Measurement of arginine derivatives in pediatric patients with chronic kidney disease using high-performance liquid chromatography-tandem mass spectrometry

Wang, Sihe; Vicente, Faye B.; Miller, Alan L.; Brooks, Ellen R.; Price, Heather E.; Smith, Frederick

doi:10.1515/cclm.2007.277

Cited by 24 publications

(15 citation statements)

References 33 publications

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“…All specimens were processed in the main hospital laboratory with immediate centrifugation and storage of plasma at −70°C for batched analysis. Plasma ADMA was measured by the gold-standard method of high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described [27]—except that ADMA-d 7 was incorporated as the internal standard, sample supernatant was dried to completion and reconstituted in mobile phase, and a Phenomenex Luna Silica column was used.…”

Section: Methodsmentioning

confidence: 99%

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Weiss

Jennings

et al. 2012

PLoS ONE

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BackgroundGenetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.Methodology/Principal FindingsIn a prospective study, blood and buccal swabs were obtained from 82 patients ≤18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the −871 6g/7g insertion/deletion and −449G/C single nucleotide polymorphisms. Shock type (“warm” versus “cold”) was characterized by clinical assessment. The −871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between −871 6g/7g genotypes. While genotype frequencies also did not vary between groups for the −449G/C SNP (p = 0.75), septic patients with at least one −449G allele had lower ADMA (median, IQR 0.36, 0.30–0.41 µmol/L) than patients with the −449CC genotype (0.55, 0.49–0.64 µmol/L, p = 0.008) and exhibited a higher incidence of “cold” shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.Conclusions/SignificanceThe −449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with “cold” shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology.

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Section: Methodsmentioning

confidence: 99%

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Weiss

Jennings

et al. 2012

PLoS ONE

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“…Fasting plasma specimens were aliquoted and archived at −80°C until analysis. ADMA, SDMA, and L-Arg were measured by the gold standard method, high-performance liquid chromatography (HPLC)-tandem mass spectrometry, using a commercially available internal standard with minimized sample matrix effect [16]. The analysis was carried out with our validated method using a Waters 2795 Alliance HT HPLC system coupled to a Micromass Quattro micro API triple-quadrupole mass spectrometer (Waters, Milford, MA).…”

Section: Methodsmentioning

confidence: 99%

Methylated arginine derivatives in children and adolescents with chronic kidney disease

et al. 2009

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Asymmetric dimethylarginine (ADMA), a methylated L: -arginine (Arg) derivative is associated with endothelial dysfunction, vasoconstriction, and hypertension in animals and humans. We examined the relationship between these derivatives, estimated glomerular filtration rate (eGFR), and awake (AW) and asleep (AS) blood pressure (BP) load in children and adolescents (n = 28) with stage 2-3 chronic kidney disease (CKD) and in matched intra-familial controls (n = 10). Plasma L: -Arg, ADMA, and symmetric dimethylarginine (SDMA) levels were measured by high-performance liquid chromatography-tandem mass spectrometry. Subjects wore a 24-hr ambulatory BP monitor with BP load >95th percentile. ADMA, SDMA/ADMA ratio and SDMA were 38-200% higher in CKD patients while L: -Arg/ADMA and L: -Arg/SDMA ratios and the L: -Arg level were 11-64% lower. The eGFR explained 42-60% of L: -Arg/SDMA, SDMA/ADMA, and SDMA variability (n = 38). Using linear regression, SDMA and SDMA/ADMA separately explained 15-38% of AW and AS systolic (S) BP and diastolic (D) BP load variability (p < 0.001-0.022). Using multivariate stepwise regression with eGFR held constant, SDMA/ADMA was a significant independent variable for AW DBP load (p = 0.03). In conclusion, BP load and a disproportionate elevation of SDMA are seen in children and adolescents with stage 2-3 (mild-moderate) CKD. SDMA is a strong marker for reduced eGFR and serves as a moderate but significant indicator of 24-hr BP load variability.

