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• W2037709367 abstract "The rationale of this study is based on the fact that, both proteinuria and elevated asymmetric dimethyl arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not enough knowledge about any association between the levels of proteinuria and ADMA levels. Seventy-eight non-diabetic patients (42 men, 36women, mean age of 26.1±5.2 years) with proteinuria having normal glomerular filtration rate were enrolled along with 38 healthy subjects (20men, 18women, mean age of 26.9±5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5 g/day in 38 patients. Both groups had similar age, gender, and body mass index distributions. Serum ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were significantly higher in patients than in healthy control subjects. The above parameters were higher in the nephrotic range proteinuria group when compared to patients having protein levels below 3.5 g/day. There were significant correlations between the levels of proteinuria and the above parameters. According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly associated with proteinuria. Further studies are recommended to find out whether elevated ADMA levels are implicated in the high cardiovascular risk of proteinuric nephropathies. The rationale of this study is based on the fact that, both proteinuria and elevated asymmetric dimethyl arginine (ADMA) levels have been linked to the progression of vascular disease. Currently, there is not enough knowledge about any association between the levels of proteinuria and ADMA levels. Seventy-eight non-diabetic patients (42 men, 36women, mean age of 26.1±5.2 years) with proteinuria having normal glomerular filtration rate were enrolled along with 38 healthy subjects (20men, 18women, mean age of 26.9±5.9 years). Proteinuria was below 3.5 g/day in 40 patients and above 3.5 g/day in 38 patients. Both groups had similar age, gender, and body mass index distributions. Serum ADMA, symmetric dimethyl arginine (SDMA), immunoreactive insulin, and high sensitivity C reactive protein (hsCRP) levels were measured. Insulin resistance was determined by homeostasis model assessment (HOMA). Serum ADMA, SDMA, insulin, hsCRP levels, and HOMA indexes were significantly higher in patients than in healthy control subjects. The above parameters were higher in the nephrotic range proteinuria group when compared to patients having protein levels below 3.5 g/day. There were significant correlations between the levels of proteinuria and the above parameters. According to the regression analysis, levels of proteinuria and hsCRP were significant determinants of serum ADMA levels. Our results indicate that, independent of other risk factors, ADMA is directly associated with proteinuria. Further studies are recommended to find out whether elevated ADMA levels are implicated in the high cardiovascular risk of proteinuric nephropathies. Proteinuria is now recognized as an important cardiovascular risk factor not only in disease states such as diabetes mellitus and hypertension,1.Dinneen S.F. Gerstein H.C. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature.Arch Intern Med. 1997; 157: 1413-1418Crossref PubMed Scopus (0) Google Scholar,2.Jager A. Kostense P.J. Ruhe H.G. et al.Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study.Arterioscler Thromb Vasc Biol. 1999; 19: 617-624Crossref PubMed Scopus (330) Google Scholar but also in the general population3.Jee S.H. Boulware L.E. Guallar E. et al.Direct, progressive association of cardiovascular risk factors with incident proteinuria: results from the Korea Medical Insurance Corporation (KMIC) study.Arch Intern Med. 2005; 165: 2299-2304Crossref PubMed Scopus (36) Google Scholar,4.Tanihara S. Hayakawa T. Oki I. et al.NIPPON DATA Research Group. Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980–1999.J Epidemiol. 2005; 15: 146-153Crossref PubMed Scopus (18) Google Scholar where it has prognostic implications also within the normal range of albumin excretion.5.Arnlov J. Evans J.C. Meigs J.B. et al.Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study.Circulation. 2005; 112: 969-975Crossref PubMed Scopus (581) Google Scholar Furthermore, it is well demonstrated that there is a dose–response relationship between proteinuria and cardiovascular risk factors,4.Tanihara S. Hayakawa T. Oki I. et al.NIPPON DATA Research Group. Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980–1999.J Epidemiol. 