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Asymmetric Dimethylarginine Plasma Concentrations Differin Patients with End-Stage Renal Disease: Relationship toTreatment Method and Atherosclerotic Disease AFFER,* MARK BARBEY,‡ KARL M. KOCH,* and *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 Ϯ 0.5 versus 1.0 Ϯ 0.1 enous inhibitor of endothelial nitric oxide (NO) synthase. Its ␮mol/L; P Ͻ 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 Ϯ 0.70 versus 3.95 Ϯ 0.52 ␮mol/L; L-arginine and dimethylarginine levels were determined by P Ͻ 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 becaused at least in part by dysfunction of the L-arginine/NOpathway 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 theEuropean Dialysis and Transplantation Association (June 6 to 9, 1998, Rimini, ␮mol/L) significantly inhibit vascular NO formation (8,9).
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 suggesting that mechanisms other than decreased renal elimi- nation may contribute to the elevation of plasma ADMA levels in hypercholesterolemia and atherosclerosis (10). It is therefore Journal of the American Society of NephrologyCopyright 1999 by the American Society of Nephrology unclear whether elevated ADMA concentrations in patients with ESRD are a cause or a consequence of accompanying PD was 2.13 Ϯ 0.09, well above the recommended weekly Kt/Vurea The aim of this study was to determine the plasma concen- The mean serum creatinine concentration was 922 Ϯ 47 ␮mol/L, and the mean BP was 137.2 Ϯ 2.8/83.8 Ϯ 1.6 mmHg. Average serum cholesterol and triglyceride levels were 6.16 Ϯ 0.24 and 2.80 Ϯ 0.26 ship to NO formation (measured as plasma nitrate concentra- mmol/L, respectively. The body mass index averaged 23.2 Ϯ 0.6, and tions) in patients with ESRD, compared with age-matched the mean serum albumin concentration was 36.7 Ϯ 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 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 Ϯ 1.1 yr), who exhibited mean serum creatinine Materials and Methods
concentrations of 79.3 Ϯ 3.5 ␮mol/L. Average cholesterol and tri- glyceride levels were 4.86 Ϯ 0.11 and 1.61 Ϯ 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; mean age, 64.9 Ϯ 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 Ϯ 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 Ϯ 4.0 yr) had peripheral anuric. The average diuresis among the remaining 27 patients was arterial occlusive disease, as verified by angiography or duplex- sonography. The serum creatinine concentration in this group was For these patients, a venous blood sample was drawn at midweek 96.0 Ϯ 4.4 ␮mol/L; average cholesterol and triglyceride levels were before dialysis. Patients were treated with HD three times each week 6.24 Ϯ 0.22 and 1.81 Ϯ 0.14 mmol/L, respectively, and BP was and were in clinically stable conditions. The mean serum creatinine level was 707 Ϯ 108 ␮mol/L, and the mean arterial BP was 141.0 Ϯ3.4/78 Ϯ 1.7 mmHg. Average serum cholesterol and triglyceridelevels were 5.29 Ϯ 0.17 and 2.09 Ϯ 0.16 mmol/L, respectively. The body mass index averaged 23.6 Ϯ 0.6, and the mean serum albumin The plasma concentrations of L-arginine, NG,NG-DMA (ADMA), level was 37.6 Ϯ 1.1 g/L. Patients underwent standard bicarbonate and NG,NЈG-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 ␮mol/L) with steam). The average dialysis time was 270 Ϯ 6 min, blood flow was added to 0.5 ml of plasma as an internal standard. Plasma samples was 290 Ϯ 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 Ϯ 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 Ϯ 3.8%. Eluates were dried under nitrogen and resuspended in 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 ϭ 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. The OPA derivatives of L-arginine, verified peripheral arterial occlusive disease (Fontaine stage IIb to IV) ADMA, and SDMA were separated on a 250- ϫ 4.5-mm (inner alone (n ϭ 2) or in combination with a history of prior myocardial diameter), 7-␮m, Nucleosil phenyl column (Macherey and Nagel, infarction (n ϭ 20), compared with patients with ESRD without Du¨ren, Germany), with the fluorescence detector set for an excitation vascular disease (n ϭ 11). For a subgroup of eight HD-treated wavelength of 340 nm and an emission wavelength of 450 nm.
