Response to Letter Regarding Article, “Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure”
We read with interest the letter by Drs Kielstein et al about our recent article1 demonstrating that impaired renal function is independently associated with a higher risk for cardiovascular events in patients with chronic heart failure (CHF) and either preserved or reduced left ventricular ejection fraction. The authors state that, although the epidemiological relationship seems to be clear, our article did not fully account for pathophysiological mechanism(s), and point toward an important possible mechanism. In 12 patients with early CHF, Kielstein et al2 demonstrated that before angiotensin-converting enzyme (ACE) inhibitor therapy began, increased concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) were strongly related to reduced renal perfusion. Because reduced perfusion of the kidney is thought to be responsible for reduction of glomerular filtration rate (GFR) in CHF, they concluded that ADMA could be regarded as a candidate to mediate the cardio-renal link regarding impaired GFR.2 Interestingly, chronic inhibition of nitric oxide synthase in otherwise normal animals produces hypertension and focal glomerular sclerosis, the hallmark of progressive chronic kidney disease.3 The authors raise interesting and relevant points which, unfortunately, could not be addressed in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Preliminary data of a study in our own center in a larger cohort (n=86) of patients on ACE inhibition demonstrate that over the full range of severity of CHF, renal perfusion is by far the key factor in reduced GFR, followed by renin-angiotensin system activation and endothelial dysfunction. ADMA is only moderately associated with GFR and renal perfusion. Of particular interest is our finding that not only functional but also structural renal impairment is to be expected when the GFR is below 40 mL/min, as suggested by an exponential increase of urinary albumin excretion in those subjects. The lack of association we observed could be explained by the findings of Chen et al,4 who showed that long-term ACE inhibition reduced ADMA and increased plasma nitrogen oxide levels in patients with syndrome X.
The conclusion of Kielstein et al that intervention for increased levels of ADMA could possibly overcome the potential adverse renal effects of ADMA in patients with CHF is appreciated. However, the underlying mechanisms will undoubtedly be multifactorial, and a multifactorial approach will be an important target for research.
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.
Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998; 32: 958–964.
Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol. 2002; 90: 974–982.