Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Nature Clinical Practice Nephrology volume 2, pages 209–220 (2006)Cite this article

Abstract

Nitric oxide (NO) production is reduced in renal disease, partially due to decreased endothelial NO production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (e.g. those involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylaminohydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene, functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease, or both. These findings provide the rationale for novel therapies, including supplementation of dietary L-arginine or its precursor L-citrulline, inhibition of non-NO-producing pathways of L-arginine utilization, or both. Because an increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably also in CKD), lowering ADMA concentration is a major therapeutic goal; interventions that enhance the activity of the ADMA-hydrolyzing enzyme DDAH are under investigation.

Key Points

  • Production of nitric oxide (NO; from L-arginine and O2 via nitric oxide synthase [NOS]) is reduced in renal disease

  • As chronic NOS inhibition produces hypertension and renal dysfunction in animals, NO deficiency probably contributes to progression of kidney disease in humans

  • Net NO deficiency can develop in response to decreased substrate availability (e.g. perturbed synthesis or transport of arginine) and the action of endogenous NOS inhibitors (e.g. asymmetric dimethylarginine)

  • Potential therapies for kidney disease include supplementation of dietary L-arginine, inhibition of non-NO-producing biochemical processes that consume L-arginine, and decreasing the activity of asymmetric dimethylarginine

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The 24-h output of NO2 + NO3 (i.e. NOX, the stable oxidation products of NO) in subjects with normal renal function (control), patients with chronic kidney disease and approximately 25% residual renal function, and patients with end-stage renal disease undergoing peritoneal dialysis or hemodialysis.
Figure 2: Simplified schematic of the biosynthetic pathway for nitric oxide in vivo.
Figure 3: Effects on L-arginine transport in human dermal microvascular endothelial cells, human glomerular endothelial cells and bovine aortic endothelial cells of 6 h incubation with a 1 in 5 dilution of plasma from healthy subjects (control), or from patients undergoing peritoneal dialysis or hemodialysis.
Figure 4: Pathways of L-arginine metabolism.
Figure 5: Relationship between the nitric oxide synthase activity of plasma and plasma concentrations of: the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine, which is catabolized by dimethylarginine dimethylaminohydrolase; symmetric dimethylarginine, which is not a substrate of dimethylarginine dimethylaminohydrolase; and creatinine and blood urea nitrogen as indices of renal function.
Figure 6: Kaplan–Meier plot of cardiovascular event rate in patients with end-stage renal disease.

References

  1. Baylis C and Vallance P (1998) Measurement of nitrite and nitrate (NOx) levels in plasma and urine; what does this measure tell us about the activity of the endogenous nitric oxide. Current Opinion Nephrol Hypertens 7: 1–4

    Article  Google Scholar 

  2. Schmidt R et al. (1999) Indices of activity of the nitric oxide system in patients on hemodialysis. Am J Kidney Dis 34: 228–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schmidt RJ et al. (1999) Nitric oxide production is low in end stage renal disease patients on peritoneal dialysis. Am J Physiol 276: F794–F797

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmidt RJ and Baylis C (2000) Total nitric oxide production is low in patients with chronic renal disease. Kidney Int 58: 1261–1266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blum M et al. (1998) Low nitric oxide production in patients with chronic renal failure. Nephron 79: 265–268

    Article  CAS  PubMed  Google Scholar 

  6. Wever R et al. (1999) Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 19: 1168–1172

    Article  CAS  PubMed  Google Scholar 

  7. Lau T et al. (2000) Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. J Clin Invest 105: 1217–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vaziri ND et al. (1998) Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH. Am J Physiol 274: F642–F649

    CAS  PubMed  Google Scholar 

  9. Wagner L et al. (2002) Reduced NOS activity in rats with chronic renal disease due to glomerulonephritis. Kidney Int 62: 532–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Erdely A et al. (2003) Protection of Wistar Furth rats from chronic renal disease is associated with maintained renal nitric oxide synthase. J Am Soc Nephrol 14: 2526–2533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Szabo A et al. (2003) Renal neuronal nitric oxide synthase protein expression as a marker of renal function. Kidney Int 64: 1765–1771