2005; 15: 146-153Crossref PubMed Scopus (18) Google Scholar an observation in keeping with clinical studies showing that vascular function is impaired in patients with microalbuminuria6.Stehouwer C.D. Henry R.M. Dekker J.M. et al.Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothelial dysfunction – the Hoorn Study.Kidney Int Suppl. 2004; 92: S42-S44Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar,7.Jawa A. Nachimuthu S. Pendergrass M. et al.Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin converting enzyme inhibitor therapy.J Clin Endocrinol Metab. 2006; 91: 31-35Crossref PubMed Scopus (28) Google Scholar and particularly so in those with frank proteinuria.8.Watts G.F. Herrmann S. Dogra G.K. et al.Vascular function of the peripheral circulation in patients with nephrosis.Kidney Int. 2001; 60: 182-189Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Inflammation, insulin resistance, and dyslipidemia have been implicated in cardiovascular damage in proteinuric patients.8.Watts G.F. Herrmann S. Dogra G.K. et al.Vascular function of the peripheral circulation in patients with nephrosis.Kidney Int. 2001; 60: 182-189Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 9.Festa A. D'Agostino R. Howard G. et al.Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the insulin resistance atherosclerosis study.Kidney Int. 2000; 58: 1703-1710Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 10.Barzilay J.I. Peterson D. Cushman M. et al.The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.Am J Kidney Dis. 2004; 44: 25-34Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Yet, the exact pathophysiological mechanisms responsible for the high cardiovascular risk of these patients are still unclear.11.Yuyun M.F. Adler A.I. Wareham N.J. What is the evidence that microalbuminuria is a predictor of cardiovascular disease events?.Curr Opin Nephrol Hypertens. 2005; 14: 271-276Crossref PubMed Scopus (96) Google Scholar The endogeneous inhibitor of nitric oxide synthase, asymmetric dimethyl arginine (ADMA) is considered as a likely causative factor in endothelial dysfunction in humans.12.Cooke J.P. Does ADMA cause endothelial dysfunction?.Arterioscler Thromb Vasc Biol. 2000; 20: 2032-2037Crossref PubMed Scopus (524) Google Scholar,13.Perticone F. Sciacqua A. Maio R. et al.Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension.J Am Coll Cardiol. 2005; 46: 518-523Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar The relationship between ADMA and proteinuria has not been thoroughly analyzed. Fliser et al.14.Fliser D. Kronenberg F. Kielstein J.T. et al.Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study.J Am Soc Nephrol. 2005; 16: 2456-2461Crossref PubMed Scopus (290) Google Scholar reported that plasma ADMA levels were increased and positively correlated with proteinuria in patients with renal failure. As altered renal function is associated with the elevation of plasma ADMA levels,15.Zoccali C. Bode-Boger S. Mallamaci F. et al.Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.Lancet. 2001; 358: 2113-2117Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar, 16.Kielstein J.T. Boger R.H. Bode-Boger S.M. et al.Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.J Am Soc Nephrol. 2002; 13: 170-176PubMed Google Scholar, 17.Ravani P. Tripepi G. Malberti F. et al.Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach.J Am Soc Nephrol. 2005; 16: 2449-2455Crossref PubMed Scopus (333) Google Scholar, 18.Yilmaz M.I. Saglam M. Caglar K. et al.The determinants of endothelial dysfunction in chronic kidney disease: oxidative stress and asymmetric dimethylarginine.Am J Kidney Dis. 2006; 47: 42-50Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar we performed a survey to study the association between these two risk factors in a well-selected series of patients with proteinuric nephropathies and normal glomerular filtration rate (GFR). The clinical and laboratory characteristics of patients and healthy control subjects are shown in Table 1. The etiology of proteinuria is also reported in Table 2. There were no significant differences between patients and controls in terms of age, body mass index (BMI), blood urea, serum creatinine, GFR, systolic and diastolic blood pressure (BP), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. As expected, total protein concentration and serum albumin were lower in patients than in controls, but these differences did not achieve statistical