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*Department of Internal Medicine and Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany; Clinical Pharmacology Unit, Department of Pharmacology, University Hospital of Hamburg-Eppendorf, Hamburg-Eppendorf, Germany; and Department of Internal Medicine, Ruperto-Carola University, Heidelberg, Germany.
Correspondence to Dr. Danilo Fliser, Division of Nephrology, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: 49-511-532-6319; Fax: 49-511-55-23-66; E-mail: Fliser.Danilo{at}mh-hannover.de
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In the last decade, a growing body of evidence has accumulated pointing out the role of reduced bioavailability of nitric oxide (NO), a potent antiatherosclerotic molecule, in the development of endothelial dysfunction, which is the first step in the process of atherosclerosis (7). In 1992, Vallance et al. (8) first reported elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of the NO synthase, in patients with terminal renal failure. This observation boosted further research on the contribution of a dysfunction in the NO pathway secondary to accumulation of ADMA, leading to the high incidence of atherosclerosis in patients with end-stage renal disease (8,9). Indeed, in patients with renal disease as well as in patients without renal disease, increased ADMA levels correlate strongly with severity of the atherosclerotic disease (10–13). Thus, ADMA is thought to be a novel biochemical marker for atherosclerosis (14). Furthermore, in a prospective study in 225 patients receiving maintenance hemodialysis, plasma ADMA concentrations were not only related to the severity of carotid atherosclerosis, but also were the strongest predictor of cardiovascular mortality among several risk factors assessed (15).
To date, increased ADMA blood levels have been documented only in patients with advanced and terminal renal failure (8–10,15–18). It has been argued that this is the consequence of diminished renal excretion of dimethylarginines such as ADMA and its biologically inactive regioisomer symmetric dimethylarginine (SDMA) because both substances are excreted renally to some extent (9,18). Past and more recent studies have revealed that some of the potential atherogenetic risk factors (such as lipoprotein abnormalities and insulin resistance) are present very early in the course of renal disease (1,5,6,19). To explore at what stage of renal disease elevated plasma ADMA concentrations can be found, we examined nonsmoking patients with confirmed primary chronic renal disease and different degrees of renal function in a cross-sectional study. True GFR was measured by use of the inulin clearance technique. Importantly, with the exception of high BP, cardiovascular risk factors had not been treated specifically in the patients under study. The results were compared with data that were obtained from a group of nonsmoking subjects matched for age, gender, and body-mass index (BMI).
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The three groups of patients were matched with respect to age, gender, and BMI (Table 1). All patients studied had been seen as outpatients in the Department of Nephrology. Patients had a stable renal function for at least 6 mo before the study. Until enrollment into the study, none of them had been treated with vitamin B12, folate, antioxidant vitamins, vitamin D, erythropoietin, fish oil, or immunosuppressive agents, and none of them had a low-protein diet. Higher-grade proteinuria (i.e., more than 1 g/d) was present in 3 of 15 patients with moderate renal failure and in 5 of 13 patients with advanced renal failure. Hypertension according to World Health Organization criteria—that is, mean arterial BP greater than 105 mmHg, antihypertensive therapy, or both—was present in 7 of 16 patients with normal renal function, in 10 of 15 patients with moderate renal failure, and in 11 of 13 patients with advanced renal failure. Antihypertensive drugs, if present, were washed out for time periods depending on their half-life of action—that is, short-acting drugs were withdrawn for at least 3 d preceding examination, whereas long-acting drugs were washed out for at least 1 wk before examination.
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Both patients and control subjects adhered to a standardized diet for 3 d before the laboratory tests were carried out. Repeated verbal inquiries ascertained compliance. Blood samples for measurement of creatinine, L-arginine, ADMA, SDMA, total homocysteine (Hcy), and total cholesterol concentrations were taken in the morning after at least 12 h of fasting. In addition, mean arterial BP was measured oscillometrically with the patient in the supine position in a quiet environment with an automated device (Dinamap, Critikon Co., Tampa, FL). The mean of three consecutive measurements 5 min apart after a rest of at least 20 min was taken for analysis. In patients with renal disease, additional blood samples for measurement of intact parathyroid hormone concentrations were taken, and true GFR was assessed while the patient was supine by means of the steady-state inulin (Cin) infusion clearance technique, as described in detail elsewhere (20).
Biochemical Analyses
Plasma L-arginine and dimethylarginine levels were determined by HPLC by use of precolumn derivatization with o-phthalaldehyde (OPA) as described previously (21). Plasma samples and internal standards were extracted on CBA solid phase extraction cartridges (Varian, Harbor City, CA). The eluates were dried over nitrogen and dissolved in bidistilled water for HPLC analysis. Samples and standards were incubated for exactly 30 s with the OPA reagent (5.4 mg/ml OPA in borate buffer, pH 8.5, containing 0.4% mercaptoethanol) before automatic injection into the HPLC. The OPA derivatives of L-arginine, ADMA, and SDMA were separated on a C6H5 column (Macherey and Nagel, Düren, Germany) with the fluorescence monitor set at an excitation wavelength of 340 nm and an emission wavelength of 455 nm.
