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Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease: Relationship to Treatment Method and Atherosclerotic Disease

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Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease: Relationship to Treatment Method and Atherosclerotic Disease J Am Soc Nephrol 10: 594–600, 1999 Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease: Relationship to Treatment Method and Atherosclerotic Disease JAN T. KIELSTEIN,* RAINER H. BOGER,¨ † STEFANIE M. BODE-BOGER,¨ † JURGEN¨ SCHAFFER,*¨ MARK BARBEY,‡ KARL M. KOCH,* and JURGEN¨ C. FROLICH¨ † *Department of Nephrology, †Institute of Clinical Pharmacology, and ‡Department of Diagnostic Radiology, Hannover Medical School, Hannover, Germany. Abstract. Asymmetric dimethylarginine (ADMA) is an endog- than those in the control group (6.0 6 0.5 versus 1.0 6 0.1 enous inhibitor of endothelial nitric oxide (NO) synthase. Its mmol/L; P , 0.05). Plasma nitrate concentrations were signif- concentration is elevated in patients with end-stage renal dis- icantly lower in HD-treated patients, which suggests that ease (ESRD), in part because it is excreted via the kidneys. In ADMA may inhibit NO synthase. In contrast, plasma ADMA this study, the plasma concentrations of ADMA, symmetric levels and nitrate concentrations in PD-treated patients were dimethylarginine, and L-arginine were determined in relation to similar to those in control subjects. Plasma L-arginine concen- plasma nitrate levels (as an index of NO formation) for a group trations were not significantly decreased in patients with of 80 patients with ESRD. The effects of two treatment meth- ESRD. ADMA concentrations were significantly decreased 5 h ods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and after HD, compared with baseline values. ADMA levels were the role of the presence of atherosclerotic disease were evalu- significantly higher in HD-treated patients with manifest ath- ated. Forty-three patients receiving HD and 37 patients receiv- erosclerotic disease than in HD-treated patients without ath- ing PD were compared with healthy control subjects. Plasma erosclerotic disease (7.31 6 0.70 versus 3.95 6 0.52 mmol/L; L-arginine and dimethylarginine levels were determined by P , 0.05). This study confirms that ADMA is accumulated in HPLC, using precolumn derivatization with o-phthaldialde- ESRD. PD-treated patients exhibit significantly lower ADMA hyde. Plasma nitrate levels were determined by gas chroma- levels than do HD-treated patients. Accumulation of ADMA tography-mass spectrometry. Predialysis ADMA concentra- may be a risk factor for the development of endothelial dys- tions in HD-treated patients were approximately sixfold higher function and cardiovascular disease in patients with ESRD. Endothelium-derived nitric oxide (NO) plays an important role NO synthase (4). It is synthesized and metabolized by human in the regulation of BP and platelet aggregation. It is synthe- endothelial cells (5). ADMA and its biologically inactive ste- sized by stereospecific oxidation of the terminal guanidino reoisomer symmetric dimethylarginine (SDMA) are at least in nitrogen of the amino acid L-arginine (1). NO is produced by part eliminated via urinary excretion (6). Vallance et al. (7) the action of a family of NO synthases, with endothelial, were the first to report elevated plasma levels of ADMA and neuronal, and macrophage isoforms (2). SDMA in a small group of patients with end-stage renal The synthesis of NO can be selectively inhibited by gua- disease (ESRD). In their study, dimethylarginine (DMA) levels nidino-substituted analogs of L-arginine, such as N-monometh- were elevated approximately sixfold, compared with those for yl-L-arginine, which act as competitive antagonists at the active healthy control subjects. Those authors suggested that the high site of the enzyme (3). Asymmetric dimethylarginine (ADMA) incidence of conditions such as hypertension, atherosclerosis, has been recently characterized as an endogenous inhibitor of and immune dysfunction among patients with ESRD might be caused at least in part by dysfunction of the L-arginine/NO pathway secondary to accumulation of ADMA (7). Data from several experimental studies suggest that ADMA Received July 7, 1998. Accepted September 17, 1998. concentrations in a pathophysiologically high range (3 to 15 Portions of this work were presented orally at the 35th Annual Meeting of the m European Dialysis and Transplantation Association (June 6 to 9, 1998, Rimini, mol/L) significantly inhibit vascular NO formation (8,9). Italy). Moreover, it was recently found by our group that plasma Correspondence to Dr. Rainer H. Bo¨ger, Institute of Clinical Pharmacology, ADMA levels are also elevated in atherosclerotic patients and Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Ger- in hypercholesteremic subjects with normal renal function, many. Phone: 