Plasma ADMA, urinary ADMA excretion, and late mortality in renal transplant recipients

Abstract

Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTR). Elevated plasma asymmetric dimethylarginine (pADMA), an endogenous nitric oxide synthase inhibitor produced from the turnover of methylated arginine moieties in proteins, is a risk factor for CVD and mortality. It is unknown how urinary ADMA excretion (uADMA), one of the main ADMA elimination routes, is associated with long-term survival. Furthermore, the association of pADMA and uADMA with markers for turnover of arginine-methylated proteins is unknown. We analyzed ADMA using a validated GC-MS/MS method in plasma and 24-h urine samples of 685 RTR, included ≥ 1 year after transplantation. We also analyzed urine symmetric dimethylarginine (uSDMA) using the same method. Urinary creatinine and urea excretions were used as markers for turnover of muscle protein and amino acids, respectively. We applied Cox regression analyses to study associations of pADMA, uADMA, and uSDMA with all-cause and CVD mortality. Mean pADMA was 0.61 ± 0.12 µM, uADMA was 31 ± 13 µmol/24 h, and uSDMA was 52 ± 19 µmol/24 h. Over median follow-up of 5.4 [4.9-6.1] years, 147 RTR died, of which 58 (39%) from CVD. High pADMA was associated with high all-cause mortality (HR per SD [95% CI]: 1.45 [1.26-1.67], P < 0.001), while high uADMA was associated with low all-cause and CVD mortality (HR per SD [95% CI]: 0.57 [0.47-0.69], P < 0.001, and 0.55 [0.40-0.74], P < 0.001, respectively). The associations were independent of adjustment for potential confounders. Creatinine excretion was associated with both pADMA (st. β:− 0.21, P = 0.003) and uADMA (st. β: 0.49, P < 0.001), and urea excretion was associated with uADMA (st. β: 0.56, P < 0.001). Associations of uSDMA with outcomes and with creatinine excretion and urea excretion were comparable to those of uADMA. The associations of pADMA, uADMA and uSDMA with mortality were strongly affected by adjustment for creatinine excretion and urea excretion. We found for the first time that high uADMA and high uSDMA are associated with less risk of all-cause and CVD mortality. The links of uADMA and uSDMA with markers of muscle protein and amino acid turnover may serve to further understand ADMA and SDMA homeostasis and their clinical implications. Keywords Kidney transplantation • ADMA • SDMA • Muscle mass • Protein turnover • Long-term survival Abbreviations ADMA Asymmetric dimethylarginine AGXT2 Alanine-glyoxylate aminotransferase 2 BMI Body mass index BSA Body surface area CI Confidence interval CKD-EPI Chronic kidney disease epidemiology collaboration CVD Cardiovascular disease DDAH Dimethylarginine dimethylaminohydrolase D-NAME N G-Nitro-d-arginine methyl ester eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate Handling Editor: P. Beltran-Alvarez. M. Yusof Said and A. Bollenbach shared first authorship.

An Ethnic Comparison of Arginine Dimethylation and Cardiometabolic Factors in Healthy Black and White Youth: The ASOS and African-PREDICT Studies

“…The findings of the present study support the observations of the lower circulating ADMA and SDMA concentrations in black subjects measured in the SABPA study [44]. Low urinary excretion of ADMA is a cardiovascular risk factor in white adults [45,46]. The close comparability of urinary ADMA excretion in the young white and black men of the African-PREDICT study suggests that the black population is not exposed to a higher ADMA-associated cardiovascular risk than the white population, but, again, it should be taken into account that the study included healthy screening normotensives.…”

Post-translational modifications (PTM): analytical approaches, signaling, physiology and pathophysiology—part I

“…The whole-body asymmetric arginine dimethylation was investigated in adult renal transplant recipients by measuring DMA, the major metabolite of ADMA, in urine by GC–MS (Post et al 2021 ). This study revealed that the whole-body asymmetric arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients and supports the particular role of this PTM in chronic kidney disease (Frenay et al 2015 ; Said et al 2019a , b ).…”

The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine

“…High plasma ADMA was correlated with high all-cause mortality and late mortality in renal transplant recipients. In contrary, urinary excretion of ADMA and SDMA is inversely associated with cardiovascular disease (CVD) and all-cause mortality [101]. Exogenous treatment of human monocytoid cells THP-1 with micromolar concentrations of ADMA significantly upregulates the levels of IL-8, TNF-α, MCP-1, chemokine receptors CCR 2 and CXCR 2 , activation of NF-κB, and promotes monocytic binding to human umbilical vein endothelial cells [57].…”

“…Although accumulation of plasma ADMA correlates with impaired NO synthesis and contributes to the hypertension and immune dysfunction associated with chronic renal failure, it appears that the (patho)physiological impact of ADMA does not take place in plasma [91]. Plasma arginine concentrations are in the range of ~100 to 200 µM, but the plasma ADMA concentrations are much less, 0.3–1.0 µM at a typical level [54,61,101,104,105,106,107]. Thus, in the circulating bloodstream, ADMA is not competent enough against arginine for receptor binding.…”