Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients
2009; Elsevier BV; Volume: 77; Issue: 1 Linguagem: Inglês
10.1038/ki.2009.382
ISSN1523-1755
AutoresSadollah Abedini, Andreas Meinitzer, Ingar Holme, Winfried März, Gisela Weihrauch, Bengt Fellström, Alan G. Jardine, Hallvard Holdaas,
Tópico(s)Heart Failure Treatment and Management
ResumoIncreased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients. Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients. Patient and graft survival after renal transplantation has improved considerably over the recent decades. Current 5- and 10-year patient survival rates are around 85 and 66%, and allograft half-lives have improved from 7.7 years in the mid 1980s to 10.9 years in mid 1990s.1.McCullough K.P. Keith D.S. Meyer K.H. et al.Kidney and pancreas transplantation in the United States, 1998–2007: access for patients with diabetes and end-stage renal disease.Am J Transplant. 2009; 9: 894-906Crossref PubMed Scopus (92) Google Scholar However, life expectancy of renal transplant recipients is still shortened and premature graft failure is a major clinical problem. We have previously shown that atherogenic lipids are risk factors for premature cardiac events in renal transplant recipients, and that this risk is reduced by lipid-lowering therapy.2.Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar,3.Holdaas H. Fellstrom B. Cole E. et al.Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study.Am J Transplant. 2005; 5: 2929-2936Crossref PubMed Scopus (261) Google Scholar However, despite statin treatment, the risk of major cardiac events (MACEs) in this population remains elevated. In addition to traditional cardiovascular (CV) risk factors, numerous modifiable, and non-modifiable risk factors have been proposed to contribute to the excessive CV risk in renal transplant recipients,4.Holdaas H. Preventing cardiovascular outcome in patients with renal impairment: is there a role for lipid-lowering therapy?.Am J Cardiovasc Drugs. 2005; 5: 255-269Crossref PubMed Scopus (9) Google Scholar,5.Kasiske B.L. Chakkera H.A. Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation.J Am Soc Nephrol. 2000; 11: 1735-1743PubMed Google Scholar and to the risk of allograft failure.6.Fellstrom B. Holdaas H. Jardine A.G. et al.Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial.Transplantation. 2005; 79: 205-212Crossref PubMed Scopus (53) Google Scholar One potential risk factor is asymmetric dimethylarginine (ADMA), an established risk factor for CV events and all-cause mortality in other populations,7.Young J.M. Terrin N. Wang X. et al.Asymmetric dimethylarginine and mortality in stages 3 to 4 chronic kidney disease.Clin J Am Soc Nephrol. 2009; 4: 1115-1120Crossref PubMed Scopus (75) Google Scholar which has not been investigated in transplant recipients. Asymmetric dimethylarginine has also been shown in patients with chronic kidney disease (CKD) to be an important risk factor for progression to end-stage renal disease and all-cause mortality.8.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 Asymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase and reduces nitric oxide (NO) generation,9.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar,10.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 thus inhibiting the beneficial effect of NO on vasodilatation, arterial stiffness, and endothelial function.11.Palmer R.M. Ferrige A.G. Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.Nature. 1987; 327: 524-526Crossref PubMed Scopus (8979) Google Scholar,12.Furchgott R.F. Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (9605) Google Scholar ADMA levels are inversely related to glomerular filtration rate (GFR) in patients with mild-to-moderate CKD,8.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,13.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 and elevated levels have been associated with CV events and death in patients receiving hemodialysis.14.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,15.Zoccali C. Benedetto F.A. Maas R. et al.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 Thus, ADMA may be a predictor for renal graft loss, CV events and all-cause mortality in patients with different stages of CKD. The contribution of ADMA for such events in renal transplant recipients is unknown. Basic patients and demographic data in Assessment of Lescol in Renal Transplantation (ALERT) and the extension ALERT have been published previously.2.Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar,16.Holdaas H. Fellstrom B. Holme I. et al.Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.J Cardiovasc Risk. 2001; 8: 63-71Crossref PubMed Scopus (74) Google Scholar Participants in the ALERT were renal transplant recipients with stable graft function for a mean duration of 4.5 years before randomization into the trail. The treatment arms in the ALERT study were comparable with regard to baseline demographic and clinical characteristic. There were no differences in ADMA values between placebo and fluvastatin arms. In this post hoc analysis, we separated the patients into ADMA quartiles according to ADMA levels. Estimated glomerular filtration (ml/min per 1.73 m2) was calculated by using the formula from the Modification of Diet in Renal Disease study.17.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (12275) Google Scholar The demographic data are summarized in Table 1. Patients in the different ADMA quartiles are comparable with regard to age, blood pressure, lipid levels, body mass index, and serum calcium and phosphate values. There was a tendency to increased serum creatinine and decreased estimated GFR with higher ADMA levels, although ADMA was only weakly but significantly correlated with serum creatinine (r=0.218, P=0.000) and as expected inversely correlated with estimated GFR (r=-0.193, P=0.000). Hypertension and use of antihypertensive drugs was also more common in patients with higher ADMA levels.Table 1Patients' demographic data in relation to ADMA quartiles in the extension ALERTADMAADMAADMAADMA1. Q2. Q3. Q4. Q≤0.690.70–0.770.78–0.85≥0.86N=476N=462N=450N=459Patients' demographics (N=1847)Mean (s.d.)Mean (s.d.)Mean (s.d.)Mean (s.d.) Age at baseline (years)47.3 (10.5)49.8 (11.1)50.3 (10.9)51.5 (10.8) Systolic BP (mm Hg)142.9 (18.3)143.8 (18.8)144.9 (19.4)146.1 (18.7) Diastolic BP (mm Hg)85.8 (9.2)85.7 (9.65)85.5 (10.1)85.5 (10.2) Total cholesterol (mmol/l)6.5 (1.2)6.6 (1.1)6.5 (1.1)6.4 (1.1) HDL cholesterol (mmol/l)1.4 (0.4)1.3 (0.4)1.3 (0.5)1.3 (0.4) LDL cholesterol (mmol/l)4.1 (1.0)4.3 (1.0)4.2 (1.0)4.1 (1.0) Triglycerides (mmol/l)2.2 (1.2)2.2 (1.1)2.2 (1.2)2.3 (1.2) Apolipoprotein B (mg/dl)116.8 (25.5)116.3 (24.6)115.3 (27.6)116.3 (24.7) Body mass index (kg/m2)25.5 (4.3)25.0 (4.2)25.7 (4.5)25.9 (4.7) Serum creatinine (μmol/l)133.9 (46.7)135.7 (41.7)145.6 (53.9)163.0 (60.8) Estimated GFR52.5 (17.2)50.5 (14.3)48.6 (16.0)44.1 (15.9) hs-CRP (mg/l)3.8 (7.0)3.2 (5.4)3.7 (6.7)4.6 (7.7) Calcium (mmol/l)2.4 (0.1)2.4 (0.2)2.4 (0.2)2.4 (0.2) Phosphate (mg/dl)3.5 (0.6)3.6 (0.7)3.5 (0.8)3.7 (0.8) ADMA μmol/l0.64 (0.04)0.73 (0.02)0.81 (0.02)0.95 (0.10)Transplant characteristics Time on dialysis (month)22.0 (37.0)25 (39.1)31.2 (47.4)33.9 (46.0) Age at last Tx41.8 (10.9)44.7 (11.4)45.4 (11.3)46.5 (11.2) Donor age (years)38.2 (15.4)40.9 (15.0)41.7 (15.2)43.8 (15.2) Total time on RRT (years)87.2 (56.1)86.1 (56.0)90.0 (60.1)93.0 (59.1) Living-donor Tx N (%)134 (28.2)102 (22.2)97 (21.6)84 (18.3) Cold ischemia time (h)19.9 (7.2)19.6 (7.7)19.4 (7.5)19.9 (7.8)Cardiovascular risk factorsN (%)N (%)N (%)N (%) Diabetes mellitus96 (20.2)83 (18.0)86 (19.2)83 (18.1) Hypertension331 (69.5)336 (73.0)343 (76.4)361 (78.6) Left-ventricular hypertrophy48 (10.1)61 (13.3)76 (16.9)89 (19.4) Chronic heart disease41 (8.6)36 (7.8)41 (9.1)55 (12.0) Smoking: previous180 (37.8)156 (33.9)156 (34.7)158 (34.4) Smoking: current64 (13.4)88 (19.1)90 (20.0)105 (22.9)Primary renal disease Glomerulonephritis186 (39.1)163 (35.4)172 (38.3)155 (33.8) PCKD62 (13.0)74 (16.1)64 (14.3)85 (18.5) Diabetic nephropathy73 (15.3)60 (13.0)51 (11.4)56 (12.2) Pyelo-interstitial nephritis56 (11.8)59 (12.8)63 (14.0)55 (12.0) Hypertension20 (4.2)30 (6.5)19 (4.2)19 (4.1) Vasculitis2 (0.4)6 (1.3)6 (1.3)4 (0.9) SLE10 (2.1)8 (1.7)5 (1.1)7 (1.5) Other case62 (13.0)47 (10.2)52 (11.6)71 (15.5) Unknown22 (4.6)24 (5.2)29 (6.5)23 (5.0)Concomitant medication β-Blockers267 (56.1)281 (61.1)282 (62.8)316 (68.8) Calcium antagonists329 (69.1)324 (70.4)321 (71.5)323 (70.4) ACE inhibitors or AT1-blockers238 (50.0)224 (48.7)220 (49.0)233 (50.8) Diuretics213 (44.7)245 (53.3)260 (57.9)315 (68.6) α-Blockers70 (14.7)69 (15.0)77 (17.1)100 (21.8) Nitrate34 (7.1)36 (7.8)37 (8.2)47 (10.2) ASA148 (31.1)163 (35.4)168 (37.4)175 (38.1) Cumarine/Warfarin31 (6.5)42 (9.1)36 (8.0)51 (11.1) Active D-vitamin56 (11.8)57 (12.4)71 (15.8)118 (25.7)Immunosuppressants Prednisolone368 (77.3)385 (83.7)382 (85.1)377 (82.1) Cyclosporine A467 (98.1)451 (98.0)442 (98.4)446 (97.2) Azathioprine333 (70.0)323 (70.2)284 (63.3)269 (58.6) Mycophenolate mofetil55 (11.6)76 (16.5)65 (14.5)81 (17.6)ACE, angiotensin-converting enzyme; ADMA, asymmetric dimethylarginine; ALERT, Assessment of Lescol in Renal Transplantation; ASA, acetyl salicylic acid; AT1, angiotensin II receptor blocker; BP, blood pressure; GFR, glomerular filtration rate; HDL, high-density lipoprotein; hsCRP, high sensitivity C-reactive protein; IL-6, interleukin-6; LDL, low-density lipoprotein; PCKD, polycystic kidney disease; PTH, parathyroid hormone; Q, quartile; RRT, renal replacement therapy; SLE, systemic lupus erythematosus; TX, renal transplantation. Open table in a new tab ACE, angiotensin-converting enzyme; ADMA, asymmetric dimethylarginine; ALERT, Assessment of Lescol in Renal Transplantation; ASA, acetyl salicylic acid; AT1, angiotensin II receptor blocker; BP, blood pressure; GFR, glomerular filtration rate; HDL, high-density lipoprotein; hsCRP, high sensitivity C-reactive protein; IL-6, interleukin-6; LDL, low-density lipoprotein; PCKD, polycystic kidney disease; PTH, parathyroid hormone; Q, quartile; RRT, renal replacement therapy; SLE, systemic lupus erythematosus; TX, renal transplantation. Incident rates for renal, cardiac, cerebrovascular (CBV) events and for all cause of death in each quartile of ADMA are summarized in Table 2. Differences between second and fourth ADMA quartiles versus first quartile were tested using log-rank test. P-values are given versus first quartile. Kaplan–Meier curves for survivors in each quartile of ADMA are shown in Figure 1Figure 2. Figure 2 shows relative risk for study outcomes within the asymmetric dimethylarginine (ADMA) quartiles compared with the first quartile.Table 2Event rates for outcomes by ADMA quartilesADMA 1.QADMA 2.QADMA 3.QADMA 4.Q≤690.70–0.770.78–0.850.86+End pointsN=476N=460N=449N=459GFDSC N (%)79 (16.6)87 (18.9)96 (21.4)137 (29.8)P-value—0.3960.047<0.001MACE N (%)62 (13.0)62 (13.5)70 (15.6)87 (18.9)P-value—0.8130.2160.005CDNFMI N (%)42 (8.8)43 (9.3)51 (11.4)71 (15.5)P-Value—0.7600.1720.001CBV events N (%)22 (4.60)45 (9.8)55 (12.3)52 (11.3)P-value—0.003<0.001<0.001All causes of death N (%)63 (13.9)71 (15.4)86 (19.2)123 (26.9)P-value—0.5490.038<0.001ADMA, asymmetric dimethylarginine; CBV, cerebrovascular; CDNFMI, cardiac death or non-fatal myocardial infarction; GFDSC, graft failure or doubling of serum creatinine; MACE, major adverse cardiovascular events; Q, quartile.Data expressed as number of patients in quartile/number of event (%). Significance versus first quartile. Open table in a new tab Figure 2Relative risk for study outcomes within the asymmetric dimethylarginine (ADMA) quartiles compared with the first quartile.x axis, ADMA quartiles 1–4; y axis, relative risk. CBV, cerebrovascular; CDNFMI, cardiac death or non-fatal myocardial infarction; GFDSC, graft failure or doubling of serum creatinine; MACE, major cardiac event. *Denotes significant difference in relative risk compared with ADMA in first quartile, P-value <0.05. Q, quartile.View Large Image Figure ViewerDownload (PPT) ADMA, asymmetric dimethylarginine; CBV, cerebrovascular; CDNFMI, cardiac death or non-fatal myocardial infarction; GFDSC, graft failure or doubling of serum creatinine; MACE, major adverse cardiovascular events; Q, quartile. Data expressed as number of patients in quartile/number of event (%). Significance versus first quartile. The number of graft failure or doubling of serum creatinine increased in higher ADMA quartiles, and was highly significant when the third and fourth quartile was compared with the first quartile. The number of graft failure and doubling of serum creatinine almost doubled (79 (16.6%) to 137 (29.8%), P<0.001) from the first to the fourth quartile. The number of MACE and cardiac death or non-fatal myocardial infarction increased in higher ADMA quartiles. These differences were statistically significant between the first and the