    Article  CAS  PubMed  Google Scholar 

  12. Erdely A et al. (2004) Protection against puromycin aminonucleoside-induced chronic renal disease in the Wistar-Furth rat. Am J Physiol 287: F81–F89

    CAS  Google Scholar 

  13. Erdely A et al. (2003) Sexual dimorphism in the aging kidney: effects on injury and nitric oxide system. Kidney Int 63: 1021–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thambyrajah J et al. (2000) Abnormalities of endothelial function in patients with predialysis renal failure. Heart 83: 205–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Böger RH and Zoccali C (2003) ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosclerosis (Suppl 4): S23–S28

  16. Foley RN et al. (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32 (Suppl 3): S112–S119

    Article  CAS  PubMed  Google Scholar 

  17. Baigent C et al. (2000) Premature cardiovascular disease in chronic renal failure. Lancet 356: 147–152

    Article  CAS  PubMed  Google Scholar 

  18. Landray MJ et al. (2004) Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the chronic renal impairment in Birmingham (CRIB) study. Am J Kidney Dis 43: 244–253

    Article  CAS  PubMed  Google Scholar 

  19. Himmelfarb J (2004) Linking oxidative stress and inflammation in kidney disease: which is the chicken and which is the egg? Semin Dial 17: 449–454

    Article  PubMed  Google Scholar 

  20. Zatz R and Baylis C (1998) Chronic nitric oxide inhibition model six years on. Hypertension 32: 958–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peppa M et al. (2004) Glycoxidation and inflammation in renal failure patients. Am J Kidney Dis 43: 690–695

    Article  CAS  PubMed  Google Scholar 

  22. Wu G and Morris SM (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 33: 1–17

    Article  Google Scholar 

  23. Brosnan ME and Brosnan JT (2004) Renal arginine metabolism. J Nutr 134 (Suppl 10): S2791–S2795

    Article  Google Scholar 

  24. Tizianello A et al. (1980) Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J Clin Invest 65: 1162–1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reyes AA et al. (1994) Role of arginine in health and in renal disease. Am J Physiol 267: F331–F346

    CAS  PubMed  Google Scholar 

  26. Xiao S et al. (2001) Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells. Am J Physiol Renal Physiol 280: F989–F995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wagner L et al. (2002) Urea transporters are widely distributed in endothelial cells and mediate inhibition of L-arginine transport. Am J Physiol Renal Physiol 283: F578–F582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Devés R and Boyd CAR (1998) Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev 78: 487–545

    Article  PubMed  Google Scholar 

  29. Swendseid ME et al. (1975) Amino acid metabolism in the chronically uremic rat. Clin Nephrol 3: 240–246

    CAS  PubMed  Google Scholar 

  30. Bergström J et al. (1990) Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. Kidney Int 38: 108–114

    Article  PubMed  Google Scholar 

  31. Vallance P et al. (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572–575

    Article  CAS  PubMed  Google Scholar 

  32. Fleck C et al. (2001) Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in renal failure patients. Kidney Int Suppl 78: S14–S18

    Article  CAS  PubMed  Google Scholar 

  33. Kielstein JT et al. (1999) Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 10: 594–600

    CAS  PubMed  Google Scholar 

  34. Wahbi N et al. (2001) Dimethylarginines in chronic renal failure. J Clin Pathol 54: 470–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bogle RG et al. (1995) Induction of NG-monomethyl-L-arginine uptake: a mechanism for differential inhibition of NO synthases? Am J Physiol Cell Physiol 269: C750–C756

    Article  CAS  Google Scholar 

  36. Closs EI et al. (1997) Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier HCAT-2B. Nitric Oxide 1: 65–73

    Article  CAS  PubMed  Google Scholar 

  37. Schwartz IF et al. (2006) Arginine uptake is attenuated, through modulation of cationic amino acid transporter-1, in uremic rats. Kidney Int 69: 298–303

    Article  CAS  PubMed  Google Scholar 

  38. Mendes Ribeiro AC et al. (1999) Identification of system y+L as the high-affinity transporter for L-arginine in human platelets: up-regulation of L-arginine influx in uraemia. Eur J Physiol 438: 573–575

    CAS  Google Scholar 

  39. Mendes Ribeiro AC et al. (1997) Transport of L-arginine and the nitric oxide inhibitor NG-monomethyl-L-arginine in human erythrocytes in chronic renal failure. Clin Sci 93: 57–64

