dimethylarginine and Kidney-Diseases

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Topics: Arginine; Disease Progression; Humans; Kidney Diseases

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as a putative biomarker in cardiovascular and renal disease. Elevated plasma levels of ADMA are the consequence of increased synthesis, reduced renal clearance or reduced enzymatic degradation. Based upon the metabolic fate the highest plasma concentrations of ADMA have been reported in patients with renal failure in whom this molecule accumulates. However, the range of published ADMA levels in patients with chronic renal failure as well as in patients with end-stage renal failure undergoing maintenance hemodialysis, peritoneal dialysis or kidney transplant recipients is widely scattered and overlaps with the levels reported in healthy individuals. This wide distribution can in part be explained by different bioanalytical techniques and the lack of standardization of such assays. This review summarizes available literature on ADMA in patients with kidney disease and stresses the urgent need for a consensus regarding reference values for different analytical methods in order to appreciate the prognostic significance of elevated ADMA levels. At present, one cannot advocate this molecule for risk assessment or individual patient prognosis in the clinical work-up of patients with renal impairment.

Topics: Adult; Aged; Animals; Arginine; Biomarkers; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nephrology; Reference Values; Reproducibility of Results

This review summarizes current knowledge on asymmetric dimethylarginine, renal function in health and disease, and renal disease progression and examines interventions that may modify the plasma concentration of this methylarginine.. Nitric oxide deficiency may occur in patients with chronic kidney disease and may contribute to accelerate progression of chronic kidney disease, hypertension and cardiovascular complications. An increase of endogenous nitric oxide inhibitors like asymmetric dimethylarginine seems to play a major role in this process. The kidneys are crucial in both, in re-absorbing and generating L-arginine as well as in eliminating asymmetric dimethylarginine primarily by the enzyme dimethylarginine dimethylaminohydrolase and to a minor degree by urinary excretion. Asymmetric dimethylarginine accumulation predicts both accelerated renal function loss and death in patients with chronic kidney disease and incident cardiovascular complications in patients with end stage renal disease.. Asymmetric dimethylarginine is a new risk factor potentially implicated in the progression of renal insufficiency and in the high rate of cardiovascular complications of patients with chronic kidney disease.

Topics: Arginine; Enzyme Inhibitors; Humans; Kidney Diseases; Nitric Oxide; Nitric Oxide Synthase; Sodium

Although the high risk for cardiovascular events in patients with end-stage renal disease (ESRD) is well known, recent data provide compelling evidence that even mild to moderate kidney disease is an important and independent risk factor for cardiac events. This increased risk does not seem to be explained by traditional risk factors as defined by the Framingham cohort. The examination of nontraditional risk factors has resulted in the identification of, among others, oxidant stress, hyperhomocystinemia, carbamylation, nitric oxide synthase inhibitors, and abnormal lipoproteins as potential pathways to explain the accelerated atherosclerosis in patients with kidney disease. Well-designed clinical trials should lead to the clarification of the relative importance of these factors in the pathogenesis of atherosclerotic disease.

Topics: Arginine; Cardiovascular Diseases; Humans; Hyperhomocysteinemia; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Lipoproteins; Lipoproteins, LDL; Nitric Oxide Synthase; Oxidative Stress; Proteinuria; Renal Dialysis; Risk Factors

Equations used to estimate glomerular filtration rate (GFR) are not accurate in patients with cirrhosis. We aimed to develop a new equation to estimate the GFR in subjects with cirrhosis and compare its performance with chronic kidney disease epidemiology collaboration (CKD-EPI) cystatin C and creatinine-cystatin C equations, which were derived in populations without cirrhosis.. From 2010 through 2014, we measured GFR in 103 subjects with cirrhosis based on non-radiolabeled iothalamate plasma clearance. We measured blood levels of creatinine, cystatin C, β-trace protein, β2-microglobulin, L-arginine, and symmetric and asymmetric dimethylarginines simultaneously with GFR. Multivariate linear regression analysis was performed to develop models to estimate GFR. Overall accuracy, defined by the root mean square error (RMSE) of our newly developed model to estimate GFR, was compared with that of the CKD-EPI equations. To obtain an unbiased estimate of our new equation to estimate GFR, we used a leave-one-out cross-validation strategy.. After we considered all the candidate variables and blood markers of GFR, the most accurate equation we identified to estimate GFR included serum levels of creatinine and cystatin C, as well as patients' age, sex, and race. Overall, the accuracy of this equation (RMSE = 22.92) was superior to that of the CKD-EPI cystatin C equation (RMSE = 27.27, P = .004). Among subjects with cirrhosis and diuretic-refractory ascites, the accuracy of the equation we developed to estimate GFR (RMSE = 19.36) was greater than that of the CKD-EPI cystatin C (RMSE = 27.30, P = .003) and CKD-EPI creatinine-cystatin C equations (RMSE = 23.37, P = .004).. We developed an equation that estimates GFR in subjects with cirrhosis and diuretic-refractory ascites with greater accuracy than the CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin C equation.

Topics: Adult; Aged; Arginine; Ascites; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Liver Cirrhosis; Male; Middle Aged

Renal disease is a risk factor for vascular diseases and for dementia, and renal insufficiency can be a feature of Alzheimer's disease (AD). Evidence has suggested that vascular mechanisms mediate the link between renal disease and dementia. Our study sought to test this hypothesis by examining renal and vascular functioning in AD by investigating estimated glomerular filtration rates (eGFR), calculated from serum creatinine concentrations, and established biomarkers of vascular functioning, asymmetrical dimethylarginine (ADMA) and plasma homocysteine (Hcy), in individuals with mild to moderate AD (n = 34) and a group of older adult controls (n = 34). We found significantly reduced eGFR, indicative of impaired renal functioning, in individuals with AD (M = 62.9, SD = 15.2) compared with controls (M = 73.6, SD = 11.8). However, concentrations of ADMA and Hcy did not differ between patient and control groups (ADMA: M = 0.47; M = 0.50; Hcy: M = 17.2; M = 14.9; patients and controls). The criteria for a mediation analysis were not met, as concentrations of ADMA and Hcy did not predict AD, indicating that these biomarkers of vascular functioning did not mediate a relationship between renal functioning and AD. This study indicated that renal insufficiency may independently contribute to AD pathology, and other vascular mechanisms may influence a relationship between renal impairment and AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Arginine; Biomarkers; Case-Control Studies; Creatinine; Female; Glomerular Filtration Rate; Homocysteine; Humans; Kidney Diseases; Male; Mental Status Schedule; Multivariate Analysis; Risk Factors; Vascular Diseases

Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.

Topics: Adult; Animals; Arginine; Arterial Pressure; Atherosclerosis; Child; Endothelium; Humans; Hypertension; Immunity, Innate; Inflammation Mediators; Kidney Diseases; Lipoproteins, HDL; Mice; Mice, Inbred C57BL; Nitric Oxide; Signal Transduction; Superoxides; Toll-Like Receptor 2; Wound Healing

Dimethylarginines are inhibitors of NO synthesis and are involved in the pathogenesis of vascular diseases. In this study, we ask the question if asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels change during fatal and reversible acute rejection, and contribute to the pathogenesis of chronic vasculopathy.. The Dark Agouti to Lewis rat strain combination was used to investigate fatal acute rejection. Fischer 344 kidneys were transplanted to Lewis rats to study reversible acute rejection episode and the process of chronic rejection. Isograft recipients and untreated Lewis rats were used as controls. l-arginine derivatives were determined by HPLC, and ADMA-metabolizing enzymes were studied by quantitative RT-PCR and western blotting.. Renal transplantation transiently increased dimethylarginine levels independent of acute rejection. ADMA plasma levels did not importantly differ between recipients undergoing fatal or reversible acute rejection, whereas SDMA was even lower in recipients of Fisher 344 grafts. In comparison to isograft recipients, ADMA and SDMA levels were slightly elevated during reversible, but not during the process of chronic rejection. Increased dimethylarginine levels, however, did not block NO synthesis. Interestingly, protein methylation, but not ADMA degradation, was increased in allografts.. Our data do not support the concept that renal allografts are protected from fatal rejection by dimethylarginines. Dimethylarginines may play a role in triggering chronic rejection, but a contribution to vascular remodelling itself is improbable. In contrast, differential arginine methylation of yet unknown proteins by PRMT1 may be involved in the pathogenesis of acute and chronic rejection.