Samples were eluted from the column with 0.96 citric acid/methanol 2:1, pH 6.8, at a flow rate of 1 ml/min. The coefficients of variation of this method is 5.2% within assay and 5.5% between assay; the detection limit of the assay is 0.1 µmol/L. Plasma inulin concentration was measured enzymatically by use of inulinase as described by Kuehnle et al. (22), and inulin clearance was calculated as described elsewhere (20). Intact parathyroid hormone was measured with an immunoradiometric assay (normal range, 1.2 to 6.0 pmol/L) and total plasma Hcy with a fluorescence-polarization immunoassay (normal range, 5.0 to 15.0 µmol/L). All other measurements were performed with routine laboratory tests that used certified assay methods.
Statistical Analyses
The SPSS software package (SPSS 10.0.7 for Windows; SPSS, Inc., Chicago, IL) was used for statistical analysis. After confirming approximate normality of the data distribution, control subjects and the three groups of patients with renal disease were compared by a two-tailed ANOVA. When this procedure gave significant results, between-group comparison was carried out by t test for random data. Pearson’s correlation analysis between GFR on the one hand and L-arginine, ADMA, SDMA, and Hcy on the other hand was performed in pooled patients’ data only. Correlations between ADMA and age, mean arterial BP, proteinuria, serum cholesterol, and Hcy levels were analyzed as well. All data are presented as mean ± SD. Differences were considered as significant at P < 0.05, and Bonferroni or Bonferroni-Holm corrections for multiple comparison were applied.
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Irrespective of its potential pathophysiologic role in thE development of atherosclerosis, increased plasma ADMA levels obviously characterize patients with renal disease as a separate population when compared with normotensive subjects without renal and cardiac disease. Accordingly, blood ADMA levels were found to be increased to the same extent in both patients with immune renal disease (i.e., IgA GN) and in patients with nonimmune renal disease (i.e., ADPKD). Thus, ADMA may be an early indicator of—and potentially even a causal agent in the genesis of—excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with primary renal disease (10).
In this context, it is of interest that a study documented impaired acetylcholine-induced endothelium-dependent vasorelaxation in patients with ADPKD and normal renal function (23). Although the mean age of these patients was somewhat higher than that of patients with ADPKD with normal renal function in our study, all of them had BP values still within the normal range, as documented by 24-h ambulatory BP measurement. Thus, impaired endothelium-dependent vasorelaxation could not be the consequence of high BP. This observation is in line with our finding that ADMA blood concentrations in normotensive and hypertensive patients with renal disease were increased to the same extent. Endothelium-dependent vasorelaxation is induced by the NO synthase activator acetylcholine and is a fundamental function of the healthy endothelium. Its impairment is thought to be a hallmark of incipient atherosclerosis at the level of small arteries (14), and two large, prospective, controlled studies have demonstrated a significant relationship between endothelial dysfunction and the later development of manifest atherosclerotic disease—that is, cardiovascular events (24,25).
ADMA is a potent inhibitor of the NO synthase, and increased levels could thus be responsible for the impaired acetylcholine-induced endothelium-dependent vasorelaxation (26), at least in patients with renal disease. Furthermore, normal elasticity of large arterial vessels is in part NO dependent, and in patients with end-stage renal disease, vascular remodeling coupled with endothelial dysfunction is a strong predictor of cardiovascular mortality (27). To obtain relatively homogeneous and comparable cohorts of controls subjects and patients, we excluded subjects with manifest cardiovascular disease in our population under study on the basis of noninvasive evaluation. This may explain why increased plasma ADMA concentrations in our patients were not associated with manifest cardiovascular problems. Further studies exploring the association between increased ADMA levels and cardiovascular pathology in patients with renal disease by more sensitive (invasive) techniques (e.g., acetylcholine-induced, endothelium-dependent vasorelaxation) are therefore warranted.
It appears paradoxical that in patients with renal disease, ADMA should be increased even though GFR values are still within the normal range. We caution, however, that apparently normal renal function, as documented by normal GFR, does not necessarily exclude reduction of functional parenchyma by the disease process. Adaptive changes in glomerular filtration dynamics and single-nephron GFR may keep whole-kidney GFR within the normal range despite considerable reduction of tubular cell mass. Other cardiovascular risk factors, such as increased Lp(a) concentrations (5) or insulin resistance (19), are found to be present in patients with incipient renal disease as well, and a recent post hoc analysis of the HOPE study revealed that the presence of even mild renal insufficiency is a potent predictor of cardiovascular mortality independent of known cardiovascular risk factors such as microalbuminuria (28). Increased ADMA levels in patients with renal disease could be the result of reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that metabolizes ADMA (but not SDMA) to citrulline (29,30). The enzyme is present in abundance in renal tissue—that is, in endothelial cells within the glomerulus and in renal vessels, and particularly in renal tubular cells (30,31). It regulates (intra)cellular methylarginine levels, thereby governing cell-specific L-arginine uptake and NO generation in tubular cells (31). We propose the hypothesis that destruction of DDAH-rich renal tissue impairs renal degradation of ADMA, eventually leading to increased plasma levels. A complementary explanation may be that salt retention accompanying impaired renal function might affect the activity of DDAH and thus increase ADMA levels (32).
Plasma concentrations of L-arginine were similar in the group of control subjects and in patients with renal disease so that the L-arginine/ADMA ratio was markedly decreased in patients. A decrease of the L-arginine/ADMA ratio was associated with clinically manifest atherosclerosis in several studies (11,14). The ratio of both substances is thought to govern cell-specific L-arginine uptake and NO generation, not only in renal tubular cells but also in endothelial cells. In contrast to ADMA, plasma concentrations of SDMA were comparable in control subjects and patients with renal disease with normal GFR, but steadily increased in patients with progressive loss of renal function. As a consequence, SDMA but not ADMA levels were significantly correlated with GFR, probably reflecting a progressive loss of renal excretion capacity for this substance. This observation confirms earlier results of MacAllister et al. (9), who found markedly increased plasma SDMA levels in patients with terminal renal failure despite only moderately increased ADMA levels. The correlation between GFR and ADMA levels in our patients was weak, at least across a range of GFR between 140 to 20 ml·min-1·1.73 m2, suggesting that pronounced accumulation of ADMA due to impaired renal excretory function may indeed occur only with severe impairment of renal function. The biologic significance of SDMA is still uncertain because no direct inhibitory effect on NO synthase was documented (14). At high concentrations, however, it may indirectly interfere with NO metabolism by blocking cellular L-arginine uptake (31). The results of the study we present here warrant further research to elucidate the role of methylarginines in renal disease.
By using the inulin clearance for the measurement of true GFR, we could clearly document that total plasma Hcy concentrations increase with progressive renal failure (6). The correlation between GFR and plasma Hcy concentrations was remarkable, pointing to a very close relationship between renal function and Hcy metabolism (6). In this respect, Hcy resembles intact parathyroid hormone—its plasma concentrations were strongly associated with GFR as well (r = -0.64, P < 0.0001). Regardless of the role of increased Hcy levels as a cardiovascular risk factor in patients with renal disease (6), it is of interest that the metabolic pathways generating Hcy and ADMA are closely coupled. ADMA is generated via post-translational methylation of arginine residues of nucleolar proteins, and some authors argue that these methyl groups may come from the demethylation process of methionine to Hcy (33). In our patients with normal renal function, Hcy concentrations were comparable to those in control subjects, suggesting that factors other than hyperhomocystinemia are responsible for increased ADMA levels. Last, but not least, total serum cholesterol concentrations were comparable in the group of patients with renal disease and normotensive control subjects matched with respect to age, gender, and BMI. This observation is of importance because hypercholesterinemia was shown to be associated with increased plasma ADMA concentrations in vivo, and an inhibitory effect of LDL cholesterol on DDAH activity was documented in vitro (34).
In conclusion, increased plasma concentrations of ADMA—that is, the only biologically active endogenous NO synthase inhibitor (26,35)—are found at a very early stage of renal disease, even when GFR is still within the normal range. Because of the marked increase with almost no overlap between control subjects and patients with renal disease, ADMA by itself may be an indicator of incipient renal disease. This observation has several implications for further research and for the management of patients with renal disease. Numerous recent studies have documented a potential role of ADMA in the process of atherosclerosis (14). It remains to be seen whether interventions such as supplementation with L-arginine or administration of NO donors, preferably early on in the course of renal disease, are able to modulate the atherogenic profile of patients with renal disease and interfere with progression of renal failure (36,37).
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R. Saran, J. E. Novak, A. Desai, E. Abdulhayoglu, J. S. Warren, R. Bustami, G. J. Handelman, D. Barbato, W. Weitzel, L. G. D'Alecy, et al. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study Nephrol. Dial. Transplant., November 1, 2003; 18(11): 2415 - 2420. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, H. Haller, and D. Fliser Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol. Dial. Transplant., July 1, 2003; 18(7): 1245 - 1248. [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
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K. Amann, C. Ritz, M. Adamczak, and E. Ritz Why is coronary heart disease of uraemic patients so frequent and so devastating? Nephrol. Dial. Transplant., April 1, 2003; 18(4): 631 - 640. [Abstract] [Full Text] [PDF]
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L. Brattstrom Pregnancy-related decrease in total plasma homocysteine Am. J. Clinical Nutrition, April 1, 2003; 77(4): 993 - 993. [Full Text] [PDF]
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N.N. Chan, W.B. Chan, J.C.N. Chan, K.J. Bennett-Richards, M. Kattenhorn, A. Donald, G. Oakley, L. Rees, J.E. Deanfield, and Z. Varghese Reduction of Total Homocysteine Levels by Oral Folic Acid Fails to Improve Endothelial Function in Children With Chronic Renal Failure * Response Circulation, January 7, 2003; 107 (1): e6 - e7. [Full Text] [PDF]
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