Asymmetric dimethylarginine in homocystinuria due to cystathionine β-synthase deficiency: Relevance of renal function
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Objective Vascular disease is associated with increased plasma asymmetric dimethylarginine (ADMA) and homocysteine, and both are increased in renal failure. In cystathionine β-synthase deficiency (CBS) there is severe hyperhomocysteinaemia, precocious vascular disease, and endothelial dysfunction. We investigated whether ADMA levels are elevated in CBS patients with and without renal impairment, and whether lowering plasma homocysteine also lowers ADMA.
Methods We measured plasma homocysteine, arginine, asymmetric and symmetric dimethylarginines, nitrate + nitrite, creatinine and cystatin C in 23 CBS-deficient patients and 24 age-matched controls.
Results In the patients, nitrate + nitrite and the ratio L-arginine/ADMA were markedly reduced (21.6 ± 6.1 vs 57.7 ± 7.5 μmol/L and 132.9 ± 24.7 vs 181.9 ± 56.1, respectively, p < 0.001 for both), reflecting endothelial dysfunction. Plasma ADMA for the group was moderately increased (0.55 ± 0.08 vs 0.49 ± 0.07 μmol/L, p = 0.018), but this was due to significantly higher levels than controls in only those 7 of the 23 patients who had elevated cystatin C levels (0.59 ± 0.08 vs 0.49 ± 0.07 mg/L, p = 0.007). Posttreatment total homocysteine in patients varied widely (15–285, median 92 μmol/L), but was not correlated with ADMA or other measured variables. In three newly-diagnosed patients, marked reduction of total homocysteine during treatment produced minimal changes in ADMA.
Conclusions ADMA levels were significantly increased only in the CBS-deficient patients with elevated cystatin C levels, and not in those with normal renal function. The reported relationship between hyperhomocysteinaemia and ADMA may not be direct, but could be secondary to reduced renal function.
- Achan V, Broadhead M, Malaki M, et al (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23: 1455–1459.
- Boger RH (2003) The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res 59: 824–833. CrossRef
- Boger RH, Lentz SR, Bode-Boger SM, et al (2001) Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci (Lond) 100: 161–167.
- Celermajer DS, Sorensen K, Ryalls M, et al (1993) Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 22: 854–858.
- Cusworth DC, Gattereau A (1968) Inhibition of renal tubular reabsorption of homocystine by lysine and arginine. Lancet 2: 916–917.
- Dayal S, Arning E, Bottiglieri T, et al (2004) Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke 35: 1957–1962. CrossRef
- Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40: 221–226. CrossRef
- Doshi S, McDowell I, Goodfellow J, et al (2005) Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia. Metabolism 54: 351–360. CrossRef
- Gaustadnes M, Wilcken B, Oliveriusova J, et al (2002) The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype–phenotype correlations and response to treatment. Hum Mutat 20: 117–126. CrossRef
- Granger DL, Taintor RR, Boockvar KS, Hibbs JB Jr (1996) Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 268: 142–151.
- Holven KB, Haugstad TS, Holm T, et al (2003) Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 89: 359–363. CrossRef
- Jonasson TF, Hedner T, Hultberg B, Ohlin H (2003) Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease. Eur J Clin Invest 33: 543–549. CrossRef
- Kielstein JT, Boger RH, Bode-Boger SM, et al (2002) Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 13: 170–176.
- Knight EL, Verhave JC, Spiegelman D, et al (2004) Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 65: 1416–1421. CrossRef
- Koenig W, Twardella D, Brenner H, Rothenbacher D (2005) Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem 51: 321–327.
- Laterza OF, Price CP, Scott MG (2002) Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 48: 699–707.
- Lentz SR, Rodionov RN, Dayal S (2003) Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA. Atheroscler Suppl 4: 61–65. CrossRef
- Mudd SH, Skovby F, Levy HL, et al (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37: 1–31.
- Nijveldt RJ, Van Leeuwen PA, Van Guldener C, et al (2002) Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans. Nephrol Dial Transplant 17: 1999–2002.