Topics: Acute Disease; Animals; Arginine; Blotting, Western; Chronic Disease; Graft Rejection; Immunoenzyme Techniques; Kidney Diseases; Kidney Transplantation; Male; Nitrates; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Protein-Arginine N-Methyltransferases; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transplantation, Homologous

As an endogenous inhibitor of nitric oxide production, asymmetric dimethylarginine (ADMA) is reported to be associated with coronary artery disease (CAD).. We measured plasma levels of ADMA, nitrate + nitrite (NOx), total homocysteine (tHCY), and renal function in 106 people with angiographic evidence of coronary artery disease (CAD), including 46 with single vessel disease and 60 with double/triple vessel disease, and in 70 age-matched individuals without any angiography evidence of CAD. Also the levels of these parameters were evaluated according to their history of MI. Plasma tHcy and ADMA were measured by HPLC and the levels of NOx using the Griess reaction.. Levels of ADMA, ACE and tHcy levels were significantly higher and NO level was significantly lower in CAD patients compared with controls but there were no significant differences among patients with or without history of MI and between patients with single compared to those with double/triple vessel disease. Additionally a negative correlation was found between ADMA-NOx (r = -0.396, p = 0.001) and between tHcy-NOx (r = -0.262, p = 0.027). In the entire study group, ADMA level was significantly higher in patients with creatinine clearance (CrCl) < 91 mL/min than in patients with CrCl > or = 91 mL/min (0.60 +/- 0.23 micromoles/L versus 0.49 +/- 0.25 micromoles/L, p = 0.05).. We suggest that there is an abnormal plasma ADMA-to-NO balance in patients with documented CAD and that this may be due at least in part to an associated reduction in renal function.

Topics: Aged; Arginine; Case-Control Studies; Coronary Artery Disease; Female; Homeostasis; Homocysteine; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Nitric Oxide

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ-or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.

Topics: Amidohydrolases; Animals; Arginine; Capillaries; Chronic Disease; Disease Models, Animal; Disease Progression; Fibrosis; Gene Expression Regulation, Enzymologic; Genetic Therapy; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

The aim of this study was to investigate the possible relationship among dimethylarginines (asymmetric, ADMA; symmetric, SDMA) and homocysteine (Hcy) levels in subjects affected by chronic, mild to intermediate, hyperhomocysteinemia. ADMA and SDMA were assayed by an optimised HPLC method in 75 patients (Hcy = 20.8 micromol/L, 17.1-30.2; median and percentile range) and, for comparison, in 85 healthy subjects (Hcy = 8.0 micromol/L, 7.0-9.1). In controls, the cut-off values were set at 0.61 micromol/L for ADMA and 0.56 or 0.48 micromol/L for male and female SDMA, respectively. In patients, ADMA and SDMA levels were increased (p < 0.001) with respect to controls, but no correlation with Hcy was observed. Hyperhomocysteinemic subjects showed a different behaviour in respect to ADMA and SDMA levels and this allowed their stratification in 3 subgroups characterized by ADMA and SDMA in the normal range, only SDMA, or both ADMA and SDMA over the cut-off values. A lack of correlation with Hcy was again observed, thus minimizing the direct role of Hcy on ADMA and SDMA metabolism and suggesting the need for further studies on this issue.

Topics: Adult; Arginine; Chronic Disease; Female; Homocysteine; Humans; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests