Response to Letter Regarding Article, “Renal Function as a Predictor of Outcome in a Broad Spectrum of Patients With Heart Failure”

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 article 1 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 al 2 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 (nϭ86) 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