The link between renal denervation and reduction of cardiovascular risks: Simplicity or not?

Abstract

It has been demonstrated that abnormalities of the sympathetic nervous system strongly contribute to the development and/or maintenance of multiple disease states such as hypertension, heart failure, diabetes mellitus, sleep apnea, kidney disease and arrhythmias [1]. When we look through the window of hypertension, the renal nerves have been identified as important contributors in both development and maintenance of hypertension [2]. We read with great enthusiasm the article written by Ott and colleagues evaluating the effect of renal denervation (RDN) on elevated urinary albumin-to-creatinine ratio (UACR) in patients with resistant hypertension [3]. They have subdivided the patients according to their UACR at baseline into micro(30–300 mg/g, n = 37) and macroalbuminuria (300–2200 mg/g, n = 22) and found a significant reduction in UACR in all patients (p b 0.001) and in both subgroups (p b 0.001). They have implicated that, following RDN, the magnitude of albuminuria as well as the prevalence of microand macroalbuminuria decreased in patients with treatment-resistant hypertension and concluded that, since albuminuria is an independent renal and cardiovascular risk factor, a reduction of renal and cardiovascular risk could be achieved by RDN in these patients. The effect of catheter-based RDN on resistant hypertension in humans was assessed clinically in 2009, by the first proof-of-principle multicenter study from 45 patients with treatment-resistant hypertension [4]. The initial cohort was subsequently expanded from 45 to 153 patients, and the follow-up durationwas increased to a minimum of 2 years (Symplicity HTN-1) [5]. Both studies reported promising results favoring RDN. As it was an unblinded prospective cohort study without a control group, it was soon followed by the Symplicity HTN-2 trial to further assess RDN in a randomized fashion [6]. The Symplicity HTN-2 included 106 patients with severe resistant hypertensionwhowere randomized to RDN and conventional medical therapy versus conventional medical therapy alone. RDN was found to bemore effective thanmedical therapy alone in reducing blood pressure (BP), causing a reduction of 32 mmHg in systolic and 12 mm Hg in diastolic BP in the RDN group and no significant change in the control group. However, no changes in renal function or UACRwere identified in either group. The studywasdesigned such that patients from the control group were allowed to crossover to RDN therapy after six months, provided that the BP remained uncontrolled with a systolic BP greater than 160mmHg. Interestingly, the crossover group consisting of 35 patients experienced a significant drop in BP similar to that observed in the initial RDN group at 6 months' follow-up [7]. Recently published long-term results of the Symplicity HTN-1 study also imply that the efficacy gradually increases in 3 years' follow-up [7]. There is also evidence that patients with milder forms of hypertension may benefit from RDN [8]. Furthermore, there is emerging evidence that RDN may have a role in the treatment of heart failure, obstructive sleep apnea, insulin resistance, atrial fibrillation, hypertension associatedwith end-stage renal disease and, as shown recently, even in patients with ventricular storm where sympathetic nervous system seems to have a crucial role [9–13]. Thus, given the fact that resistant hypertension and other diseases associated with elevated sympathetic tone have significant morbidity and mortality rates, RDN therapy might be expected to have a crucial role on public health. However, the results of the Symplicity-3 trial overturned this optimistic mood about the RDN [14]. In the Symplicity HTN-3 study, RDN had no significant effect on office or 24-hour ambulatory systolic BP, findings that contradict most published studies on RDN. A recent trial even suggested inferiority of RDN as compared to adjusted drug treatment [15]. There is now growing evidence of lack of BP response following RDN in up to 50% of cases in some reports [16,17]. Clinical use of RDN had significantly increased after the encouraging results of Symplicity HTN-1 trial [5]. Afterwards, clinical studies with encouraging results appeared in the literature [18–20]. Parallel to these developments, medical device companies fancied RDN as the next big innovation and as a blockbuster therapy for millions of patients with resistant hypertension. But, what exactly happened that suddenly reversed this optimistic mood? Actually, it seems like there is no significant change; only the puzzle pieces are beginning to fall into place. Possibly because of the methodological problems involved in the initial studies, exaggerated interpretations led to heightened expectations from this exciting new treatment modality. There are three crucial points which need to be discussed.