Effects of phosphate on vascular function under normal conditions and influence of the uraemic state.

AIMS: Increased serum phosphorus levels are associated with cardiovascular disease in patients with chronic kidney disease (CKD) and in the general population. High phosphate levels may play a direct role in vascular dysfunction. We investigated here the effects of phosphate loading and of the phosphate binder sevelamer-HCl on vascular function. METHODS AND RESULTS: CKD and non-CKD C57/BL6 mice were used to study the effects of CKD, phosphate, and sevelamer-HCl on vascular function and structure. In vitro, phosphate exhibited a direct vasoconstrictor effect on aortic rings. This effect was smaller in vessels from CKD than non-CKD mice and it was abolished by reactive oxygen species inhibitor dimethylthiourea. A high-phosphate diet (1.3%) increased phenylephrine-induced contraction and lowered acetylcholine-induced relaxation of aortic rings ex vivo, both in non-CKD and CKD mice. It also induced endothelial cell detachment. Sevelamer-HCl exposure in vitro normalized the endothelial dysfunction induced by 3.0 mM phosphate and restored endothelial integrity. Sevelamer-HCl treatment of CKD mice under normal diet (0.65% phosphate) improved the endothelial dysfunction, aortic systolic expansion rate, and pulse wave velocity, and it reduced the endothelial expression of adhesion molecules. CONCLUSION: Changes in extracellular phosphorus concentrations may directly modulate vascular function and thereby modulate the vascular smooth muscle response to physiological or pathological stimuli in normal and CKD mice. Whether serum phosphorus lowering and/or dietary phosphate restriction can improve arterial function in humans remains to be established.

Chronic renal failure alters endothelial function in cerebral circulation in mice.

We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-γ (PPARγ)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium-dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARγ (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production.

Circulating levels of osteopontin are closely related to glomerular filtration rate and cardiovascular risk markers in patients with chronic kidney disease.

BACKGROUND: The pleiotropic cytokine osteopontin (OPN) is thought to be involved in the pathogenesis of atherosclerosis. However, the relationship between OPN and renal function, a cardiovascular risk factor itself, is not known. Therefore, we assessed the relationship between OPN plasma levels and renal function in patients at different stages of chronic kidney disease (CKD). METHODS: We studied 49 non-diabetic and non-smoking patients with primary kidney disease at different CKD stages (K/DOQI 1-5). True glomerular filtration rate (GFR) in patients was assessed using the inulin-clearance technique. To examine the role of an abrupt change in GFR on circulating OPN, 15 living related kidney donors were studied before and after unilateral nephrectomy. Twenty matched non-smoking healthy subjects served as controls. RESULTS: OPN plasma levels in patients with CKD stage 1 (i.e. GFR above 90 mL min(-1) 1.73 m(-2)) were comparable with controls. OPN levels increase in a linear fashion with declining GFR (r = -0.9, P < 0.0001), so that the increase in OPN mirrors the severity of renal impairment. After unilateral nephrectomy, circulating OPN increased significantly in parallel to the decrease in GFR. We found a direct association between OPN and other markers of renal function (serum-creatinine, homocysteine and symmetric dimethylarginine,) as well as with cardiovascular risk factors such as asymmetric dimethylarginine (r = 0.36, P = 0.0213). CONCLUSION: There is a close inverse association between GFR and circulating OPN in patients with CKD. Furthermore, OPN plasma levels correlate with established cardiovascular risk markers in patients with CKD. Assessment of renal function is important for the interpretation of OPN levels in patients with atherosclerotic disease.