- Nijveldt RJ, Siroen MP, Teerlink T, van Leeuwen PA (2004) Elimination of asymmetric dimethylarginine by the kidney and the liver: a link to the development of multiple organ failure? J Nutr 134: 2848S–2852S; discussion 2853S.
- Paroni R, Fermo I, Fiorina P, Cighetti G (2005) Determination of asymmetric and symmetric dimethylarginines in plasma of hyperhomocysteinemic subjects. Amino Acids 28: 389–394. CrossRef
- Perkins BA, Nelson RG, Krolewski AS (2005) Cystatin C and the risk of death. N Engl J Med 353: 842–844.
- Pullin CH, Bonham JR, McDowell IF, et al (2002) Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria. J Inherit Metab Dis 25: 107–118. CrossRef
- Ridker PM, Brown NJ, Vaughan DE, et al (2004) Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 109: IV6–19.
- Savvidou MD, Hingorani AD, Tsikas D, et al (2003) Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361: 1511–1517. CrossRef
- Shlipak MG, Sarnak MJ, Katz R, et al (2005) Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 352: 2049–2060. CrossRef
- Stuhlinger MC, Oka RK, Graf EE, et al (2003) Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 108: 933–938. CrossRef
- Sydow K, Hornig B, Arakawa N, et al (2004) Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 9: 93–101. CrossRef
- Tarnow L, Hovind P, Teerlink T, et al (2004) Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes. Diabetes Care 27: 765–769.
- Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA (2002) Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem 303: 131–137. CrossRef
- Tran CT, Leiper JM, Vallance P (2003) The DDAH/ADMA/NOS pathway. Atheroscler Suppl 4: 33–40. CrossRef
- Valkonen VP, Paiva H, Salonen JT, et al (2001) Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358: 2127–2128. CrossRef
- Vallance P, Leiper J (2004) Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol (2) Vallance and Leiper 2004: Reference incomplete: please add details
- Vallance P, Leone A, Calver A, et al (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572–575.
- Wanby P, Brattstrom L, Brudin L, et al (2003) Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Scand J Clin Lab Invest 63: 347–353.
- Wang J, Sim AS, Wang XL, et al (2005) Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease. Atherosclerosis [Epub ahead of print]. (3) Wang J, et al (2005): Add details if now available
- Wilcken DE, Wilcken B (1997) The natural history of vascular disease in homocystinuria and the effects of treatment. J Inherit Metab Dis 20: 295–300. CrossRef
- Wilcken DE, Dudman NP, Tyrrell PA, Robertson MR (1988) Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease. Metabolism 37: 697–701. CrossRef
- Wilcken DE, Wang XL, Adachi T, et al (2000) Relationship between homocysteine and superoxide dismutase in homocystinuria: possible relevance to cardiovascular risk. Arterioscler Thromb Vasc Biol 20: 1199–1202.
- Yamamoto M, Hara H, Adachi T (2000) Effects of homocysteine on the binding of extracellular-superoxide dismutase to the endothelial cell surface. FEBS Lett 486: 159–162.
- Yap S, Boers GH, Wilcken B, et al (2001) Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 21: 2080–2085.
- Ziegler S, Mittermayer F, Plank C, et al (2005) Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease. J Clin Endocrinol Metab 90: 2175–2178. CrossRef
- Zoccali C, Bode-Boger S, Mallamaci F, et al (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358: 2113–2117. CrossRef
- Asymmetric dimethylarginine in homocystinuria due to cystathionine β-synthase deficiency: Relevance of renal function
Journal of Inherited Metabolic Disease
Volume 29, Issue 1 , pp 30-37
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- 1. University of New South Wales, Sydney, Australia
- 2. The Professorial Suite, Prince of Wales Hospital, Barker Street, Randwick, Sydney, NSW, 2031, Australia
- 3. The Prince of Wales Hospital, Sydney, Australia
- 5. Children’s Hospital at Westmead, Sydney, Australia
- 4. The University of Sydney, Sydney, Australia