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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      Asymmetrical dimethylarginine in renal disease: limits of variation or variation limits? A systematic review.

      American journal of nephrology
      Adult, Aged, Animals, Arginine, analogs & derivatives, blood, Biological Markers, Female, Humans, Kidney Diseases, diagnosis, Kidney Failure, Chronic, Male, Middle Aged, Models, Biological, Nephrology, standards, Reference Values, Reproducibility of Results

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          Abstract

          Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a putative biomarker in cardiovascular and renal disease. Elevated plasma levels of ADMA are the consequence of increased synthesis, reduced renal clearance or reduced enzymatic degradation. Based upon the metabolic fate the highest plasma concentrations of ADMA have been reported in patients with renal failure in whom this molecule accumulates. However, the range of published ADMA levels in patients with chronic renal failure as well as in patients with end-stage renal failure undergoing maintenance hemodialysis, peritoneal dialysis or kidney transplant recipients is widely scattered and overlaps with the levels reported in healthy individuals. This wide distribution can in part be explained by different bioanalytical techniques and the lack of standardization of such assays. This review summarizes available literature on ADMA in patients with kidney disease and stresses the urgent need for a consensus regarding reference values for different analytical methods in order to appreciate the prognostic significance of elevated ADMA levels. At present, one cannot advocate this molecule for risk assessment or individual patient prognosis in the clinical work-up of patients with renal impairment. 2007 S. Karger AG, Basel

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          Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study

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            Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.

            Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known. In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2+/-1.4% from 58.9+/-2.0 bpm (P<0.001) and cardiac output by 14.8+/-1.2% from 4.4+/-0.3 L/min (P<0.001). ADMA also increased mean blood pressure by 6.0+/-1.2% from 88.6+/-3.4 mm Hg (P<0.005) and SVR by 23.7+/-2.1% from 1639.0+/-91.6 dyne. s. cm-5 (P<0.001). Handgrip exercise increased cardiac output in control subjects by 96.8+/-23.3%, but in subjects given ADMA, cardiac output increased by only 35.3+/-10.6% (P<0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26+/-0.32 to 2.73+/-0.59 after ADMA injection (P<0.01). We estimate that humans generate approximately 300 micromol of ADMA per day, of which approximately 250 micromol is metabolized by DDAHs. This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.
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              Symmetric dimethylarginine (SDMA) as endogenous marker of renal function--a meta-analysis.

              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. 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. 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)]. 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.
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