Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine?

Jan T. Kielstein1,, Stefanie M. Bode-Böger2, Hermann Haller1 and Danilo Fliser1

1 Department of Internal Medicine, Medical School Hannover and 2 Institute of Clinical Pharmacology, Otto-von-Guericke University Magdeburg, Germany

Keywords: elderly; glomerulosclerosis; hypertension; renal perfusion; renovascular esistance

Age-related changes of renal haemodynamics

Normal human ageing occurs with morphological and functional changes in nearly all organ systems, and the kidney is no exception to this rule. Even in individuals without primary renal disease, kidney structure and function deteriorate with senescence to some extent. Recent studies have revealed, however, that age-related renal changes are accelerated by co-morbid conditions such as hypertension, atherosclerosis and heart failure [15].

Results from the seminal ‘Baltimore Longitudinal Study on Aging’ and from several cross-sectional studies have shown that the decrease of glomerular filtration rate (GFR) in healthy elderly subjects is less than was thought previously [1,3,6,7]. In some elderly individuals, even no change of GFR was documented over a time span of at least 25 years [6]. Thus, in a reasonable number of healthy elderly subjects, the GFR remains within the (lower) normal range. In contrast, effective renal plasma flow (ERPF) decreases proportionally more than GFR, and this finding may explain in part the observed increase of filtration fraction (FF) in elderly individuals, i.e. the ratio between GFR and ERPF [3,7]. Furthermore, the decrease of ERPF out of proportion to the blood pressure in the healthy elderly implies that the renovascular resistance (RVR) must be elevated. Indeed, we and others have shown that RVR is significantly increased in normotensive elderly individuals without cardiovascular disease [3,8]. Renal vasoconstriction is even more pronounced in the elderly with co-morbidity such as hypertension or heart failure [3,7,9]. Thus, the hallmark of renal ageing is increased basal renovascular tone accompanied by reduced perfusion, and these age-related changes are accentuated in patients with cardiovascular co-morbidity. In addition, the ability of (post-glomerular) vessels to dilate in response to stimuli such as acetylcholine, amino acids or nitric oxide (NO) is also reduced in the elderly [1012]. It is still unresolved whether these age-related changes in renal haemodynamics are caused by structural abnormalities, or whether there also exists a functional abnormality, i.e. reduced capacity of renal vessels to dilate as a consequence of reduced availability of (or responsiveness to) vasodilator substances. Experimental studies and studies in humans support the latter concept [1013]. In this context, it has to be pointed out that the renal microvasculature is particularly sensitive to NO synthase (NOS) inhibition; this has been demonstrated in animal experiments as well as in human studies [1416]. The observation points to an important role for NO in the regulation of (basal) medullary blood flow, and in the control of the pressure-natriuresis [16].

Ageing and asymmetric dimethylarginine

In a cross-sectional study of a random population sample, a significant positive correlation was found between age, blood pressure and plasma levels of asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of NOS [17]. ADMA is released from proteins that have been post-translationally methylated and subsequently hydrolysed. These proteins are found largely in the nucleolus and appear to be involved in RNA processing and transcriptional control. Two types of enzymes methylate arginine residues: type I protein arginine methyltransferase forms ADMA, whereas type II forms symmetric dimethylarginine, i.e. the biologically inactive stereoisomer of ADMA. ADMA is excreted by the kidneys to some extent, but the predominant degradation pathway is by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyses ADMA to dimethylamine and L-citrulline (Figure 1Go) [18,19]. Co-localization of DDAH and NOS in various cell types including renal tubular cells supports the hypothesis that the intracellular concentration of ADMA is regulated actively and cell specifically in NO-generating cells [20]. Further evidence for this hypothesis comes from results of a recently published experimental study showing an inhibitory effect of NO on DDAH activity, thus regulating its own (local) concentration via the metabolism of ADMA [21] (Figure 1Go). Several experimental and clinical studies have documented that DDAH activity is reduced in the presence of hypercholesterolaemia and insulin resistance [19,22], i.e. conditions that have a high prevalence among elderly subjects. Direct measurements of DDAH activity are not yet available, however, and age-related alterations in DDAH activity have not been reported so far.