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“…However, others reported even a significant decrease in circulating ADMA levels in young diabetics with a mean age of 12 years and mean HbA 1c of 8.2 % (Huemer et al 2011). Comparably higher ADMA concentrations were also found in children with renal diseases (Lücke et al 2008;Brooks et al 2009;Wang et al 2007), in hypercholesterolemia (Hasanoğlu et al 2011), as well as in arterial hypertension (Sladowska-Kozłowska et al 2012) and pulmonary hypertension (Sanli et al 2012). The children examined in the present study did not have elevated concentrations of creatinine, cholesterol and triglycerides; also, they had no microalbuminuria, arterial hypertension or pulmonary hypertension (Table 1).…”

Section: Amino Acids Of the L-arg/no Pathwaymentioning

confidence: 97%

“…Other important factors to be considered in the discussion are the influence of renal function, glucose or insulin on the metabolism and elimination of ADMA (Vallance et al 1992;Cighetti et al 2009;Lajer et al 2009;Tarnow et al 2004). Like in adults, the circulating ADMA concentration has been shown to be elevated in children when renal function was impaired (Wang et al 2007;Lücke et al 2008;Brooks et al 2009). …”

Section: Amino Acids Of the L-arg/no Pathwaymentioning

confidence: 99%

The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus

et al. 2015

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High circulating levels of asymmetric dimethylarginine (ADMA) and low circulating levels of homoarginine (hArg) are known cardiovascular risk factors in adults. While in adults with type 1 diabetes mellitus (T1DM) circulating ADMA is significantly elevated, in children and adolescents the reported ADMA data are contradictory. In 102 children with T1DM and 95 healthy controls (HC) serving as controls, we investigated the L-arginine (Arg)/nitric oxide (NO) pathway. Children with T1DM were divided into two groups, i.e., in children with newly diagnosed diabetes mellitus [T1DM-ND; n = 10; age, 8.8 (4.4-11.2) years; HbA1c, 13 (8.9-13.9) %] and in those with long-term treatment [T1DM-T; n = 92; age, 12.5 (10.5-15.4) years; HbA1c, 8.0 (7.2-8.6) %]. The age of the HC was 11.3 (8-13.3) years. Amino acids and NO metabolites of the Arg/NO pathway, creatinine and the oxidative stress biomarker malondialdehyde (MDA) were measured by GC-MS or GC-MS/MS. Plasma hArg, ADMA and the hArg/ADMA molar ratio did not differ between the T1DM and HC groups. There was a significant difference between T1DM-T and HC with regard to plasma nitrite [0.53 (0.48-0.61) vs 2.05 (0.86-2.36) µM, P < 0.0001] as well as to urinary nitrite [0.09 (0.06-0.17) vs 0.22 (0.13-0.37) μmol/mmol creatinine, P < 0.0001]. Plasma, but not urinary nitrite, differed between T1DM-ND and HC [0.55 (0.50-0.66) vs 2.05 (0.86-2.36) µM, P < 0.0001]. Plasma MDA did not differ between the groups. The urinary nitrate-to-nitrite molar ratio (UNOXR), a measure of nitrite-dependent renal carbonic anhydrase (CA) activity, was higher in T1DM-T [1173 (738-1481), P < 0.0001] and T1DM-ND [1341 (1117-1615), P = 0.0007] compared to HC [540 (324-962)], but did not differ between T1DM-T and T1DM-ND (P = 0.272). The lower nitrite excretion in the children with T1DM may indicate enhanced renal CA-dependent nitrite reabsorption compared with healthy children. Yet, lower plasma nitrite concentration in the T1DM patients may have also contributed to the higher UNOXR. Patients' age correlated positively with plasma hArg and hArg/ADMA and urinary DMA/ADMA. Plasma ADMA and urinary ADMA, DMA, nitrite and nitrate correlated negatively with age of the T1DM-T children. Significant correlations were found between plasma hArg and plasma Arg (r = 0.468, P < 0.0001), and urinary DMA (r = -0.426, P = 0.0001), ADMA (r = -0.266, P = 0.021) and nitrate (r = -0.234, P = 0.043). Plasma hArg correlated positively with age at diagnosis (r = +0.337, P = 0.002). ADMA, but not hArg, correlated with HbA1c in T1DM-T (r = -0.418, P < 0.0001) and T1DM-ND (r = +0.879, P = 0.0016). The greatest differences between T1DM-T and T1DM-ND were observed for urinary ADMA, DMA/ADMA ratio, nitrite and nitrate. The Arg/NO pathway is altered in T1DM in childhood and adolescence, yet the role and the importance of hArg and ADMA in T1DM remain to be elucidated. In young T1DM patients, oxidative stress (lipid peroxidation) is not elevated.

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Measurement of arginine derivatives in pediatric patients with chronic kidney disease using high-performance liquid chromatography-tandem mass spectrometry

Abstract: The method exhibited no observable ion suppression in the patient specimens tested and has an acceptably short analytical cycle time. Children with CKD had higher levels of ADMA and SDMA than the healthy siblings.

Cited by 24 publications

References 33 publications

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Methylated arginine derivatives in children and adolescents with chronic kidney disease

The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus

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