significance. Patients had significantly higher levels of ADMA, symmetric dimethyl arginine (SDMA), insulin and high sensitivity C reactive protein (hsCRP) concentrations, and homeostasis model assessment (HOMA) indexes than controls (P<0.001 for all).Table 1Clinical and laboratory features of the patient and control groupsControls (n=38)Patients (n=78)Group I proteinuria (<3.5 g/day) (n=40)Group II proteinuria (>3.5 g/day) (n=38)P*Patients versus control. These variables are matched for in analyses.P**t-test; According to the severity of proteinuria (between Group I and Group II).Age (years)26±626±525±425±60.400†t-test,0.695Sex (M/F)20/1842/3622/1820/180.356‡χ2 test.0.436GFR (ml/min/1.73 m2)117±7115±9106±9105±70.186†t-test,0.165Serum creatinine (mg/dl)0.86±0.20.79±0.20.78±0.20.80±0.20.225†t-test,0.385Blood urea (mg/dl)35±1035±1035±1034±100.852†t-test,0.674Total protein (g/dl)6.7±0.45.7±1.16.8±0.44.1±0.40.060†t-test,<0.001Serum albumin (g/dl)4.1±0.33.0±1.13.7±0.32.3±0.40.072†t-test,<0.001Systolic BP (mm Hg)130±6130±14129±8130±80.332§Mann–Whitney U-test,0.577Diastolic BP (mm Hg)83±483±483±483±30.764§Mann–Whitney U-test,0.208Total cholesterol (mg/dl)179±18177±19174±16175±170.211§Mann–Whitney U-test,0.372Triglycerides (mg/dl)120±14127±23126±22125±240.119†t-test,0.245LDL cholesterol (mg/dl)103±14105±16105±15107±170.678†t-test,0.649HDL cholesterol (mg/dl)42±640±540±437±50.267†t-test,0.908BMI (kg/m2)26±227±226±227±20.834†t-test,0.813Amount of proteinuria (g/day)0.09±0.033.8±2.81.3±0.46.3±1.6<0.001†t-test,<0.001HsCRP (mg/l)1.8±0.69.7±4.07.2±4.212.4±1.6<0.001†t-test,<0.001FPG (mg/dl)78±979±880±779±80.871†t-test,<0.001Insulin (μIU/ml)6±212±49±214±4<0.001†t-test,<0.001HOMA1.2±0.32.3±0.81.8±0.52.8±0.4<0.001†t-test,<0.001SDMA (μmol/l)0.90±0.231.81±0.691.45±0.382.18±0.76<0.001†t-test,<0.001ADMA (μmol/l)1.08±0.131.92±0.651.48±0.322.39±0.58<0.001†t-test,<0.001ADMA, asymmetric dimethyl arginine; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; F, female; GFR, glomerular filtration rate; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; hsCRP, high sensitive C reactive protein; LDL, low-density lipoprotein; M, male; SDMA, symmetric dimethyl arginine.* Patients versus control. These variables are matched for in analyses.† t-test,§ Mann–Whitney U-test,‡ χ2 test.** t-test; According to the severity of proteinuria (between Group I and Group II). Open table in a new tab Table 2Etiology of proteinuria according to pathologic diagnosisEtiology of proteinuriaProteinuria (<3.5 g/day) Group I (n=40)Proteinuria (≥3.5 g/day) Group II (n=38)FSGS1414IgAN36Secondary FSGS5—Membranous nephropathy9—MPGN1—Minimal mesengial proliferation6—Lupus nephritis22Minimal change disease—16FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; MPGN, membranoproliferative glomerulonephritis. Open table in a new tab ADMA, asymmetric dimethyl arginine; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; F, female; GFR, glomerular filtration rate; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; hsCRP, high sensitive C reactive protein; LDL, low-density lipoprotein; M, male; SDMA, symmetric dimethyl arginine. FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; MPGN, membranoproliferative glomerulonephritis. The characteristics of Group I (proteinuria <3.5 g/day) and Group II patients (proteinuria >3.5 g/day) are also presented in Table 1. No significant differences were observed between these subgroups as for age, BMI, sex, blood urea, creatinine, systolic and diastolic BPs, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. Group II patients had not only higher serum ADMA levels but also higher (P<0.001) levels of hsCRP (12.4±1.6 mg/l) than Group I patients (7.2±4.2 mg/l) (Figure 1). Also, the fasting glucose, insulin, HOMA index, and SDMA levels of patients were significantly higher and total protein, albumin levels were significantly lower, in Group II when compared to those of Group I patients. Of note, serum ADMA concentrations in Group I patients without nephrotic range proteinuria were also significantly higher than those of healthy controls (1.48±0.32 vs 1.08±0.13 μmol/l, respectively, P<0.001) (Figure 1). In the aggregate (Group I and Group II patients), serum ADMA concentrations were associated with proteinuria levels (r=0.78, P<0.001) (Figure 2). Serum ADMA concentrations were also positively correlated with serum insulin levels (r=0.37, P=0.001), HOMA indexes (r=0.32, P=0.004) and hsCRP levels (r=0.61, P<0.001), and GFR (r=-0.360, P=0.001) and