Letter by Kielstein et al Regarding Article, “Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure”
To the Editor:
Chronic renal disease, even with minor impairment of renal function, has only recently been recognized as a cardiovascular risk factor. Hillege et al1 confirmed and extended this knowledge substantially in their article. In their study, renal impairment was predictive of adverse outcome in patients with a broad spectrum of heart failure. Although the epidemiological relationship seems to be clear beyond any doubt, theories on the pathophysiological mechanism(s) underpinning such a link have not taken into full account all the available knowledge on this issue. One particular mechanism, the increased concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), would fit well with the findings in this study. In patients with renal diseases, ADMA is increased even when the glomerular filtration rate is still within the normal range.2
Epidemiological studies showed that ADMA is a strong predictor of cardiovascular mortality in patients with coronary artery disease and patients with moderate renal failure, as well as in dialysis patients.3,4 Acute infusion of ADMA in healthy volunteers reduces cardiac output, increases systemic vascular resistance, and triggers a well-defined decrease in renal perfusion.5 Most importantly, ADMA is strongly associated with renal hemodynamic changes in patients with early heart failure, therefore should be regarded as a potential candidate mediating the cardio-renal link.
We believe that there is solid evidence indicating that the incorporation of renal function testing into algorithms assessing the cardiovascular risk profile should go beyond measuring serum creatinine. It cannot be over-emphasized that serum creatinine only rises after a substantial loss of glomerular function and depends on many other factors like gender, weight, and race. Estimation of glomerular filtration rate by using the Cockroft-Gault or the Modification of Diet in Renal Disease Study formula, as used in the study by Hillege et al,1 and screening for microalbuminuria should become standard of care.
Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, Granger CB, Michelson EL, Ostergren J, Cornel JH, de Zeeuw D, Pocock S, van Veldhuisen DJ. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006; 113: 671–678.
Kielstein JT, Boger RH, Bode-Boger SM, Frolich JC, Haller H, Ritz E, Fliser D. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol. 2002; 13: 170–176.
Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Munzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res. 2005; 97: e53–e59.
Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F, Zoccali C. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol. 2005; 16: 2449–2455.
Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation. 2004; 109: 172–177.