patients, additional heparinized blood samples for the analysis of Samples were eluted from the column with 0.96% citric acid/methanol ADMA, SDMA, L-arginine, and nitrate were drawn 1, 5, and 18 h (2:1, pH 6.8), at a flow rate of 1 ml/min. Standard curves generated for after the end of a dialysis session (duration, 4.5 h). These patients (five ADMA and SDMA in water and in pooled human plasma showed female and three male patients; mean age, 63.1 Ϯ 4.5 yr) had been linearity over a concentration range from 0.1 to 16 ␮mol/L. The receiving HD for a median of 18 mo (range, 1 to 82 mo). The mean coefficients of variation of this method were 5.2% within assays and serum creatinine concentration was 760 Ϯ 49 ␮mol/L, and the mean 5.5% between assays; the detection limit was 0.1 ␮mol/L.
arterial BP was 133.8 Ϯ 9.7/81.3 Ϯ 3.7 mmHg. Average serum The ADMA/creatinine ratio was calculated, as ADMA (micromo- cholesterol and triglyceride levels were 5.33 Ϯ 0.50 and 2.44 Ϯ 0.42 lar)/creatinine (micromolar) ϫ 10Ϫ3, for patients for whom multiple samples were drawn before and after HD sessions, to assess the The second group consisted of 37 patients (16 female and 21 male different effects of HD treatment on methylarginine levels, as opposed patients) receiving PD (24 patients undergoing nightly intermittent to serum creatinine levels. Plasma nitrate was assayed as its pentaflu- PD, nine continuous ambulatory PD, three continuous cyclic PD, and orobenzyl derivative by gas chromatography-mass spectrometry, as one intermittent PD; mean age, 46.4 Ϯ 2.5 yr), who had received PD described previously (14). The detection limit of the method was 20 for a median of 55 mo (range, 7 to 168 mo). These patients exhibited fmol of nitrite or nitrate. Intra- and interassay variabilities were residual diuresis of 658 Ϯ 129 ml of urine/24 h. Thirteen of the 37 Ͻ3.8%. Serum creatinine concentrations were determined spectro- (35%) patients receiving PD were anuric. The average diuresis among photometrically with the alkaline picric acid method, in an automatic the remaining 24 patients was 1015 Ϯ 151 ml/24 h (P ϭ not signif- analyzer (Beckman, Galway, Ireland). Protein concentrations were determined spectrophotometrically using the biuret method. All other Journal of the American Society of Nephrology laboratory data were obtained from routine laboratory tests, using Table 1. ADMA, SDMA, L-arginine, L-arginine/ADMA ratio, and nitrate concentration as determinants ofnitric oxide synthesis in control subjects (control) Data are presented as mean Ϯ SEM unless otherwise stated. Sta- tistical significance was tested using ANOVA, followed by the Fisher protected least significant difference test for comparisons betweenpatient groups. Repeated measurements were tested for statistical significance using ANOVA and the Scheffe´ F test. Statistical signif- icance was accepted for P Ͻ0.05.
Plasma L-Arginine, ADMA, SDMA, and NitrateConcentrations in ESRD a Data are mean Ϯ SEM. Results are given as ␮mol/L. ADMA, Compared with control subjects, HD-treated patients exhib- asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; ited significantly higher plasma ADMA concentrations (P Ͻ PD, peritoneal dialysis; HD, hemodialysis.
b P Ͻ 0.05 versus control.
0.05) (Figure 1). Plasma SDMA levels were also significantly c P Ͻ 0.05 versus PD.
higher, but L-arginine concentrations were not significantlydifferent between the two groups (Table 1). Plasma nitrateconcentrations were significantly lower in HD-treated patientsthan in control subjects (Table 1).
change in plasma ADMA and SDMA concentrations was ob- ADMA levels in PD-treated patients were not different from served. When the concentrations of these L-arginine analogs those in control subjects (P Ͼ 0.05) (Figure 1). However, were expressed with respect to serum creatinine concentra- SDMA concentrations in the PD-treated group were signifi- tions, there was a significant elevation 1 h after dialysis, cantly higher than those in control subjects (P Ͻ 0.05) (Table compared with predialysis concentrations (ADMA, 0.86 Ϯ 1). L-Arginine and nitrate concentrations and the L-arginine/ 0.20 versus 2.02 Ϯ 0.33; P Ͻ 0.05). Five hours after the end of ADMA ratio were not significantly different, compared with the HD session, ADMA concentrations were significantly de- those for the control group (P Ͼ 0.05) (Table 1).
creased, below values measured 1 h after dialysis. ADMA HD-treated patients exhibited significantly higher mean levels then continuously increased until 18 h after dialysis ADMA concentrations, compared with PD-treated patients.
(Figure 2). A similar time course was observed for SDMA SDMA, L-arginine, and nitrate concentrations did not differ levels (Table 2). However, it seemed that the reduction in significantly between these groups. The L-arginine/ADMA ra- plasma SDMA levels at 5 h after dialysis was not as marked as tio in the HD-treated patients was significantly lower than that that for ADMA. Plasma L-arginine concentrations remained in the PD-treated patients (Table 1).
unchanged after HD. Plasma nitrate levels and total proteinconcentrations did not change significantly.
Effects of HD on the Time Course of PlasmaL-Arginine, DMA, and Nitrate Levels For eight HD-treated patients, the changes in the plasma ADMA Concentrations with Respect to Renal levels of L-arginine, DMA, and nitrate were assessed before and after one HD session. One hour after the end of dialysis, no HD-treated patients with atherosclerosis exhibited signifi- cantly higher ADMA levels than did HD-treated patients with-out atherosclerosis (7.31 Ϯ 0.70 ␮mol/L [n ϭ 22] versus3.95 Ϯ 0.52 ␮mol/L [n ϭ 11]; P Ͻ 0.05) (Figure 3). Similarly,patients with peripheral arterial occlusive disease with normalrenal function exhibited significantly higher ADMA levelsthan did healthy control subjects (3.23 Ϯ 0.33 ␮mol/L [n ϭ 33]versus 1.01 Ϯ 0.05 ␮mol/L [n ϭ 37]; P Ͻ 0.05) (Figure 3).
There was no significant difference in ADMA levels betweenHD-treated patients without atherosclerosis and patients withperipheral arterial occlusive disease with normal renal func-tion. A similar pattern of SDMA concentrations was observed(Table 3). Plasma L-arginine concentrations did not differ Figure 1. Plasma asymmetric dimethylarginine (ADMA) concentra- among control patients, patients with peripheral arterial occlu- tions in healthy control subjects (1.0 Ϯ 0.1 ␮mol/L, n ϭ 37), perito- sive disease, and patients with ESRD with atherosclerosis.
neal dialysis (PD)-treated patients (2.1 Ϯ 0.4 ␮mol/L, n ϭ 37), and However, patients with ESRD without atherosclerosis exhib- hemodialysis (HD)-treated patients (6.0 Ϯ 0.5 ␮mol/L, n ϭ 43). Eachpoint represents one individual. Horizontal bars indicate the mean Ϯ ited lower plasma L-arginine concentrations than did patients with ESRD with atherosclerotic disease.
Our finding that DMA levels are significantly higher in patients with ESRD than in healthy control subjects is consis-tent with the first description by Vallance et al. (7), whostudied nine HD-treated patients. They reported a mean totalDMA level of 8.7 Ϯ 0.7 ␮mol/L. This concentration was sixtimes higher than that measured for control subjects (1.2 Ϯ 0.1 ␮mol/L) (7). In other studies, lower concentrations of DMAwere reported. MacAllister et al. (15) found elevated ADMAand SDMA levels (0.9 Ϯ 0.1 and 3.8 Ϯ 0.4 ␮mol/L, respec-tively) in six HD-treated patients. Anderstam et al. (16) re-ported ADMA levels of 0.6 Ϯ 0.2 ␮mol/L in 19 patients, andno difference between PD and HD. However, in these studiesADMA and SDMA levels in control subjects were also verylow. The relative increase in DMA levels was 2.5- to sixfold inall of these studies. Comparing two treatment methods forpatients with ESRD, i.e., HD and PD, we found that PD-treatedpatients exhibited lower plasma ADMA concentrations thandid HD-treated patients. This difference may be caused bydifferences in dialytic clearance of ADMA with the two treat-ment methods or the metabolism of ADMA.
The origin of ADMA in human plasma is currently unclear.
Figure 2. (A) Time course of plasma ADMA concentrations in eight Animal studies suggest that the relatively low levels of ADMA HD-treated patients before and 1, 5, and 18 h after a 4.5-h dialysis and SDMA present in plasma from healthy rabbits are derived session. Each line represents the time course of ADMA concentrations mainly from the degradation of methylated proteins (6). Dif- in one subject. The thick line indicates the mean Ϯ SEM. *P Ͻ 0.05 ferent methyltransferases seem to be responsible for L-arginine by ANOVA. (B) Time course of plasma ADMA/creatinine ratios in methylation in various tissues; the enzyme present in the vas- eight HD-treated patients before and 1, 5, and 18 h after a 4.5-h culature mainly yields ADMA, as judged by the observation dialysis session. Each line represents the time course of ADMA/ that cultured human endothelial cells release more ADMA than creatinine ratios in one subject. The thick line indicates the mean ϮSEM. *P Ͻ 0.05 by ANOVA.
Urinary excretion is the main elimination route for SDMA in rabbits, whereas NG-monomethyl-L-arginine and ADMA are Discussion
partly eliminated by other metabolic pathways (6). In rats, The major findings of this study are that: (1) ADMA and Ogawa and coworkers (19) demonstrated that 14C-labeled SDMA are accumulated in patients with ESRD; (2) ADMA ADMA is metabolized to citrulline by the enzyme DMA dim- levels are significantly lower in patients with ESRD treated ethylaminohydrolase (DDAH), which is present in various with PD than in those treated with HD; (3) elevated ADMA tissues of rats and human subjects (5,20,21). These tissues levels are accompanied by low plasma levels of nitrate, the include the kidneys, the vasculature, and other tissues in which oxidative metabolite of NO; and (4) regardless of renal func- this enzyme is colocalized with isoforms of NO synthase and tion, patients with atherosclerosis have higher plasma levels of may affect NO-mediated cell function (20,22). DDAH pres- ADMA than those without atherosclerosis.
ence and activity have also been demonstrated in human en- Table 2. Time course of plasma L-arginine, SDMA, SDMA/creatinine ratio as determinants of nitric oxide synthesis in 10 HD patients before, 1, 5 and 18 h after a 4.5-h dialysis sessiona a Data are mean Ϯ SEM. Abbreviations as in Table 1.
Journal of the American Society of Nephrology thors reported the exact time point of blood withdrawal, withrespect to the end of dialysis session. The data presented hereshow that the timing of blood withdrawal is very important forassessing the effects of HD on DMA levels.
Several studies performed in vitro suggest that ADMA, at concentrations between 1 and 10 ␮mol/L, inhibits NO elabo-ration by NO synthase in the presence of L-arginine in isolatedblood vessels, in cultured macrophages, and in cultured endo- Figure 3. Plasma ADMA concentrations in healthy control subjects, thelial cells (8,9,17,18). Because intracellular ADMA levels patients with peripheral arterial occlusive disease (PAOD), and pa- have been shown to be approximately one order of magnitude tients with end-stage renal disease (ESRD) treated with HD, without greater than the levels in conditioned cell culture media, the or with concomitant atherosclerosis. Each point represents one indi-vidual. Horizontal bars indicate the mean accumulation of ADMA observed in patients with ESRD may be sufficient to cause clinically relevant inhibition of endothe-lial NO elaboration (17).
In 1992, Vallance et al. (7) hypothesized that inhibition of dothelial cells (5,23). In isolated rat aortic rings studied ex vivo, vascular NO formation caused by accumulated ADMA might inhibition of DDAH activity causes vasoconstriction, which is be responsible for cardiovascular disorders such as hyperten- reversed by L-arginine (23). Differences in the tissue origin of sion and atherosclerosis, which are frequently observed in ADMA and SDMA and differences in the metabolism of these ESRD. Since then, the presence of dysfunctional endothelium- compounds may have contributed to the differences in plasma dependent vasodilation in this disease has been confirmed in ADMA and SDMA levels in this study. Further investigation several clinical investigations: Joannides et al. (24) showed will be needed to identify the influence of ESRD and different that flow-induced, NO-dependent forearm vasodilation was treatment regimens on the metabolism of DMA.
impaired in adult patients receiving HD. Kari et al. (25) foundimpaired flow-induced, NO-dependent vasodilation in children with chronic renal failure. This was associated with elevated The data presented here showed that 1 h after HD, there ADMA levels and reduced levels of nitrosothiols in plasma.
were slight increases in plasma ADMA and SDMA concentra- Moreover, Hand et al. (26) demonstrated that the defect of tions, which were significant when the concentrations of DMA endothelium-dependent vasodilation that was present in pa- forms were expressed with respect to serum creatinine concen- tients with ESRD before HD was reversed after HD sessions.
trations. This suggests that dialytic clearance for creatinine is Furthermore, L-arginine, but not D-arginine, restored endothe- greater than for ADMA and SDMA. Part of the increase could lial function independently of HD. This study strongly supports also be the result of redistribution of tissue DMA into the the hypothesis that levels of ADMA present in the plasma of plasma compartment during HD. Hemoconcentration did not patients with ESRD induce clinically relevant inhibition of play a role in this increase, because there was no significant endothelial NO synthase activity, because competitive inhibi- change in total protein levels during HD. At 5 h after the HD tion of NO synthase by ADMA can be overcome by excess session, plasma ADMA levels were decreased by 65%, com- pared with 1 h after dialysis; levels slowly increased again until In this study we measured the plasma concentration of 18 h after HD. This slow increase is probably attributable to nitrate, a final oxidative metabolite of NO. Nitrate levels were accumulation of newly synthesized DMA released into plasma.
significantly lower at baseline in HD-treated patients than in Our data confirm the decrease in plasma ADMA concentra- matched healthy control subjects. After HD, nitrate levels tions of approximately 40% that was previously reported by transiently increased and finally returned to baseline. These Vallance et al. (7) and by Anderstam et al. (16). MacAllister et data are in accordance with studies performed by other inves- al. (15) found a smaller (approximately 20%) decrease in tigators who also found evidence for reduced basal NO pro- plasma ADMA levels after HD. However, none of those au- duction in patients with ESRD (28) and increased NO forma- Table 3. L-arginine and SDMA plasma concentrations in healthy controls, PAOD patients, and ESRD patients maintained on hemodialysis without or with concomitant atherosclerosisa a Data are mean Ϯ SEM. Results are given as ␮mol/L. PAOD, peripheral arterial occlusive disease; ESRD, end-stage renal disease.
tion during HD (29,30). Using stable-isotope techniques, cardiovascular disease are not proof of accelerated atheroscle- Rhodes et al. (31) recently found that in human subjects the rosis in patients undergoing maintenance dialysis. Many pa- major portion of circulating nitrite/nitrate is derived directly tients undergoing dialysis have more or less marked vascular from the L-arginine/NO pathway. Although we cannot exclude lesions at the start of dialysis treatment, and the risk factors the possibility that differences in dietary nitrate intake ac- present in the predialysis phase may be of primary importance counted at least in part for differences in plasma nitrate levels for the manifestation of cardiovascular disease. Multiple between patient groups in this study, accumulated evidence known cardiovascular risk factors have been shown to be from these studies suggests that NO production is altered in present in patients with ESRD (41– 44). Elevated ADMA lev- ESRD. This is further supported by the recent finding of els may be a newly identified, preexistent risk factor for impaired endothelium-dependent, NO-mediated vasodilation in patients undergoing dialysis (24 –26). Increased ADMA In conclusion, we have demonstrated that ADMA is accu- levels may be one important factor determining endothelial mulated during chronic renal failure. Different dialysis treat- ment strategies affect ADMA levels differently. The presenceof atherosclerosis is associated with higher ADMA levels in Consequences of Reduced NO Elaboration in ESRD patients with normal renal function, as well as in patients Aside from volume changes during HD, acute alterations in undergoing dialysis, but this phenomenon may be unrelated to NO formation during HD may contribute to peridialytic BP renal handling of ADMA. Reduced NO elaboration secondary instability in HD-treated patients (32–34). Changes in ADMA- to accumulation of ADMA may be an important pathogenic induced inhibition of endothelial NO production may contrib- factor for atherosclerosis in chronic renal failure.
ute to this phenomenon. In the long term, chronic reduction ofNO synthase activity secondary to accumulation of ADMA Acknowledgments
may contribute to the pathogenesis of hypertension and ath- The authors gratefully acknowledge the excellent technical assis- erosclerosis. Chronic inhibition of NO synthesis has been tance of T. Suchy, F.-M. Gutzki, and B. Schubert. The authors are shown to produce hypertension (35) and to accelerate athero- grateful to their colleagues Drs. Hilfenhaus, Jonassen, Lorenzen, Lu¨th, sclerosis in animal models (13,36,37). Chronically elevated Riechers, and Zaunbauer for help in collecting the clinical data from ADMA concentrations may induce similar proatherogenic ef- fects, like those observed in these experimental models (17).
Our group previously reported that plasma ADMA concen- References
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