negatively correlated with serum albumin levels (r=-0.66, P<0.001). Serum SDMA concentrations were negatively correlated with GFR (r=-0.225, P=0.048), hsCRP (r=0.401, P<0.001), and proteinuria (r=0.497, P<0.001) (Figure 2). Other than ADMA and SDMA levels, the amount of proteinuria levels were also correlated with serum insulin (r=0.53, P<0.001), HOMA (r=0.55, P<0.001), and hsCRP levels (r=0.64, P<0.001). In order to clarify whether the association between ADMA and proteinuria was independent of other risk factors, we undertook a multiple regression analysis considering demographic factors (age and sex) and covariates that resulted to be associated with proteinuria in the univariate analysis (hsCRP and HOMA index) as well as the GFR. In this model, the association between ADMA and proteinuria was weaker than that observed in univariate analysis but still significant (Table 3). Levels of proteinuria (β=649, P<0.001) and hsCRP (β=0.199, P=0.033) were independently related to ADMA levels (Figure 3).Table 3Analysis of association between proteinuria and some different parameters by univariate and multivariate linear regressionParametersUnivariate β (P)MultivariateaTerminal model=0.593 × ADMA+0.295 × HOMA+0.148 × hsCRP. β (P)ADMA (μmol/l)0.78 (<0.001)0.59 (<0.001)HOMA0.55 (<0.001)0.29 (<0.001)hsCRP (mg/l)0.62 (<0.001)0.15 (0.068)GFR (ml/min/1.73 m2)−0.35 (0.002)—SBP (mm Hg)0.03 (0.823)—Total cholesterol (mg/dl)0.1 (0.388)—Age (year)−0.23 (0.145)—Sex0.07 (0.555)—ADMA, asymmetric dimethyl arginine; GFR, glomerular filtration rate; HOMA, homeostasis model assessment; hsCRP, high sensitive C reactive protein; SBP, systolic blood pressure.a Terminal model=0.593 × ADMA+0.295 × HOMA+0.148 × hsCRP. Open table in a new tab ADMA, asymmetric dimethyl arginine; GFR, glomerular filtration rate; HOMA, homeostasis model assessment; hsCRP, high sensitive C reactive protein; SBP, systolic blood pressure. As expected, because of the characteristics of selected patients, further adjustments for serum cholesterol and systolic BP did not materially change the strength of the association between ADMA and proteinuria. The risk of cardiovascular events is increased at an early stage in patients with renal disease.19.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8250) Google Scholar It was shown that even mild renal dysfunction and/or the presence of albuminuria is associated with increased cardiovascular mortality and morbidity.3.Jee S.H. Boulware L.E. Guallar E. et al.Direct, progressive association of cardiovascular risk factors with incident proteinuria: results from the Korea Medical Insurance Corporation (KMIC) study.Arch Intern Med. 2005; 165: 2299-2304Crossref PubMed Scopus (36) Google Scholar, 4.Tanihara S. Hayakawa T. Oki I. et al.NIPPON DATA Research Group. Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980–1999.J Epidemiol. 2005; 15: 146-153Crossref PubMed Scopus (18) Google Scholar, 20.Pontremoli R. Leoncini G. Ravera M. et al.Microalbuminuria, cardiovascular, and renal risk in primary hypertension.J Am Soc Nephrol. 2002; 13: S169-S172Crossref PubMed Google Scholar Several potential causative factors have been suggested to be responsible for this outcome, including endothelial dysfunction, vascular calcification, oxidative stress, and inflammation.9.Festa A. D'Agostino R. Howard G. et al.Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: the insulin resistance atherosclerosis study.Kidney Int. 2000; 58: 1703-1710Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 10.Barzilay J.I. Peterson D. Cushman M. et al.The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.Am J Kidney Dis. 2004; 44: 25-34Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 21.Deckert T. Feldt-Rasmussen B. Borch-Johnsen K. et al.Albuminuria reflects widespread vascular damage. The Steno hypothesis.Diabetologia. 1989; 32: 219-226Crossref PubMed Scopus (1260) Google Scholar Endothelial dysfunction is currently considered a critical step for the development of atherosclerosis.22.Bonetti P.O. Lerman L.O. Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk.Arterioscler Thromb Vasc Biol. 2003; 23: 168-175Crossref PubMed Scopus (1671) Google Scholar Albuminuria is considered as a marker of renal and systemic vascular damage.6.Stehouwer C.D. Henry R.M. Dekker J.M. et al.Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothelial dysfunction – the Hoorn Study.Kidney Int Suppl. 2004; 92: S42-S44Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 7.Jawa A. Nachimuthu S. Pendergrass M. et al.Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin converting enzyme inhibitor therapy.J Clin Endocrinol Metab. 2006; 91: 31-35Crossref PubMed Scopus (28) Google Scholar, 23.Paisley K.E. Beaman M. Tooke J.E. et al.Endothelial dysfunction and inflammation in asymptomatic proteinuria.Kidney Int. 2003; 63: 624-633Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Paisley et al.23.Paisley K.E. Beaman M. Tooke J.E. et al.Endothelial dysfunction and inflammation in asymptomatic proteinuria.Kidney Int. 2003; 63: 624-633Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar have shown that endothelial dysfunction is present in patients with asymptomatic proteinuria and attributed this alteration to altered regulation of nitric oxide system. On the other hand, dyslipidemia was implicated in the impaired endothelial functions of patients with nephrotic proteinuria.8.Watts G.F. Herrmann S. Dogra G.K. et al.Vascular function of the peripheral circulation in patients with nephrosis.Kidney Int. 2001; 60: 182-189Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Our study shows that ADMA, a competitive nitric oxide synthase inhibitor which seems to be involved in endothelial dysfunction in essential hypertension24.Perticone F. Sciacqua A. Maio R. et al.Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension.J Am Coll Cardiol. 2005; 46: 518-523Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar and which is increased in the early stages of chronic kidney disease (CKD),23.Paisley K.E. Beaman M. Tooke J.E. et al.Endothelial dysfunction and inflammation in asymptomatic proteinuria.Kidney Int. 2003; 63: 624-633Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar is strongly associated with proteinuria. Importantly, our findings obtained in a study population without overt dyslipidemia show that the link between ADMA and proteinuria in CKD is independent of hypercholesterolemia, that is, a typical finding in nephrotic syndrome and a factor which per se may increase serum ADMA levels.25.Boger R.H. Tsikas D. Bode-Boger S.M. et al.Hypercholesterolemia impairs basal nitric oxide synthase turnover rate: a study investigating the conversion of L-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate by gas chromatography–mass spectrometry.Nitric Oxide. 2004; 11: 1-8Crossref PubMed Scopus (43) Google Scholar ADMA is the major inhibitor of nitric oxide biosynthesis and its elevation is associated with endothelial dysfunction.12.Cooke J.P. Does ADMA cause endothelial dysfunction?.Arterioscler Thromb Vasc Biol. 2000; 20: 2032-2037Crossref PubMed Scopus (524) Google Scholar Increased plasma concentrations of ADMA have been described mainly in renal failure.15.Zoccali C. Bode-Boger S. Mallamaci F. et al.Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.Lancet. 2001; 358: 2113-2117Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar,16.Kielstein J.T. Boger R.H. Bode-Boger S.M. et al.Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.J Am Soc Nephrol. 2002; 13: 170-176PubMed Google Scholar Numerous other conditions including diabetes mellitus, hypercholesterolemia, hypertension, cardiac ischemia, and congestive heart failure have been described in association with high ADMA levels.26.Surdacki A. Nowicki M. Sandmann J. et al.Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension.J Cardiovasc Pharmacol. 1999; 33: 652-658Crossref PubMed Scopus (371) Google Scholar, 27.Boger R.H. Bode-Boger S.M. Szuba A. et al.Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia.Circulation. 1998; 98: 1842-1847Crossref PubMed Scopus (1062) Google Scholar, 28.Lin K.Y. Ito A. Asagami T. et al.Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase.Circulation. 2002; 106: 987-992Crossref PubMed Scopus (607) Google Scholar, 29.Usui M. Matsuoka H. Miyazaki H. et al.Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure.Life Sci. 1998; 62: 2425-2430Crossref PubMed Scopus (206) Google Scholar, 30.Miyazaki H. Matsuoka H. Cooke J.P. et al.Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis.Circulation. 1999; 99: 1141-1146Crossref PubMed Scopus (704) Google Scholar Our findings indicate that proteinuria is another factor strongly associated with high ADMA. A relationship between ADMA and proteinuria was noted in a recent cohort study by Fliser et al.14.Fliser D. Kronenberg F. Kielstein J.T. et al.Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study.J Am Soc Nephrol. 