View larger version (27K):
[in this window]
[in a new window]
 
Fig. 1.  Biochemical pathways for generation and degradation of the endogenous nitric oxide synthase inhibitor ADMA (for explanation, also see text).

 

Asymmetric dimethylarginine and renal ageing

Whatever the cause(s) of increased ADMA blood levels in the elderly, they may reduce NO availability by NOS inhibition and thus contribute to endothelial dysfunction and arteriosclerosis, and finally lead to increased renovascular resistance and hypertension [19,23]. This hypothesis is supported by the finding of significantly increased plasma ADMA concentrations even in non-smoking healthy normotensive elderly subjects, in parallel with significantly reduced renal perfusion (Table 1Go) [24]. Furthermore, in logistic regression analysis, the plasma ADMA level was the only significant predictor of reduced ERPF and increased RVR, explaining a large part of their variability in elderly individuals. A significant relationship between plasma ADMA and the level of blood pressure was also documented, and this observation is in line with recently published results [17]. Although the increase of plasma ADMA levels in normotensive and hypertensive elderly subjects as compared with normotensive young subjects was moderate, we emphasize that according to several studies in different populations, even small differences in mean plasma ADMA levels (i.e. ~1 µmol/l) are associated with a deterioration of endothelial function and a significant increase in the rate of cardiovascular events in the long term [18,25,26]. Taken together, these findings are compatible with the notion that an increase of blood ADMA levels with senescence is linked to the reduction of renal perfusion and increase in blood pressure. Indirect support for this assumption comes from studies in laboratory animals, in which administration of ADMA significantly reduced renal perfusion and increased renovascular tone, and, in parallel, blood pressure [27]. We have confirmed these findings in healthy subjects, in whom systemic ADMA infusion significantly decreased ERPF and increased RVR and mean arterial blood pressure [28].


View this table:
[in this window]
[in a new window]
 
Table 1.  ADMA blood concentrations, renal haemodynamics and blood pressure in young and elderly normotensive subjects and elderly hypertensive patients

 
In summary, recent studies provide evidence for a significant relationship between increased blood levels of the endogenous NOS inhibitor ADMA, and reduced renal perfusion and high blood pressure in senescence. The role of ADMA in the pathophysiology of age-related endothelial dysfunction, resulting in increased renovascular tone and blood pressure, has to be elucidated further.

Notes

Correspondence and offprint requests to: J. T. Kielstein, MD, Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Email: Kielstein{at}yahoo.com Back

References

  1. Lindeman RD, Tobin JD, Shock NW. Association between blood pressure and the rate of decline in renal function with age. Kidney Int 1984; 26:861–868[ISI][Medline]
  2. Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 1987; 31:1153–1159[ISI][Medline]
  3. Fliser D, Franek E, Joest M, Block S, Mutschler E, Ritz E. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int 1997; 51:1196–1204[ISI][Medline]
  4. Bleyer AJ, Shemanski LR, Burke GL, Hansen KJ, Appel RG. Tobacco, hypertension, and vascular disease: risk factors for renal function decline in an older population. Kidney Int 2000; 57:2072–2079[CrossRef][ISI][Medline]
  5. Ribstein J, Du Cailar G, Mimran A. Glucose tolerance and age-associated decline in renal function of hypertensive patients. J Hypertens 2001; 19:2257–2264[CrossRef][ISI][Medline]
  6. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33:278–285[ISI][Medline]
  7. Fliser D, Ritz E. The relationship between hypertension and renal function and its therapeutic implications in the elderly. Gerontology 1998; 44:123–131[CrossRef][ISI][Medline]
  8. Schmieder RE, Schachinger H, Messerli FH. Accelerated decline in renal perfusion with aging in essential hypertension. Hypertension 1994; 23:351–357[Abstract]
  9. Cody RJ, Torre S, Clark M, Pondolfino K. Age-related hemodynamic, renal, and hormonal differences among patients with congestive heart failure. Arch Intern Med 1989; 149:1023–1028[Abstract]
  10. Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol 1993; 3:1371–1377[Abstract]
  11. Higashi Y, Oshima T, Ozono R, Matsuura H, Kajiyama G. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension 1997; 30:252–258[Abstract/Free Full Text]
  12. Fuiano G, Sund S, Mazza G et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int 2001; 59:1052–1058[CrossRef][ISI][Medline]
  13. Sabbatini M, Sansone G, Uccello F et al. Functional versus structural changes in the pathophysiology of acute ischemic renal failure in aging rats. Kidney Int 1994; 45:1355–1361[ISI][Medline]
  14. Lahera V, Salom MG, Miranda-Guardiola F, Moncada S, Romero JC. Effects of NG-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol 1991; 261:F1033–F1037[ISI][Medline]
  15. Broere A, Van Den Meiracker AH, Boomsma F, Derkx F, Man in't Veld AJ, Schalekamp MADH. Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME. Am J Physiol 1998; 275:F870–F877[ISI][Medline]
  16. Granger JP, Alexander BT. Abnormal pressure-natriuresis in hypertension: role of nitric oxide. Acta Physiol Scand 2000; 68:161–168[CrossRef]
  17. Miyazaki H, Matsuoka H, Cooke JP et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 1999; 99:1141–1146[Abstract/Free Full Text]
  18. Kielstein JT, Boger RH, Bode-Boger SM et al. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol 2002; 13:170–176[Abstract/Free Full Text]
  19. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol 2000; 20:2032–2037[Abstract/Free Full Text]
  20. Tojo A, Welch WJ, Bremer V et al. Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 1997; 52:1593–1601[ISI][Medline]
  21. Leiper J, Murray-Rust J, McDonald M, Vallance P. S-nitrosylation of dimethylarginine dimethylamino-hydrolase regulates enzyme activity: further interaction between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc Natl Acad Sci USA 2002; 99:13527–13532[Abstract/Free Full Text]
  22. Stuhlinger MC, Abbasi F, Chu JW et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. J Am Med Assoc 2002; 287:1420–1426[Abstract/Free Full Text]
  23. Xiong Y, Yuan LW, Deng HW, Li YJ, Chen BM. Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin Exp Pharmacol Physiol 2001; 28:842–847[CrossRef][ISI][Medline]
  24. Kielstein JT, Bode-Böger SM, Frölich C, Ritz E, Haller H, Fliser D. Asymmetric dimethylarginine blood pressure and renal perfusion in elderly subjects. Circulation 2003; 107:1891–1895[Abstract/Free Full Text]
  25. Zoccali C, Bode-Boger S, Mallamaci F et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001; 358:2113–2117[CrossRef][ISI][Medline]
  26. Vallance P. Importance of asymmetrical dimethylarginine in cardiovascular risk. Lancet 2001; 358:2096–2097[CrossRef][ISI][Medline]
  27. Gardiner SM, Kemp PA, Bennett T, Palmer RM, Moncada S. Regional and cardiac haemodynamic effects of NG, NG,dimethyl-L-arginine and their reversibility by vasodilators in conscious rats. Br J Pharmacol 1993; 110:1457–1464[Abstract]
  28. Kielstein JT, Impraim B, Simmel S et al. Asymmetric dimethylarginine (ADMA) is a potent and long-lasting inhibitor of nitric oxide synthase. Kidney Blood Press Res 2002; 25:130A




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (3)
Disclaimer
Request Permissions
Google Scholar
Articles by Kielstein, J. T.
Articles by Fliser, D.
PubMed
PubMed Citation
Articles by Kielstein, J. T.
Articles by Fliser, D.