Asymmetric Dimethylarginine (ADMA) Levels Are Lower in Hemodialysis Patients Treated With Paricalcitol

Abstract

IntroductionChronic kidney disease is a major public health problem. In the last decade, it has been shown that the early stages of chronic kidney disease are associated with an inflammatory condition involving an increased risk of cardiovascular morbidity and long-term mortality. In patients with chronic kidney disease and more specifically those on hemodialysis, cardiovascular events are the most common cause of death. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and may be an independent risk factor for endothelial dysfunction and cardiovascular disease.MethodsWe performed a cross-sectional analysis to identify factors that were associated with ADMA such as certain medications related to cardiovascular disease in dialysis patients.ResultsPatients who were treated with paricalcitol had significantly lower levels of ADMA (0.21 ± 0.19 μmol/l) compared with those not treated with paricalcitol (0.42 ± 0.35 μmol/l) (P = 0.00027). Dividing ADMA levels by quartiles, patients treated with paricalcitol were less likely to have very high level ADMA (P = 0.014), whereas there were no significant differences with other medications. Higher dose of paricalcitol was also related to lower levels of ADMA noting an inverse correlation (r = –0.36, P = 0.013).DiscussionHemodialysis patients treated with paricalcitol presented significantly decreased ADMA levels compared with those who did not receive this treatment. Possible beneficial effects in terms of cardiovascular morbidity and mortality by paricalcitol and its association with ADMA and nitric oxide synthesis are unknown. Studies to confirm this effect and determine the underlying pathophysiological mechanism are necessary.

Vitamin D and methylarginines in chronic kidney disease (CKD)

“…In contrast with the cross-sectional analysis by Oliva-Damaso et al,[ 16 ] paricalcitol had a robustly null effect on the plasma concentration of ADMA and SDMA and extensive interaction analyses showed no modification of the effect of paricalcitol on these methylargines in relationship with demographic factors (age, gender) and the main biomarkers of the mineral bone disorder in CKD including calcium, phosphate, 25-OH vitamin D, 1,25-(OH) 2 vitamin D, PTH and FGF23. Confounding by indication is a well-known bias of associations detected in cross-sectional studies[ 38 ].…”

“…Also because the previously mentioned links of ADMA with a fundamental biomarker of mineral bone disorders like PTH [ 12 ] and the inverse seasonal fluctuations of ADMA and 25-OH Vit D[ 36 ], vitamin D receptor activation appears to be an interesting, novel pathway to explore to mitigate ADMA accumulation in CKD. Descriptive, cross-sectional studies would support the possibility of a biologically important effect of vitamin D on ADMA levels in CKD because the plasma concentration of this compound is more than halved in patients on chronic paricalcitol treatment as compared to those that do not take this drug[ 16 ]. Furthermore, categorical analyses in the same study show that among patients in the fourth ADMA quartile the proportion of patients not on paricalcitol is 3.5 times lower than that of patients in the first ADMA quartile[ 16 ].…”

“…Descriptive, cross-sectional studies would support the possibility of a biologically important effect of vitamin D on ADMA levels in CKD because the plasma concentration of this compound is more than halved in patients on chronic paricalcitol treatment as compared to those that do not take this drug[ 16 ]. Furthermore, categorical analyses in the same study show that among patients in the fourth ADMA quartile the proportion of patients not on paricalcitol is 3.5 times lower than that of patients in the first ADMA quartile[ 16 ].…”

“…An inverse relationship between ADMA and 25-OH Vit D has been described in stage G5D CKD patients [ 15 ]. The possibility that the link between vitamin D in CKD and ADMA is causal in nature is suggested by the fact that in cross sectional analyses the plasma concentration of ADMA is halved in patients on treatment with vitamin D receptor antagonists like paricalcitol as compared to patients not receiving such a treatment [ 16 ]. Of note, in the same study an apparent dose-response relationship between the dose of paricalcitol and the degree of ADMA suppression was described [ 16 ].…”

“…The possibility that the link between vitamin D in CKD and ADMA is causal in nature is suggested by the fact that in cross sectional analyses the plasma concentration of ADMA is halved in patients on treatment with vitamin D receptor antagonists like paricalcitol as compared to patients not receiving such a treatment [ 16 ]. Of note, in the same study an apparent dose-response relationship between the dose of paricalcitol and the degree of ADMA suppression was described [ 16 ]. However precious for hypothesis generation, cross sectional analyses are inherently inadequate to assess causation[ 17 ] and therefore it remains unresolved whether activation of the vitamin D receptor may suppress ADMA.…”