2005; 16: 2456-2461Crossref PubMed Scopus (290) Google Scholar in patients with CKD and mild proteinuria (average 24 h protein excretion 0.9 g) and mild to moderate CKD. The strength of this association was much weaker (r=0.18) than that observed in the present study (r=0.77), which dealt with patients with normal GFR (average 115 ml/min) and more severe proteinuria (average 3.7 g/24 h). Thus, our data suggest that proteinuria is an important determinant of ADMA at a very early stage of renal disease and that this association may be confounded by reduced renal excretion of this dimethylarginine when renal insufficiency supervenes. ADMA interacts in a complex way with traditional and non-traditional risk factors.31.Kielstein J.T. Zoccali C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age?.Am J Kidney Dis. 2005; 46: 186-202Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar,32.Stuhlinger M.C. Abbasi F. Chu J.W. et al.Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.JAMA. 2002; 287: 1420-1426Crossref PubMed Scopus (537) Google Scholar Proteinuria is now considered as a major cardiovascular risk factor,3.Jee S.H. Boulware L.E. Guallar E. et al.Direct, progressive association of cardiovascular risk factors with incident proteinuria: results from the Korea Medical Insurance Corporation (KMIC) study.Arch Intern Med. 2005; 165: 2299-2304Crossref PubMed Scopus (36) Google Scholar,4.Tanihara S. Hayakawa T. Oki I. et al.NIPPON DATA Research Group. Proteinuria is a prognostic marker for cardiovascular mortality: NIPPON DATA 80, 1980–1999.J Epidemiol. 2005; 15: 146-153Crossref PubMed Scopus (18) Google Scholar but the relationship between ADMA and proteinuria has hitherto received little attention. The question is of relevance because mechanism(s) conducive to cardiovascular risk in proteinuric patients are still incompletely understood. Increased ADMA appears to be a potential link between proteinuria and endothelial dysfunction and atherosclerotic complications. It is important to note that, in our study, ADMA levels increased in parallel to the elevation of insulin levels, HOMA, and hsCRP. Previously, the association between insulin sensitivities and ADMA levels was reported in healthy adults.32.Stuhlinger M.C. Abbasi F. Chu J.W. et al.Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.JAMA. 2002; 287: 1420-1426Crossref PubMed Scopus (537) Google Scholar The data about the relationship between ADMA and inflammation were also mentioned both in patients with end-stage renal disease and chronic cytomegalovirus infection.33.Zoccali C. Benedetto F.A. Maas R. et al.CREED Investigators. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease.J Am Soc Nephrol. 2002; 13: 490-496Crossref PubMed Google Scholar,34.Weis M. Kledal T.N. Lin K.Y. et al.Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis.Circulation. 2004; 109: 500-505Crossref PubMed Scopus (125) Google Scholar These associations may potentially confound the interpretation of the ADMA proteinuria link because proteinuria per se is also associated both with high CRP and reduced insulin sensitivity. Although the link between ADMA and proteinuria remains to be specifically investigated in mechanistic and intervention studies, the multiple regression analysis showing that proteinuria is an independent correlate of ADMA suggests that this link is not the mere result of the confounding effect of inflammation and insulin resistance. There may be several scenarios to explain the relationship between proteinuria and ADMA elevation. Proteinuria is a state of increased protein turnover. When proteins undergo proteolysis, free methylarginines (ADMA and SDMA) are released as recently described for states of increased protein metabolism and insulin resistance.35.Marliss E.B. Chevalier S. Gougeon R. et al.Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover.Diabetologia. 2006; 49: 351-359Crossref PubMed Scopus (112) Google Scholar The association between the proteinuria and SDMA levels in the present study strengthens this notion. In addition, the positive correlation between the ADMA and albumin levels may point out another mechanism of" @default.
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• W2037709367 title "ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease" @default.
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• W2037709367 doi "https://doi.org/10.1038/sj.ki.5001632" @default.
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