    Article  CAS  PubMed  Google Scholar 

  40. Cross JM et al. (2001) Acute administration of L-arginine does not improve arterial endothelial function in chronic renal failure. Kidney Int 60: 2318–2323

    Article  CAS  PubMed  Google Scholar 

  41. Bennett–Richards KJ et al. (2002) Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure. Kidney Int 62: 1372–1378

    Article  PubMed  Google Scholar 

  42. Hand MF et al. (1998) Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. Kidney Int 53: 1068–1077

    Article  CAS  PubMed  Google Scholar 

  43. De Nicola L et al. (1999) Randomized, double-blind, placebo-controlled study of arginine supplementation in chronic renal failure. Kidney Int 56: 674–684

    Article  CAS  PubMed  Google Scholar 

  44. Zhang XZ et al. (2001) L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction. Clin Nephrol 55: 453–459

    PubMed  Google Scholar 

  45. Peters H et al. (1999) From rats to man: a perspective on dietary L-arginine supplementation in human renal disease. Nephrol Dial Transplant 14: 1640–1650

    Article  CAS  PubMed  Google Scholar 

  46. McDonald KK et al. (1997) A caveolar complex between the cationic amino acid transporter 1 and endothelial nitric-oxide synthase may explain the “arginine paradox”. J Biol Chem 272: 31213–31216

    Article  CAS  PubMed  Google Scholar 

  47. Kurtz S and Harrison DG (1997) Insulin and the arginine paradox. J Clin Invest 99: 369–370

    Article  Google Scholar 

  48. Palmer RMJ et al. (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333: 664–666

    Article  CAS  PubMed  Google Scholar 

  49. Li C et al. (2005) Interaction of the eNOS with the CAT-1 arginine transporter enhances NO release by a mechanism not involving arginine transport. Biochem J 386: 567–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Segal MS et al. (2006) Endothelial health and diversity in the kidney. J Am Soc Nephrol 7: 323–324

    Article  Google Scholar 

  51. Zani BG and Bohlen HG (2005) Transport of extracellular L-arginine via cationic amino acid transporter is required during in vivo endothelial NO production. Am J Physiol Heart Circ Physiol 289: H1381–H1390

    Article  CAS  PubMed  Google Scholar 

  52. Ishizuka S et al. (2000) Agmatine inhibits cell proliferation and improves renal function in anti-Thy-1 glomerulonephritis. J Am Soc Nephrol 11: 2256–2264

    CAS  PubMed  Google Scholar 

  53. Schwartz D et al. (1997) Agmatine affects glomerular filtration via a nitric oxide synthase-dependent mechanism. Am J Physiol 272: F597–F601

    CAS  PubMed  Google Scholar 

  54. Morrissey JJ and Klahr S (1997) Agmatine activation of nitric oxide synthase in endothelial cells. Proc Assoc Am Physicians 109: 51–57

    CAS  PubMed  Google Scholar 

  55. Li H et al. (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280: E75–E82

    Article  CAS  PubMed  Google Scholar 

  56. Sabbatini M et al. (2003) Arginase inhibition slows the progression of renal failure in rats and renal ablation. Am J Physiol Renal Physiol 284: F680–F687

    Article  CAS  PubMed  Google Scholar 

  57. Zhang C et al. (2004) Upregulation of vascular arginase in hypertension decreases nitric oxide mediated dilation of coronary arterioles. Hypertension 44: 935–943

    Article  CAS  PubMed  Google Scholar 

  58. Johnson FK et al. (2005) Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. Am J Physiol Regul Integr Comp Physiol 288: 1057–1062

    Article  CAS  Google Scholar 

  59. Demougeot C et al. (2005) Arginase inhibition reduces endothelial dysfunction and blood pressure rising in SHR. J Hypertension 23: 971–978

    Article  CAS  Google Scholar 

  60. Xiao S et al. (2000) Plasma from ESRD patients inhibits nitric oxide synthase (NOS) activity in cultured human and bovine endothelial cells. Acta Phys Scand 168: 175–179

    Article  CAS  Google Scholar 

  61. McAllister RJ et al. (1994) Effects of guanidino and uremic compounds on nitric oxide pathways. Kidney Int 45: 737–742

