribute to accelerated arteriosclerosis in chronic kidney disease. Kidney transplantation (KTx) improves both survival and endothelial function of dialysis patients. In a prospective study, we tested to which extent KTx changes EPC biology. We studied number and function (migratory activity, adhesion to extracellular matrix proteins and to mature endothelial cells [EC]) of EPC in 20 patients during dialysis and 3, 6, 9 and 12 months after KTx. Twenty-two healthy volunteers served as matched controls. Circulating precursor populations were measured by flow cytometric analysis. Cytokines relevant for EPC mobilization were monitored. Compared to the dialysis state, KTx increased the migration of EPC to approximately 2-fold. Adhesion to fibronectin and to collagen type IV was significantly increased after KTx. An improved adhesion rate of EPC to mature EC was observed. The number of EPC decreased. The amount of precursor populations showed no difference compared to the pretransplant state. Our study shows an improved function of EPC after KTx. This finding indicates an improved potential for endothelial repair which in turn may contribute to enhanced endothelial function and reduced cardiovascular morbidity after KTx.

Endothelial dysfunction in patients with rheumatoid arthritis is associated with a reduced number and impaired function of endothelial progenitor cells.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality attributable to accelerated atherosclerosis and cardiovascular events. OBJECTIVE: To determine the role played by endothelial progenitor cells (EPC) in the defence system against arteriosclerosis. METHODS: The number and function of EPC in 13 young patients with RA with low disease activity (DAS28 3.5 (0.3)) and 13 healthy control subjects was studied. Endothelial function was investigated by agonist-induced, endothelium dependent vasodilatation measured by the forearm blood flow technique. Migratory activity and adhesion of EPC to tumour necrosis factor alpha (TNFalpha) activated mature endothelial cells and components of the extracellular matrix were tested in vitro. Putative precursor populations (CD34(+), CD34(+)/CD133(+), and CD34(+)/KDR(+) haematopoietic stem cells) were measured by flow cytometric analysis. RESULTS: Acetylcholine-induced, endothelium dependent vasodilatation was reduced by about 50% in patients with RA, indicating endothelial dysfunction, whereas endothelium-independent vasodilatation in response to glyceryl trinitrate was at control level. Significantly reduced numbers of EPC were found in the patients compared with controls. Migratory activity of EPC was decreased in patients with RA. Adhesion to mature endothelial cells after activation with TNFalpha was enhanced only in controls. The adhesion to matrix proteins and the number of putative precursor cell lineages was comparable in both groups. CONCLUSION: Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.

Role of endothelial progenitor cells in cardiovascular pathology.

Replacement of injured endothelial cells by bone marrow derived endothelial progenitor cells (EPC's) is a new pathway of vascular repair after ischemia. Endothelial progenitor cells contribute less than 0.01% to the peripheral venous compartment of mononuclear cells. The detection of EPC's requires a demonstration of CD 34 and VEGFR-2 (vascular endothelial growth factor receptor-2) antigenic cell membrane determinants and proof of endothelial characteristics after outgrowth and differentiation in cell culture. The most important stimuli to the mobilization and proliferation of EPC's are VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), erythropoietin, HMG-CoA-reductase inhibitors and tissue ischemia. In vivo in patients EPC's appear to contribute to endothelialization of vascular grafts, the formation of collaterals of ischemic limbs and the healing of myocardial infarcts. The role of EPC's in uremia is currently under investigation.