Removal of asymmetric dimethylarginine during artificial liver support using fractionated plasma separation and adsorption.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is the most potent endogenous nitric oxide synthase inhibitor. Elevated ADMA levels have been linked to increased mortality in different patient populations. Key regulation of ADMA levels mainly takes place in the liver. Hence, ADMA is elevated in liver disease. There is no specific pharmacological treatment to lower the elevated ADMA levels. Hemodialysis is of limited efficiency in removing ADMA as it is highly protein bound. Prometheus is an extracorporeal liver support system which allows the removal of protein-bound toxins. We assessed the efficiency of the Prometheus system in reducing high ADMA levels in patients with liver failure. MATERIAL AND METHODS: We studied nine patients with acute-on-chronic liver failure and concomitant renal failure already necessitating hemodialysis. Seven patients needed intensive care treatment. Two consecutive sessions of Prometheus therapy of each 4 h were performed in all patients. ADMA and its structural isomer symmetrical dimethylarginine (SDMA) were determined using liquid chromatography-mass spectrometry. RESULTS: ADMA levels correlated to model for end stage liver disease (MELD) score (r(s) = 0.62; p < 0.0001). Before Prometheus was started, levels of ADMA and SDMA were elevated (1.36 +/- 0.5 micromol/l and 1.90 +/- 0.4 micromol/l, respectively). During Prometheus treatments, plasma levels of ADMA dropped by a mean 25% (p < 0.0001) and SDMA levels by 22% (p < 0.0001). However, there was a significant rebound of ADMA levels between the two therapy sessions (p < 0.01). CONCLUSIONS: This study shows for the first time that plasma levels of ADMA can be effectively lowered by an artificial liver support system (Prometheus). Effective elimination of ADMA might explain some of the beneficial clinical effects of these systems in patients with liver failure.

Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis--a pharmacokinetic study.

BACKGROUND: Daptomycin is a new intravenous cyclic lipopeptide antibiotic, licensed for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms including both susceptible and resistant strains of Staphylococcus aureus and for the treatment of various infections due to susceptible organisms, including serious and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis with associated bacteremia. Currently, no dosing recommendations exist for this drug for patients with acute kidney injury (AKI) undergoing renal replacement therapy. The aim of this study was to evaluate pharmacokinetics of daptomycin in critically ill patients with AKI undergoing extended dialysis (ED), a frequently used mean of renal replacement therapies in intensive care units (ICUs) around the world. Patients and methods. A prospective, single-dose pharmacokinetic study was performed in the medical and surgical ICUs of a tertiary care center. The aim was to investigate critically ill patients with anuric AKI being treated with ED and receiving daptomycin (n = 10). Daptomycin (6 mg/kg) was administered 8 h before ED was started. RESULTS: Key pharmacokinetic parameters like half-life in critically ill patients treated with ED were comparable to healthy controls. The dialyser clearance for daptomycin was 63 +/- 9 ml/min. Based on the amount of the drug recovered from the collected spent dialysate, the mean fraction of the drug removed by one dialysis treatment was 23.3%. CONCLUSION: Our data suggest that patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m(2); blood and dialysate flow, 160 ml/min; ED time, 480 min) and employing current dosing regimen, 6 mg/kg daptomycin every 48 h, run the risk of becoming significantly under dosed if one adheres to a twice daily dosing schedule that is recommended for patients on maintenance haemodialysis. Our data suggest that a daily dose of 6 mg/kg daptomycin is necessary in this special patient population to avoid under dosing, which may have detrimental effects in critically ill patients suffering from life-threatening infections.

Symmetric dimethylarginine (SDMA) as endogenous marker of renal function--a meta-analysis.

BACKGROUND: Dosing of most drugs must be adapted in renal insufficiency, making accurate assessment of renal function essential in clinical medicine. Furthermore, even modest impairment of renal function has been recognized as a cardiovascular risk factor. The purpose of this analysis was to identify the role of symmetric dimethylarginine (SDMA), the structural isomer of the cardiovascular risk marker asymmetric dimethylarginine, as an endogenous marker of renal function. METHODS: Comprehensive searches of Medline and the Cochrane Library from 1970 to February 2006 were performed to identify studies that evaluated the correlation between SDMA and renal function. The search was augmented by scanning references of identified articles and reviews. The correlation coefficients (R) were recorded from each study for the values of 1/SDMA and clearance estimates and for SDMA and creatinine levels. The summary correlation coefficients with 95% confidence intervals (CIs) were pooled using the random-effects method. RESULTS: In 18 studies involving 2136 patients systemic SDMA concentrations correlated highly with inulin clearance [R = 0.85 (CI 0.76-0.91, P < 0.0001)], as well as with various clearance estimates combined [R = 0.77 (CI 0.65-0.85, P < 0.0001)] and serum creatinine [R = 0.75 (CI 0.46-089, P < 0.0001)]. CONCLUSIONS: SDMA exhibits some properties of a reliable marker of renal function. Future studies have to clarify whether SDMA is indeed suited to improve diagnosis and eventually optimize care of patients.