49 511 532 4631; Fax: 49 511 532 5199; E-mail: boeger.rainer @mh-hannover.de suggesting that mechanisms other than decreased renal elimi- 1046-6673/1003-0594$03.00/0 nation may contribute to the elevation of plasma ADMA levels Journal of the American Society of Nephrology in hypercholesterolemia and atherosclerosis (10). It is therefore Copyright © 1999 by the American Society of Nephrology unclear whether elevated ADMA concentrations in patients J Am Soc Nephrol 10: 594–600, 1999 ADMA Levels in ESRD 595 6 with ESRD are a cause or a consequence of accompanying PD was 2.13 0.09, well above the recommended weekly Kt/Vurea cardiovascular disease. value of 2.0 (12). The aim of this study was to determine the plasma concen- The mean serum creatinine concentration was 922 6 47 mmol/L, and the mean BP was 137.2 6 2.8/83.8 6 1.6 mmHg. Average serum trations of ADMA, SDMA, and L-arginine and their relation- 6 6 ship to NO formation (measured as plasma nitrate concentra- cholesterol and triglyceride levels were 6.16 0.24 and 2.80 0.26 mmol/L, respectively. The body mass index averaged 23.2 6 0.6, and tions) in patients with ESRD, compared with age-matched the mean serum albumin concentration was 36.7 6 0.8 g/L. Heparin- control subjects with normal renal excretory function. The ized blood samples from fasting subjects were obtained during routine effects of two treatment methods, i.e., hemodialysis (HD) and morning visits in the PD clinic. peritoneal dialysis (PD), on these parameters were also evaluated. The control group consisted of 37 elderly, healthy, normotensive subjects with no apparent disease (13 female and 24 male patients; mean age, 68.3 6 1.1 yr), who exhibited mean serum creatinine Materials and Methods concentrations of 79.3 6 3.5 mmol/L. Average cholesterol and tri- Patients and Study Design glyceride levels were 4.86 6 0.11 and 1.61 6 0.12 mmol/L, respec- Four groups of individuals were included in this study, after they tively. The presence of cardiovascular or metabolic disease was ex- had given informed consent for participation. The first group con- cluded by medical histories, physical examinations, and routine sisted of 43 patients receiving HD (20 female and 23 male patients; laboratory tests. mean age, 64.9 6 1.6 yr) who had been treated with HD for a median An additional control group consisted of 33 patients with manifest of 38 mo (range, 1 to 200 mo), with residual diuresis of 582 6 95 ml arteriosclerotic disease and normal renal function. These patients (13 of urine/24 h. Sixteen of the 43 (37%) HD-treated patients were female and 20 male patients; mean age, 61.4 6 4.0 yr) had peripheral anuric. The average diuresis among the remaining 27 patients was arterial occlusive disease, as verified by angiography or duplex- 776 6 116 ml/24 h. sonography. The serum creatinine concentration in this group was For these patients, a venous blood sample was drawn at midweek 96.0 6 4.4 mmol/L; average cholesterol and triglyceride levels were before dialysis. Patients were treated with HD three times each week 6.24 6 0.22 and 1.81 6 0.14 mmol/L, respectively, and BP was and were in clinically stable conditions. The mean serum creatinine 152.1 6 3.2/79.4 6 2.0 mmHg. level was 707 6 108 mmol/L, and the mean arterial BP was 141.0 6 3.4/78 6 1.7 mmHg. Average serum cholesterol and triglyceride levels were 5.29 6 0.17 and 2.09 6 0.16 mmol/L, respectively. The Biochemical Analyses G G body mass index averaged 23.6 6 0.6, and the mean serum albumin The plasma concentrations of L-arginine, N ,N -DMA (ADMA), level was 37.6 6 1.1 g/L. Patients underwent standard bicarbonate and NG,N9G-DMA (SDMA) were measured by HPLC with precolumn HD with biocompatible membranes (Hemophan® [Gambro Medizin- derivatization with o-phthaldialdehyde (OPA), using a modification of technik, Munich, Germany] and polyamide membranes, sterilized a previously published method (13). L-Homoarginine (10 mmol/L) with steam). The average dialysis time was 270 6 6 min, blood flow was added to 0.5 ml of plasma as an internal standard. Plasma samples was 290 6 8 ml/min, and dialysate flow was 500 ml/min. The delivered and standards were extracted on solid-phase extraction cartridges dialysis dose measured by urea reduction rate was 67.2 6 1.1%, well (CBA Bond Elut; Varian, Harbor City, CA). The recovery rates were above the suggested dialysis dose (by urea reduction rate) of 65% 82.9 6 3.8%. Eluates were dried under nitrogen and resuspended in (11). double-distilled water for HPLC analysis. Samples and standards were Subgroup analysis was performed for patients with ESRD with incubated with OPA reagent (5.4 mg/ml OPA in borate buffer, pH 8.4, atherosclerotic vascular disease (n 5 22), which was defined as the containing 0.4% 2-mercaptoethanol) for exactly 30 s before automatic presence of clinically and angiographically or duplex-sonographically injection into the HPLC system.
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