    Article  Google Scholar 

  62. Leiper J and Vallance P (1999) Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43: 542–548

    Article  CAS  PubMed  Google Scholar 

  63. Achan V 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

    Article  CAS  PubMed  Google Scholar 

  64. Kielstein JT et al. (2004) Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetric dimethylarginine in humans. Circulation 109: 172–177

    Article  CAS  PubMed  Google Scholar 

  65. Vallance P and Leiper J (2005) ADMA and kidney disease—marker or mediator. J Am Soc Nephrol 16: 2254–2256

    Article  PubMed  Google Scholar 

  66. Scalera F et al. (2005) Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol 16: 892–898

    Article  CAS  PubMed  Google Scholar 

  67. Ueno S et al. (1992) Distribution of free methylarginines in rat tissues and in the bovine brain. J Neurochem 59: 2012–2016

    Article  CAS  PubMed  Google Scholar 

  68. Casellas P and Jeanteur P (1978) Protein methylation in animal cells. I. Purification and properties of S-adenosyl-L-methionine: protein (arginine) N-methyltransferase from Krebs II ascites cells. Biochim Biophys Acta 519: 243–254

    Article  CAS  PubMed  Google Scholar 

  69. Casellas P and Jeanteur P (1978) Protein methylation in animal cells. II. Inhibition of S-adenosyl–L–methionine: protein (arginine) N–methyltransferase by analogs of S-adenosyl-L-homocysteine. Biochim Biophys Acta 519: 255–268

    Article  CAS  PubMed  Google Scholar 

  70. Liu Q and Dreyfuss G (1995) In vivo and in vitro arginine methylation of RNA–binding proteins. Mol Cell Biol 15: 2800–2808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Böger RH et al. (2000) LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 87: 99–105

    Article  PubMed  Google Scholar 

  72. Osanai T et al. (2003) Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells. Hypertension 42: 985–990

    Article  CAS  PubMed  Google Scholar 

  73. Leiper JM et al. (1999) Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 343: 209–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tojo A et al. (1997) Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 52: 1593–1601

    Article  CAS  PubMed  Google Scholar 

  75. Kimoto M et al. (1993) Detection of NG, NG-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch Biochem Biophys 300: 657–662

    Article  CAS  PubMed  Google Scholar 

  76. Nijveldt RJ et al. (2003) Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol Dial Transplant 18: 2542–2550

    Article  CAS  PubMed  Google Scholar 

  77. Nijveldt RJ et al. (2002) Net renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine in fasting humans. Nephrol Dial Transplant 17: 1999–2002

    Article  CAS  PubMed  Google Scholar 

  78. MacAllister RJ et al. (1996) Regulation of nitric oxide synthesis by dimethlarginine dimethylaminohydrolase. British J Pharm 119: 1533–1540

    Article  CAS  Google Scholar 

  79. Dayoub H et al. (2003) Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 108: 3042–3047

    Article  CAS  PubMed  Google Scholar 

  80. Tran CT et al. (2000) Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 68:101–105

    Article  CAS  PubMed  Google Scholar 

  81. Jones LC et al. (2003) Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem Biophys Res Commun 310: 836–843

    Article  CAS  PubMed  Google Scholar 

  82. Akbar F et al. (2005) Haplotypic association of DDAH1 with susceptibility to pre-eclampsia. Mol Hum Reprod 11: 73–77

    Article  CAS  PubMed  Google Scholar 

  83. Pettersson A et al. (1998) Increased circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in preeclampsia. Acta Obstet Gynecol Scand 77: 808–813

    Article  CAS  PubMed  Google Scholar 

  84. Ito A et al. (1999) Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99: 3092–3095

    Article  CAS  PubMed  Google Scholar 

  85. Leiper J et al. (2002) S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci USA 99: 13527–13532

    Article  CAS  PubMed  Google Scholar 

  86. Millatt LJ et al. (2003) Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 108: 1493–1498

    Article  CAS  PubMed  Google Scholar 

  87. Lin KY et al. (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106: 987–992

    Article  CAS  PubMed  Google Scholar 

  88. Stuhlinger MC et al. (2001) Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 104: 2569–2575

    Article  CAS  PubMed  Google Scholar 

  89. Kimoto M et al. (1995) Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level. Br J Pharmacol 135: 1175–1182

    Google Scholar 

  90. Saran R et al. (2003) Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study. Nephrol Dial Transplant 18: 2415–2420

