Symmetric Dimethylarginine Concentrations Research Articles

Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: high plasma levels as combined risk markers for sepsis survival

BackgroundNitric oxide (NO) regulates processes involved in sepsis progression, including vascular and immune function. NO is generated by nitric oxide synthases (NOS) from L-arginine. Cellular L-arginine uptake is inhibited by symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) is a competitive inhibitor of NOS. Increased inhibitor blood concentrations lead to reduce NO bioavailability. The aim of this study was to determine whether plasma concentrations of SDMA and ADMA are markers for sepsis survival.MethodThis prospective, single center study involved 120 ICU patients with sepsis. Plasma SDMA and ADMA were measured on admission (day 1), day 3 and day 7 by mass spectrometry together with other laboratory markers. The sequential organ failure assessment (SOFA) score was used to evaluate sepsis severity. Survival was documented until day 28. Groups were compared using the Mann-Whitney U test, chi-squared test or non-parametric analysis of variance (ANOVA). Mortality was assessed using Kaplan-Meier curves and compared using the log-rank test. Specific risk groups were identified using a decision tree algorithm.ResultsMedian plasma SDMA and ADMA levels were significantly higher in non-survivors than in survivors of sepsis: SDMA 1.14 vs. 0.82 μmol/L (P = 0.002) and ADMA 0.93 vs. 0.73 μmol/L (P = 0.016). ANOVA showed that increased plasma SDMA and ADMA concentrations were significantly associated with SOFA scores. The 28-day mortality was compared by chi-square test: for SDMA the mortality was 12% in the lower, 25% in the intermediate and 43% in the 75th percentile (P = 0.018); for ADMA the mortality was 18–20% in the lower and intermediate but 48% in the 75th percentile (P = 0.006). The highest mortality (61%) was found in patients with plasma SDMA > 1.34 together with ADMA levels > 0.97 μmol/L.ConclusionsIncreased plasma concentrations of SDMA and ADMA are associated with sepsis severity. Therefore, our findings suggest reduced NO bioavailability in non-survivors of sepsis. One may use individual SDMA and ADMA levels to identify patients at risk. In view of the pathophysiological role of NO we conclude that the vascular system and immune response are most severely affected when SDMA and ADMA levels are high.

Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy.

Background: Fabry disease (FD) is characterized by early development of vasculopathy and endothelial dysfunction. However, it is unclear whether these findings also play a pivotal role in cardiac manifestation. As Fabry cardiomyopathy (FC) is the leading cause of death in FD, we aimed to gather a better insight in pathological mechanisms of the disease.Methods: Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of >12 mm in cardiac magnetic resonance imaging and serum level of proBNP, high sensitive Troponin T (hsT), and globotriaosylsphingosine (lyso-GB3) were obtained. A multiplex ELISA-Assay for 23 different angiogenesis markers was performed in pooled samples. Markers showing significant differences among groups were further analyzed in single samples using specific Elisa antibody assays. L-homoarginine (hArg), L-arginine, asymmetric (ADMA), and symmetric Dimethylarginine (SDMA) were quantified by liquid chromatography—mass spectrometry.Results: Angiostatin and matrix metalloproteinase 9 (MMP-9) were elevated in FD patients compared to controls independently of the presence of FC (angiostatin: 98 ± 25 vs. 75 ± 15 ng/mL; p = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 μg/mL; p = 0.002). SDMA concentrations were highest in patients with FC (0.90 ± 0.64 μmol/l) compared to patients without (0.57 ± 0.10 μmol/l; p = 0.027) and vs. controls (0.58 ± 0.12 μmol/l; p = 0.006) and was positively correlated with indexed LV-mass (r = 0.61; p = 0.003), hsT (r = 0.56, p = 0.008), and lyso-Gb3 (r = 0.53, p = 0.013). Accordingly, the ratio of L-homoarginine to SDMA (hArg/SDMA) was lowest in patients with FC (2.63 ± 1.78) compared to controls (4.16 ± 1.44; p = 0.005). For L-arginine, hArg and ADMA no significant differences among groups could be detected, although a trend toward higher ADMA and lower hArg levels could be observed in the FC group. Furthermore, a significant relationship between kidney and cardiac function could be revealed (p = 0.045).Conclusion: Elevated MMP-9 and angiostatin levels suggest an increased extracellular matrix turnover in FD patients. Furthermore, endothelial dysfunction may also be involved in FC, as SDMA and hArg/SDMA are altered in these patients.

Establishment of reference intervals for serum symmetric dimethylarginine in adult nonracing Greyhounds.

The reference intervals (RIs) for the renal biomarkers urea and creatinine, in Greyhounds, are higher than those for non-sighthound breeds. A recent study has demonstrated a higher concentration of another biomarker of renal function, symmetric dimethylarginine (SDMA), in Greyhounds compared with other dog breeds, and thus a breed-specific RI for serum SDMA may be appropriate for Greyhounds. Greyhounds appear to be predisposed to renal disease, and the establishment of an appropriate RI for SDMA may improve the ability to identify early renal dysfunction in this breed. The aim of this study was to establish an RI for serum SDMA in nonracing Greyhounds and to determine whether the RI for Greyhounds is different from that of non-sighthound breeds. Blood samples were collected from 101 clinically healthy, nonracing Greyhounds for serum SDMA measurements. Results from Greyhounds were compared with serum SDMA concentrations measured in a group of non-sighthound dogs (n=24) of similar weight, age, and sex, and with a previously established canine serum SDMA RI. The serum SDMA RI for Greyhounds was 6.3-19.9μg/dL (0.31-0.99μmol/L). Greyhounds had a significantly higher mean value (13.1μg/dL) than that of the non-sighthound dogs (10.2μg/dL) (P<.001), and the RI of Greyhounds was different from previously established canine RIs for SDMA. This study supports the use of a Greyhound-specific RI for SDMA. Using previously established canine RIs for this breed could result in the overdiagnosis of renal disease.

Histoplasmose pulmonar grave em um gato doméstico: tratamento com Anfotericina B e Itraconazol

Background: Histoplasmosis is a systemic mycosis whose etiologic agent is the fungus Histoplasma capsulatum. This fungal infection, which is the second most frequent systemic mycotic fungal disease in felines in the United States, has rarely been found in cats in Brazil. This paper reports on a case of acute pulmonary histoplasmosis in a domestic cat treated with oral itraconazole associated with amphotericin B administered subcutaneously. This treatment resulted in clinical remission of the patient’s symptoms, as evidenced by radiographic follow-ups.Case: A domestic cat suffering from acute dyspnea was taken to a veterinary clinic. The animal was subjected to emergency oxygen therapy, and kept at rest through sedation with midazolam. A physical examination revealed normally colored mucosa, 8% dehydration, bristly fur, body condition score 2/9, tachypnea with respiratory rate of 100 breaths per minute and expiratory dyspnea. The radiographic examination showed marked opacification of all the pulmonary fields, with a mixed pattern (interstitial and alveolar) of heterogeneous appearance and diffuse distribution, which are changes consistent with an inflammatory infectious process (pneumonia). A cytological analysis of the pleural fluid revealed round to oval-shaped intracytoplasmic structures, varying in size from 2 to 4 μm, inside foamy macrophages, consistent with Histoplasma capsulatum. Based on the diagnosis of pulmonary histoplasmosis, and in view of the patient’s acute respiratory distress, it was decided to treat the cat using itraconazole associated with amphotericin B. Itraconazole was administered orally at a dose of 100 mg/cat every 24 h, while amphotericin B was administered subcutaneously at a dose of 0.5 mg/kg, combined with 100 mL of sodium chloride 0.9% and 100 mL of 5% glycated serum, with monitoring of serum concentrations of symmetric dimethylarginine (SDMA). Amphotericin B was administered every 48 h up to the 7th dose, followed by three times a week up to the 11th dose, and then twice a week up to the 16th dose. The animal was released from the veterinary hospital 10 days after its admission, showing a considerably improved respiratory condition and a respiratory rate of 40 breaths per minute. Continuation of the antifungal treatment with itraconazole was prescribed, maintaining the same dose and frequency of administration until a new recommendation would be made, as well as frequent return visits for the administration of amphotericin B and reassessment of the animal. The administration of amphotericin B was discontinued when the animal’s respiratory condition stabilized; hence, the feline received a total of 16 doses of the drug. The animal showed remission of clinical respiratory symptoms, confirmed by follow-up chest X-rays, which revealed significantly less radiodense pulmonary parenchyma in response to treatment with itraconazole and amphotericin B. Five months after beginning its treatment, the cat is being treated orally with itraconazole (100 mg/cat, every 24 h), without recrudescence of the clinical symptoms.Discussion: To date, six cases of feline histoplasmosis have been reported in Brazil, only one of which had pulmonary involvement and was treated successfully. The use of oral itraconazole associated with subcutaneous amphotericin B has proved to be effective for the treatment of acute pulmonary histoplasmosis in domestic cats. Note that a rapid diagnosis of pulmonary disease is essential in order to immediately implement a combined drug therapy linked with monitoring to ensure the protocol is safe for the patient

A simple reversed‐phase HPLC method for the estimation of dimethylarginines and homocysteine in plasma and serum

AbstractElevated concentrations of asymmetric dimethylarginine, symmetric dimethylarginine and homocysteine are considered as common risk factors for cardiovascular diseases. A simple reversed‐phase high‐performance liquid chromatography method has been developed to simultaneously detect these biomarkers in plasma and serum. Straightforward sample preparation involves direct derivatization of deproteinized serum/plasma with phenyl isothiocyanate. Dimethylarginines and homocysteine are resolved using a 250 × 4.6 mm I.D, C18 column and a linear gradient of sodium acetate buffer/acetonitrile. Calibration curves of peak area verses concentration are linear with correlation coefficients near unity. The intraday and interday precisions measured by coefficient of variation of peak areas were 1.34–9.7, 2.7–6.7 and 0.3–7.1 for asymmetric dimethylarginine, symmetric dimethylarginine and homocysteine, respectively. The recoveries of asymmetric dimethylarginine, symmetric dimethylarginine and homocysteine are above 86%. Minimal sample preparation, good recoveries and fast run time makes this method suitable for the analysis of plasma and serum.

Serum concentrations of asymmetric and symmetric dimethylarginine are associated with mortality in acute heart failure patients

BackgroundSerum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine are established predictors of total and cardiovascular mortality. However, the predictive capacity of ADMA and SDMA for hospital and 3-months mortality of patients with acute heart failure (AHF) is unknown. Methods & resultsOut of 152 included AHF patients, 79 (52%) were female, and the mean patient age was 75.2 ± 10.3 years. Hospital and three-month mortality rates were 14.5% and 27.4%, respectively. Serum ADMA and SDMA levels at admission, determined by reversed phase high performance liquid chromatography, were higher in patients having at least one of the three signs implying venous volume overload (enlarged liver, ascites, peripheral edema), a consequence of right-sided heart failure, compared to patients without those signs. Univariable logistic regression analyses revealed a significant positive association of ADMA and SDMA concentrations with hospital mortality [odds ratio (OR) and 95% confidence interval (CI) per standard deviation (SD) increase: 2.22 (1.37–3.79), p = 0.002, and 2.04 (1.34–3.18), p = 0.001, respectively], and 3-months mortality [2.06 (1.36–3.26), p = 0.001, and 2.52 (1.67–4.04), p < 0.001, respectively]. These associations remained significant after adjusting for age, sex, mean arterial pressure, low-density lipoprotein cholesterol, glomerular filtration rate, and N-terminal pro-brain natriuretic peptide. ConclusionsWe conclude that ADMA and SDMA concentrations are associated with hospital and 3-month mortality and are increased by venous volume overload in AHF patients.

Serum Symmetric Dimethylarginine as an Early Marker of Excretory Dysfunction in Canine Leishmaniosis (L. infantum) Induced Nephropathy.

The aims of the study were to determine whether symmetric dimethylarginine (SDMA) was increased in dogs with leishmaniosis and to assess its relationship with creatinine concentration and urinary protein : creatinine ratio (UPC) to determine its utility as a marker of early excretory dysfunction. Fifty-three dogs with leishmaniosis classified according to the LeishVet clinical staging (stage I, n = 5, stage II, n = 30; stage III, n = 12; stage IV, n = 6) were selected and compared with 41 clinically healthy dogs. Thirty-nine dogs with leishmaniosis were also followed up for six months. SDMA concentrations on the day of diagnosis were significantly higher in dogs with leishmaniosis with respect to control dogs and in dogs from LeishVet stage IV when compared with the other stages. Increased UPC (>0.5), SDMA (>19 μg/dL), and creatinine concentrations (≥1.4 mg/dL) were found in 47.1%, 15.1%, and 9.4% of dogs with leishmaniosis, respectively. SDMA concentration was increased in 24% of proteinuric dogs, in 7% of nonproteinuric dogs, and in four of five dogs with increased creatinine. SDMA concentration ≥ 25 μg/dL was associated with clinical chronic kidney disease (CKD) after six months. Our results did not demonstrate advantages in using SDMA concentration as an early marker of CKD when compared to creatinine and UPC in canine leishmaniosis.

Relationship of asymmetric dimethylarginine levels with disease severity and pulmonary hypertension in chronic obstructive pulmonary disease

Background:Asymmetric dimethylarginine (ADMA) has emerged as a risk marker for many conditions related to pulmonary hypertension (PH); however, little is known about ADMA and symmetric dimethylarginine (SDMA) plasma concentrations in chronic obstructive pulmonary disease (COPD). Our interest centers on the role of ADMA in regulation of endothelial function in COPD and secondary PH. The aim of the present study was to evaluate the serum ADMA, SDMA, and L-arginine concentrations in COPD and its association with PH.Methods:Patients with diagnosis of COPD underwent pulmonary function tests, echocardiography, and laboratory investigations including ADMA, SDMA, and L-arginine.Results:Serum concentrations of ADMA, SDMA, and L-arginine tend to increase as COPD progresses. Patients with PH had higher concentrations of ADMA, SDMA, and L-arginine compared to cases with normal pulmonary arterial pressure (PAP); the difference was not statistically significant.Conclusions:Our results show that increased ADMA, SDMA, and L-arginine concentrations are associated with increased PAP measurements in patients with COPD, however, the relationship is not statistically significant.

Evaluation of Serum Symmetric Dimethylarginine Concentration as a Marker for Masked Chronic Kidney Disease in Cats With Hyperthyroidism.

BackgroundHyperthyroidism can complicate (mask) the diagnosis of chronic kidney disease (CKD) because it increases glomerular filtration rate and decreases body muscle mass, both of which can lower serum creatinine concentrations. Currently, there is no clinical test that can reliably predict which hyperthyroid cats have concurrent azotemic CKD that will become apparent after treatment of the hyperthyroidism.ObjectivesTo investigate serum symmetric dimethylarginine (SDMA) concentration as a potential marker of masked azotemia in untreated hyperthyroid cats.AnimalsTwo hundred and sixty‐two hyperthyroid cats and 206 aged‐matched, clinically normal cats.MethodsProspective study. We measured creatinine, urea nitrogen, SDMA, T4, and TSH concentrations before and 1, 3, and 6 months after treatment with radioiodine (131I) and classified 131I‐treated cats as azotemic or nonazotemic based on persistent, post‐treatment creatinine concentrations >2.1 mg/dL. Groups were compared via nonparametric tests, and diagnostic accuracy was determined by receiver operating characteristic analysis and logistic regression.ResultsNo hyperthyroid cats were azotemic before treatment, but 42 (16%) became azotemic when rechecked at 4–8 months (median, 6 months) after 131I treatment; of these, 14 had high SDMA concentrations before treatment. As a diagnostic test for pre‐azotemic (masked) CKD in untreated hyperthyroid cats, SDMA showed a sensitivity of 33.3% and specificity of 97.7%.Conclusions and Clinical ImportanceFinding a high serum SDMA concentration in a hyperthyroid cat can help predict development of azotemia after treatment. The test has high diagnostic test specificity (few false‐positive results) but relatively low sensitivity (fails to predict azotemia in most hyperthyroid cats).

Symmetric Dimethylarginine in Cats with Hypertrophic Cardiomyopathy and Diabetes Mellitus.

BackgroundSymmetric dimethylarginine (SDMA) has been increasingly used as a marker of early chronic kidney disease (CKD) in cats, but little is known about the influence of comorbidities on SDMA in this species.HypothesisHypertrophic cardiomyopathy (HCM) and diabetes mellitus (DM), independently of CKD, are associated with changes in serum SDMA.AnimalsNinety‐four cats (17 with CKD, 40 with HCM, 17 with DM, and 20 healthy controls).MethodsCase‐control study. Clinical examination, echocardiography, ECG, blood pressure, CBC, biochemistry, thyroxine, and SDMA measurement were performed. Urinalysis was performed in controls and cats with CKD and DM. Analysis of variance was used to compare overall differences in the log‐transformed SDMA data among groups. A random forest algorithm was applied to explore which clinical and other factors influenced serum SDMA.ResultsMedian (range) serum SDMA for the renal group (positive control) was 19 (10–93) μg/dL, whereas for the control group (negative control), it was 10 (5–15) μg/dL. For the cardiac and diabetic groups, serum SDMA was 9 (4–24) μg/dL and 7 (3–11) μg/dL, respectively. The renal group had significantly higher SDMA concentrations and the diabetic group significantly lower SDMA concentrations compared to all other groups.Conclusions and Clinical ImportanceSerum SDMA concentrations in cats with HCM were not significantly different from those of healthy control cats. Cats with DM, however, had significantly lower SDMA concentrations than controls, a finding that needs further investigation and should be kept in mind when evaluating renal function of cats with this endocrinopathy.

Inverse correlation between maternal plasma asymmetric dimethylarginine (ADMA) and birthweight percentile in women with impaired placental perfusion: circulating ADMA as an NO-independent indicator of fetal growth restriction?

L-Arginine (Arg) is the enzymatic precursor of nitric oxide (NO) which has multiple biological functions. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO. We hypothesized that the ADMA and SDMA have additional biological functions in pregnancy, beyond NO synthesis, and may play a role in the regulation of birthweight (BW). To investigate this issue, we measured the plasma concentration of ADMA, SDMA, Arg and the NO metabolites nitrite and nitrate, at 23-25weeks of gestation in women with normal placental function (Group 1) and in women with impaired placental perfusion; 19 of these women had normal outcome (Group 2), 14 had a fetus that was growth restricted (Group 3), and 10 women eventually developed preeclampsia (Group 4). BW percentile was found to inversely correlate with maternal plasma ADMA concentration in Group 3 (r=-0.872, P<0.001) and in Group 4 (r=-0.800, P<0.05). But, BW percentile did not correlate with the maternal plasma concentration of Arg, SDMA, nitrate or nitrite. Our results suggest that maternal plasma ADMA concentration is an important indicator of fetal growth restriction in women with impaired placental perfusion independent of NO.

Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y⁺LAT2 Carrier-Mediated Loss.

Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y+LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y+LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y+LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y+LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y+LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.

Evaluation of Serum Symmetric Dimethylarginine Concentrations in Dogs with Chronic Mitral Valve Insufficiency

Evaluation of Serum Symmetric Dimethylarginine Concentrations in Dogs with Chronic Mitral Valve Insufficiency

Does cardiac resynchronization therapy restore peripheral circulatory homeostasis?

AimsTo evaluate whether peripheral circulatory ‘remodelling’ as measured by changes in vascular compliance and in markers of nitric oxide signalling contributes to patient response to cardiac resynchronization therapy (CRT).Methods and resultsEffects of CRT were evaluated in 33 patients pre‐procedure and 6 months post‐procedure. Peak oxygen consumption, 6 min walk distance, New York Heart Association class, and quality of life score were evaluated. Augmentation index and its interactions with nitric oxide (NO) were evaluated by applanation tonometry. Platelet NO responsiveness and content of thioredoxin‐interacting protein were assessed. Plasma concentrations of N‐terminal proBNP, asymmetric and symmetric dimethylarginine (SDMA), high sensitivity C‐reactive protein, catecholamines, and matrix metalloproteinases‐2 and ‐9 were assessed. Despite significant improvement in 6 min walk distance (P = 0.005), New York Heart Association class (P < 0.001), quality of life (P = 0.001), and all echocardiographic parameters post‐CRT, there were no significant changes in augmentation index measurements, thioredoxin‐interacting protein content, and platelet NO response. Significant falls in N‐terminal proBNP (P = 0.008) and SDMA (P = 0.013; independent of renal function) occurred. Falls in SDMA predicted reduction in high‐sensitivity C‐reactive protein (P = 0.04) and increases in peak oxygen consumption (P = 0.04). There were no correlations between changes in echocardiographic parameters and those in vascular function.ConclusionsThese data suggest that the beneficial effects of CRT over 6 months are independent of any change in peripheral NO‐related signalling. However, there is evidence that suppression of inflammation occurs, and its magnitude predicts extent of clinical improvement.

Serum symmetric dimethylarginine and creatinine in Birman cats compared with cats of other breeds.

Objectives The aim of this study was to assess whether, in contrast to serum creatinine, which is higher in Birman cats than in other breeds, the serum concentration of symmetric dimethylarginine (SDMA) is comparable in clinically healthy Birmans and in the general feline population. This could allow, in this breed, to better evaluate chronic kidney disease (CKD). Methods Serum creatinine and SDMA were measured in clinically healthy Birmans (n = 50) and in cats of other breeds (n = 46), and the results were statistically compared. A breed-specific reference interval (RI) was established for Birmans and compared with the RI for the general feline population (0.0-14.0 µg/dl). Results Creatinine (1.58 ± 0.36 mg/dl) and SDMA (12.2 ± 2.8 µg/dl) were higher ( P <0.001) in Birmans than in cats of other breeds (1.19 ± 0.17 mg/dl; 10.3 ± 2.5 µg/dl). In 20/50 Birman cats (40.0%) serum creatinine was higher than both the non-breed-specific RI of our laboratory and the threshold recommended to classify cats as IRIS stage 2 (1.6 mg/dl). The concentration of SDMA was higher than the pre-existing RI in 10/50 Birmans (20.0%) and in four cats of other breeds (8.7%). Among Birmans, the proportion of cats with SDMA >14 µg/dl was lower ( P <0.017) than the proportion of cats with creatinine >1.60 mg/dl. However, the deviation from the upper limit of the RI was lower than the analytical variability of the method in 7/10 Birmans and in 4/4 cats of other breeds. The breed-specific RI (3.5-18.7 µg/dl) overlapped with the pre-existing one. Conclusions and relevance SDMA may be a better marker of CKD in Birman cats than creatinine when non-breed-specific RIs are utilised. The coupled analysis of creatinine and SDMA could help prevent errors in diagnosing and staging CKD in Birman cats.

Vitamin D and methylarginines in chronic kidney disease (CKD).

BackgroundVitamin D associates with the plasma concentration of the endogenous inhibitor of the nitric oxide system asymmetric dimethyl arginine (ADMA) and cross-sectional studies in CKD patients treated with the vitamin D receptor activator paricalcitol show that plasma ADMA is substantially less than in those not receiving this drug.MethodsIn the frame of a randomized, double-blind, placebo controlled trial, the Paracalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY), we investigated whether vitamin D receptor activation by paricalcitol (2 μg/day x 12 weeks) affects the plasma concentration of ADMA and symmetric dimethyl arginine (SDMA) in 88 patients with stage 3 to 4 CKD.ResultsParicalcitol produced the expected small rise in serum calcium and phosphate and a marked PTH suppression. However, ADMA [Paricalcitol: baseline 0.75 μMol/L (95%CI: 0.70–0.81), 12 week 0.72 μMol/L (95%CI: 0.66–0.78); Placebo: baseline 0.75 μMol/L (95%CI: 0.70–0.90) 12 weeks 0.70 μMol/L (95%CI: 0.66–0.74)] and SDMA [Paricalcitol: baseline 0.91 μMol/L (95%CI: 0.82–1.00), 12 week 0.94 μMol/L (95%CI: 0.82–0.1.06); Placebo: baseline 0.91 μMol/L (95%CI: 0.82–1.06) 12 weeks 0.99 μMol/L (95%CI: 0.88–1.10)] remained unchanged during the trial and 2 weeks after stopping these treatments.ConclusionsParicalcitol does not modify plasma ADMA and SDMA in patients with stage 3–4 CKD. The apparent beneficial effects of paricalcitol on ADMA registered in cross-sectional studies is likely attributable to confounding by indication rather than to a true effect of this drug on ADMA metabolism.

Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (rs = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (rs = −0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.

Evaluation of Gastric pH and Serum Gastrin Concentrations in Cats with Chronic Kidney Disease.

BackgroundChronic kidney disease (CKD) is a highly prevalent condition in cats. Advanced CKD is associated with hyporexia and vomiting, which typically are attributed to uremic toxins and gastric hyperacidity. However, gastric pH studies have not been performed in cats with CKD.Hypothesis/ObjectivesTo determine if cats with CKD have decreased gastric pH compared to age‐matched, healthy cats. Based on previous work demonstrating an association of hypergastrinemia and CKD, we hypothesized that cats with CKD would have decreased gastric pH compared to healthy, age‐matched control cats.Animals10 CKD cats; 9 healthy control cats.MethodsAll cats with concurrent disease were excluded on the basis of history, physical examination, CBC, plasma biochemistry profile, urinalysis, urine culture, serum total thyroxine concentration, and serum symmetric dimethylarginine concentration (controls only) obtained within 24 hours of pH monitoring and assessment of serum gastrin concentrations. Serum for gastrin determination was collected, and 12‐hour continuous gastric pH monitoring was performed in all cats. Serum gastrin concentration, mean pH, and percentage time that gastric pH was strongly acidic (pH <1 and <2) were compared between groups.ResultsNo significant differences in serum gastrin concentrations were observed between groups (medians [range]: CKD, 18.7 ng/dL [<10–659.0]; healthy, 54.6 ng/dL [<10–98.0]; P‐value = 0.713) or of any pH parameters including mean ± SD gastric pH (CKD, 1.8 ± 0.5; healthy, 1.6 ± 0.3; P‐value = 0.23).Conclusions and Clinical ImportanceThese findings suggest that cats with CKD may not have gastric hyperacidity compared to healthy cats and, therefore, may not need acid suppression. Thus, further studies to determine if there is a benefit to acid suppression in cats with CKD are warranted.

Detrimental effects of a bout of physical exercise on circulating endogenous inhibitors of endothelial function in patients with coronary artery disease.

A bout of intense physical activity has been shown to transiently impair endothelial function; however, the underlying mechanisms are unclear. The purpose of the review was to assess the impact of a bout of physical exercise induced by exercise stress echocardiography, on blood concentration of the endogenous inhibitors of nitric oxide synthase, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), in patients with atherosclerosis. Overall, 83 study participants were enrolled, 25 coronary artery disease (CAD) patients, 20 age and sex-matched asymptomatic study participants with at least one risk factor for CAD, and 38 healthy controls. Patients with CAD developed symptoms and/or left ventricular wall motion abnormalities during exercise; no changes were seen in study participants with risk factors, or in healthy controls. At baseline, in CAD patients and in study participants with risk factors, both ADMA and SDMA were higher than healthy controls (P < 0.001). However, a further large increase occurred during exercise stress echocardiography in both groups, regardless of development of symptoms (P < 0.001). Basal concentrations of ADMA and SDMA are high in CAD patients and in study participants with risk factors, consistent with impaired nitric oxide synthase activity in atherosclerosis. Large increase of these endogenous inhibitors of nitric oxide during intense exercise provide support to the hypothesis that in patients with atherosclerosis endothelial function may further deteriorate as a consequence of a bout of physical activity.

Influence of phenylketonuria's diet on dimethylated arginines and methylation cycle.

Phenylketonuria's (PKU) treatment based on low natural protein diet may affect homocysteine (Hcys) metabolic pathway. Hcys alteration may be related to the methylation of arginine to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), which both modify nitric oxide production. The aim of this work is to evaluate the status of Hcys formation methylation cycle and ADMA and SDMA levels in patients with PKU in order to establish a potential relationship.Forty-two early diagnosed PKU patients under dietary treatment and good adherence to their diets were enrolled in this cross-sectional study. Their nutritional and biochemical profile, as well as Hcys synthesis status, ADMA and SDMA levels were analyzed and compared with a control group of 40 healthy volunteers. ADMA and SDMA were determined by high-performance liquid chromatography system coupled to triple quadrupole mass spectrometer.In this study, 23 classic PKU, 16 moderate PKU, and 3 mild HPA were enrolled. The median age was 10 years old. Median ADMA, SDMA, and Hcys concentration levels (5.1 μM [2.3–25.7], 0.35 μM [0.18–0.57], 0.43 μM [0.26–0.61], respectively) were lower in patients with PKU (P < .001 for ADMA and SDMA) whereas vitamin B12 and folate levels (616 pg/mL [218–1943] and 21 ng/mL [5–51], respectively) were higher comparing with controls. Statistically significant correlations were found between ADMA, and Phe (r = −0.504, P = .001) and Hcys (r = −0.458, P = .037) levels. Several nutrition biomarkers, such as prealbumin, 25-hydroxy vitamin D, selenium, and zinc, were below the normal range.Our study suggests that patients with PKU suffer from poor methylation capacity. Restriction of natural proteins in addition to high intake of vitamin B12 and folic acid supplementation in the dietary products, produce an impairment of methylation cycle that leads to low Hcys and ADMA levels. As a result, methylated compounds compete for methyl groups, and there is an impairment of methylation cycle due to low Hcys levels, which is related to the lack of protein quality, despite of elevated concentrations of cofactors.