fourth quartile. Rate of CBV events increased with increasing ADMA quartiles and the number of CBV events were more than doubled (3–4 to 11.0%) from the first to the fourth quartile. Number of all cause of death increased also by ADMA quartiles and the number of events was almost doubled (13.9 to 26.8%) in the fourth quartile compared with the first quartile. The results from the Cox risk factor analyses are summarized in Table 3. The hazard ratios (HR) with 95% confidence intervals (95% CI) and corresponding P-values are shown for all study outcomes. The univariate model included continuous ADMA values and study outcomes as dependent variable. The multivariate model was adjusted for potentially important baseline covariates such as age, gender, systolic blood pressure, previous CHD, diabetes mellitus, low-density lipoprotein cholesterol, smoking, and estimated GFR.Table 3Hazard ratios for ADMA by univariate and multivariate Cox proportional hazard models in 1847 renal transplant recipientsExtension ALERT study (placebo+fluvastatin)Study end pointsHR (95% CI) univariateP-valueHR (95 % CI) multivariateP-valueGFDSC10.50 (5.34–20.66)<0.0012.78 (1.22–5.82)0.009MACE4.41 (1.92–10.14)<0.0012.61 (1.03–6.61)0.042CDNFMI7.32 (2.88–18.65)<0.0014.90 (1.70–14.10)0.003Cerebrovascular events10.32 (3.79–28.07)<0.0017.63 (2.52–23.13)<0.000All-cause death9.25 (4.50–19.00)<0.0014.87 (2.12–11.18)<0.000ADMA, asymmetric dimethylarginine; CBV, cerebrovascular events; CDNFMI, cardiac death or non-fatal myocardial infarction; GFDSC, graft failure or doubling of serum creatinine; MACE, major adverse cardiovascular events.Hazard ratios were adjusted for clinically important covariates as age, gender, systolic blood pressure, previous CHD, diabetes mellitus, LDL-cholesterol, smoking, and serum creatinine in the multivariate Cox model. Open table in a new tab ADMA, asymmetric dimethylarginine; CBV, cerebrovascular events; CDNFMI, cardiac death or non-fatal myocardial infarction; GFDSC, graft failure or doubling of serum creatinine; MACE, major adverse cardiovascular events. Hazard ratios were adjusted for clinically important covariates as age, gender, systolic blood pressure, previous CHD, diabetes mellitus, LDL-cholesterol, smoking, and serum creatinine in the multivariate Cox model. In both univariate and multivariate analysis, ADMA is associated with all study end points. ADMA is an independent predictor of GFDSC (graft failure and doubling of serum creatinine): HR 2.78 (95% CI: 1.22–5.82, P=0.009), MACE: HR 2.61 (95% CI: 1.03–6.61, P=0.042), cardiac death or non-fatal myocardial infarction: HR 4.90 (95% CI: 1.70–14.10, P=0.003), CBV events: HR 7.63 (95% CI: 2.52–23.13, P<0.001), and all-cause death: HR 4.87 (95% CI: 2.12–11.18, P<0.000). This study is the first to report that plasma levels of ADMA are associated with increased incidence of MACE, cardiac death or non-fatal myocardial infarction, CBV events, all-cause mortality, and deterioration of graft function in renal transplant recipients. Our findings in this population mirror previous reports in patient with non-transplanted patients with or without CKD.18.Ueda S. Yamagishi S. Kaida Y. et al.Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease.Nephrology (Carlton). 2007; 12: 582-590Crossref PubMed Scopus (54) Google Scholar Epidemiological studies have suggested association between ADMA and hypertension,19.Matsuoka H. Itoh S. Kimoto M. et al.Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension.Hypertension. 1997; 29: 242-247Crossref PubMed Google Scholar hypercholesterolemia,20.Boger R.H. Bode-Boger S.M. 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Hinkel U.P. et al.Switch of immunosuppression from cyclosporine A to everolimus: impact on pulse wave velocity in stable de-novo renal allograft recipients.J Hypertens. 2008; 26: 2213-2219Crossref PubMed Scopus (41) Google Scholar,28.Strozecki P. Adamowicz A. Wlodarczyk Z. et al.The influence of calcineurin inhibitors on pulse wave velocity in renal transplant recipients.Ren Fail. 2007; 29: 679-684Crossref PubMed Scopus (17) Google Scholar Owing to the pre-existing endothelial dysfunction, renal transplant recipients are at high risk for deleterious effect of inhibitors of NO, such as ADMA. There is no established therapy for elevated ADMA, although rosiglitazone, amlodipine, and valsartan decrease ADMA level.28.Strozecki P. Adamowicz A. Wlodarczyk Z. et al.The influence of calcineurin inhibitors on pulse wave velocity in renal transplant recipients.Ren Fail. 2007; 29: 679-684Crossref PubMed Scopus (17) Google Scholar,29.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 Renal transplant recipients have numerous traditional and non-traditional risk factors for CV events, and although dyslipidemia-dependent CV events, such as myocardial infarction,2.Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar are reduced by lipid-lowering therapy, there is a considerable residual risk for cardiac mortality and morbidity in these patients. Although the procedure of renal transplantation may decrease the raised level associated with hemodialysis, ADMA is still increased in renal transplant recipients compared with healthy controls.30.Yilmaz M.I. Saglam M. Caglar K. et al.Endothelial functions improve with decrease in asymmetric dimethylarginine (ADMA) levels after renal transplantation.Transplantation. 2005; 80: 1660-1666Crossref PubMed Scopus (71) Google Scholar A raised level of ADMA in our study was associated with a higher incidence of CV events. In the highest quartile of ADMA, the incidence was approximately doubled compared with that in the lowest quartile. In heart transplant patients, elevated ADMA has been associated with coronary intimal hyperplasia; treatment with sirolimus rather than mycophenolate resulted in a significant decrease in ADMA levels and reduced risk of cardiac allograft vasculopathy.31.Potena L. Fearon W.F. Sydow K. et al.Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: modulation by sirolimus.Transplantation. 2008; 85: 827-833Crossref PubMed Scopus (21) Google Scholar The experience from the heart study and our study in renal transplant recipients strongly favor an association between ADMA levels and cardiac markers and cardiac end points. Renal transplant recipients also have an increased risk for a CBV disease and, although the risk factors for ischemic versus hemorrhagic stroke may vary, stroke occurrence is several times higher than the background population.32.Abedini S. Holme I. Fellstrom B. et al.Cerebrovascular events in renal transplant recipients.Transplantation. 2009; 87: 112-117Crossref PubMed Scopus (30) Google Scholar A somewhat surprising finding in our study was that ADMA was very strongly related to the occurrence of CBV events in this population. In healthy individuals, suppressor doses of ADMA increases arterial stiffness and decreases cerebral blood flow, and ADMA thus may be involved in the pathogenesis of CBV disease.33.Kielstein J.T. Donnerstag F. Gasper S. et al.ADMA increases arterial stiffness and decreases cerebral blood flow in humans.Stroke. 2006; 37: 2024-2029Crossref PubMed Scopus (178) Google Scholar In several papers, stroke is part of a composite CV end point, but is not reported separately.18.Ueda S. Yamagishi S. Kaida Y. et al.Asymmetric dimethylarginine may be a missing link between cardiovascular disease and chronic kidney disease.Nephrology (Carlton). 2007; 12: 582-590Crossref PubMed Scopus (54) Google Scholar,34.Leong T. Zylberstein D. Graham I. et al.Asymmetric dimethylarginine independently predicts fatal and nonfatal myocardial infarction and stroke in women: 24-year follow-up of the population study of women in Gothenburg.Arterioscler Thromb Vasc Biol. 2008; 28: 961-967Crossref PubMed Scopus (118) Google Scholar An association of stroke incidence and ADMA is therefore difficult to assess. To our knowledge, our study is the first to show a strong association between ADMA levels and stroke events. In patients with CKD, the levels of ADMA are increased compared with those in patients with normal renal function. Elevated ADMA level in the circulation are a combined result of impaired kidney function and a reduced activity of the enzymatic catabolism of ADMA by dimethylarginine dimethylaminohydrolase.35.Baylis C. Arginine, arginine analogs and nitric oxide production in chronic kidney disease.Nat Clin Pract Nephrol. 2006; 2: 209-220Crossref PubMed Scopus (163) Google Scholar Plasma level of ADMA is elevated in all types of patients with impaired renal function, with maximal (sevenfold) elevation in patient with end-stage renal disease treated by hemodialysis. About 60% of ADMA is removed during a hemodialysis session.9.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar, 36.Boger R.H. Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease.Atheroscler Suppl. 2003; 4: 23-28Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 37.Busch M. Fleck C. Wolf G. et al.Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease - possible candidates for paradoxical epidemiology?.Amino Acids. 2006; 30: 225-232Crossref PubMed Scopus (58) Google Scholar Numerous experimental study suggests that reduced NO activity is involved in progressive kidney damage in patients with CKD.38.Baylis C. Mitruka B. Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.J Clin Invest. 1992; 90: 278-281Crossref PubMed Scopus (703) Google Scholar, 39.Benigni A. Zoja C. Noris M. et al.Renoprotection by nitric oxide donor and lisinopril in the remnant kidney model.Am J Kidney Dis. 1999; 33: 746-753Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 40.Erdely A. Wagner L. Muller V. et al.Protection of wistar furth rats from chronic renal disease is associated with maintained renal nitric oxide synthase.J Am Soc Nephrol. 2003; 14: 2526-2533Crossref PubMed Scopus (60) Google Scholar, 41.Fujihara C.K. de N.G. Zatz R. Chronic nitric oxide synthase inhibition aggravates glomerular injury in rats with subtotal nephrectomy.J Am Soc Nephrol. 1995; 5: 1498-1507PubMed Google Scholar, 42.Kang D.H. Nakagawa T. Feng L. et al.Nitric oxide modulates vascular disease in the remnant kidney model.Am J Pathol. 2002; 161: 239-248Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar After successful renal transplantation, ADMA is decreased and is associated with an improvement in endothelial function, albeit without any effect on graft function.30.Yilmaz M.I. Saglam M. Caglar K. et al.Endothelial functions improve with decrease in asymmetric dimethylarginine (ADMA) levels after renal transplantation.Transplantation. 2005; 80: 1660-1666Crossref PubMed Scopus (71) Google Scholar In non-transplant patients with CKD Ravani et al.8.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 showed that ADMA was a strong and independent risk marker for progression to end-stage renal disease. There are numerous reports that ADMA is associated with progressive renal dysfunction and also with progression to end-stage renal disease, but no publication has assessed ADMA as a potential risk factor for graft failure. In our study, ADMA was, after adjustments for serum creatinine and proteinuria, independently associated with long-term deterioration of graft function in renal transplant patients. Potential limitations of our study merit considerations. Although we have shown a strong association between ADMA levels and clinical outcomes, the data do not imply a causal relationship. Erythropoietin use was not registered in our database. Erythropoietin might influence endothelial cell production of ADMA,43.Scalera F. Kielstein J.T. Martens-Lobenhoffer J. et al.Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase.J Am Soc Nephrol. 2005; 16: 892-898Crossref PubMed Scopus (86) Google Scholar however, that is not likely to be a major concern in this stable cohort of renal transplant recipients with a rather well-preserved renal function after transplantation. The patients in fourth quartile had more comorbid conditions compared with patients in the first quartile, and this was reflected in increased ADMA concentrations. The strength of the study is the randomized control design, the long follow-up time and the independent adjudication of all clinical end points. In conclusion, this is the first study to report that ADMA levels are associated with deterioration of graft function, cardiac death and non-fatal myocardial infarction, CBV events, and mortality in renal transplant recipients. Increased levels of ADMA might explain some of the excess CV morbidity and mortality, and should be target for future investigations in this population. ADMA levels may be used in risk stratification and identification of renal transplant recipients at high risk of CV disease and graft loss, and may be modifiable by treatment. Clinical trials to assess the potential of therapeutic reductions in ADMA level on CV and renal end points will be eagerly awaited in this population, as ADMA might be associated with adverse outcomes. The ALERT study design and baseline data have been described previously.16.Holdaas H. Fellstrom B. Holme I. et al.Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.J Cardiovasc Risk. 2001; 8: 63-71Crossref PubMed Scopus (74) Google Scholar Briefly, ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40–80 mg daily, on cardiac and renal outcomes in 2102 renal transplant recipients over a follow-up period of 5–6 years. Eligible patients were men and women aged 30–75 years, who had received a renal transplant more than 6 months earlier and had a serum total cholesterol concentration between 4.0 and 9.0 mmol/l (155–348 mg/dl). Patients were excluded if they were on statin therapy, had familial hypercholesterolemia, or had experienced an acute rejection episode in the 3 months before randomization. In addition, patients with a predicted life expectancy of less than 1 year were excluded. Of 1787 patients who completed ALERT, 1652 (92%) were offered open-label fluvastatin 80 mg/dag in a 2-year extension to the original study. Mean total follow-up time in the extension study was 6.7 years.3.Holdaas H. Fellstrom B. Cole E. et al.Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study.Am J Transplant. 2005; 5: 2929-2936Crossref PubMed Scopus (261) Google Scholar The study adhered to the International Conference on Harmonization guidelines for Good Clinical Practice and is in accordance with the Declaration of Helsinki Principles. All participants provided written informed consent, and the ethics committee at each participating center approved the trial. Renal end point was the time to GFDSC. Cardiac end point was MACE and was defined as cardiac death, non-fatal myocardial infarction, or coronary intervention procedure. CBV event was defined as any CBV event, including fatal and non-fatal stroke. All end points were validated by an independent clinical end point committee blinded to study drug allocation.2.Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar,16.Holdaas H. Fellstrom B. Holme I. et al.Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.J Cardiovasc Risk. 2001; 8: 63-71Crossref PubMed Scopus (74) Google Scholar Inclusion laboratory values of the ALERT trial are reported previously.16.Holdaas H. Fellstrom B. Holme I. et al.Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.J Cardiovasc Risk. 2001; 8: 63-71Crossref PubMed Scopus (74) Google Scholar ADMA levels were measured in blood samples obtained at inclusion in 1847 patients.16.Holdaas H. Fellstrom B. Holme I. et al.Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.J Cardiovasc Risk. 2001; 8: 63-71Crossref PubMed Scopus (74) Google Scholar ADMA was measured in frozen serum (-80°C) with reversed-phased HPLC (high-performance liquid chromatography).44.Teerlink T. Nijveldt R.J. de J.S. et al.Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography.Anal Biochem. 2002; 303: 131-137Crossref PubMed Scopus (371) Google Scholar In the initial analysis, the treatment and placebo arms were analyzed separately for clinical events. As the two arms showed no significant heterogeneity in relationships between ADMA as a risk factor and event outcome, subsequent analysis was performed on the pooled patient population. SPSS version 16.0 (2008 SPSS, Chicago, USA) was used for statistical analysis. For normally distributed variables, mean and s.d. are presented. Demographic and clinical baseline characteristics were compared using independent samples t-test and χ2-test for continuous and categorical variables, respectively. A Cox proportional hazard model was used to analyze the relationship between risk factors and time to event for all end points. All covariates were carefully examined and fulfilled the assumptions of proportionality of HR in the Cox hazard models. Univariate and multivariate analysis were then carried out to determine the association of ADMA with cardiac and renal events (GFDSC, major adverse cardiac events (MACE—myocardial infarction, cardiac death, and coronary interventions), cardiac death and non-fatal myocardial infarction, all-cause mortality, and CBV events). Corresponding HR for group comparisons were calculated with 95% confidence limits.
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