    Article  CAS  PubMed  Google Scholar 

  91. Achan V et al. (2002) All-trans-retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res 90: 764–769

    Article  CAS  PubMed  Google Scholar 

  92. Deng S et al. (2004) Aspirin protected against endothelial damage induced by LDL: role of endogenous NO synthase inhibitors in rats. Acta Pharmacol Sin 25: 1633–1639

    CAS  PubMed  Google Scholar 

  93. DP Holden et al. (2003) Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation 108: 1575–1580

    Article  CAS  PubMed  Google Scholar 

  94. Xiao S et al. (2001) Circulating eNOS inhibitory factor in some patients with chronic renal disease. Kidney Int 59: 1466–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kielstein JT et al. (2002) Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 13: 170–176

    CAS  PubMed  Google Scholar 

  96. Zoccali C et al. (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358: 2113–2117

    Article  CAS  PubMed  Google Scholar 

  97. Zoccali C et al. (2002) Asymmetric dimethylarginine, C–reactive protein, and carotid intima–media thickness in end-stage renal disease. J Am Soc Nephrol 13: 490–496

    Article  CAS  PubMed  Google Scholar 

  98. Zoccali C et al. (2002) Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int 62: 339–345

    Article  CAS  PubMed  Google Scholar 

  99. Surdacki A et al. (1999) Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 33: 652–658

    Article  CAS  PubMed  Google Scholar 

  100. Valkonen VP et al. (2001) Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358: 2127–2128

    Article  CAS  PubMed  Google Scholar 

  101. Sydow K et al. (2004) Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 9: 93–101

    Article  PubMed  Google Scholar 

  102. Bode-Böger SM et al. (2005) Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc Med 10 (Suppl 1): S65–S71

    Article  PubMed  Google Scholar 

  103. Guthrie SM et al. (2004) The NO pathway modulates hemangioblast activity of adult hematopoietic stem cells. Blood 105: 1916–1922

    Article  PubMed  CAS  Google Scholar 

  104. Thum T et al. (2005) Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol 46: 1693–1701

    Article  CAS  PubMed  Google Scholar 

  105. Smith CL et al. (2003) Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem Biophys Res Commun 308: 984–989

    Article  CAS  PubMed  Google Scholar 

  106. Azuma H et al. (1995) Accumulation of endogenous inhibitors for nitric oxide synthesis and decreased content of L-arginine in regenerated endothelial cells. Br J Pharmacol 115: 1001–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. De Groot K et al. (2004) Uremia causes endothelial progenitor cell deficiency. Kidney Int 66: 641–646

    Article  PubMed  Google Scholar 

  108. Ravani P et al. (2005) Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol 16: 2449–2455

    Article  CAS  PubMed  Google Scholar 

  109. Fliser D et al. (2005) Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study. J Am Soc Nephrol 16: 2456–2461

    Article  CAS  PubMed  Google Scholar 

  110. Anderstam B et al. (1997) Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 18: 1437–1442

    Google Scholar 

  111. Bergamini S et al. (2004) Relationship of asymmetric dimethylarginine to haemodialysis hypotension. Nitric Oxide 11: 273–278.

    Article  CAS  PubMed  Google Scholar 

  112. Kielstein JT et al. (2004) Low dialysance of asymmetric dimethylarginine (ADMA)—in vivo and in vitro evidence of significant protein binding. Clin Nephrol 62: 295–300

    Article  CAS  PubMed  Google Scholar 

  113. Baylis C (2005) Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system. Exp Gerontol 40: 271–27855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The support of NIH grants R01 DK56843 and DK 45517 is gratefully acknowledged.

Author information

Authors and Affiliations

  1. University of Florida, Gainesville, FL, USA

    Chris Baylis

Authors
  1. Chris Baylis
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Baylis, C. Arginine, arginine analogs and nitric oxide production in chronic kidney disease. Nat Rev Nephrol 2, 209–220 (2006). https://doi.org/10.1038/ncpneph0143

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0143

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing