Catheter-based renal denervation and renal function: no evidence of harm but is there a hope of nephroprotection?

Catheter-based renal denervation (RDN) was introduced into clinical practice in 2009 [1] and immediately generated great hope and enthusiasm for the effective treatment of refractory hypertension as spectacular reductions of both systolic and diastolic blood pressure (BP) were achieved [2, 3]. It is important to stress that this invasive method was frequently performed in patients with compromised kidney function (where the use of contrast media is especially dangerous for kidney function) and was routinely done not by nephrologists (who were often not even present in the team during the work-up of the eligibility of patients for RDN), but by invasive cardiologists or radiologists. This is one of the reasons why kidney function was not systematically assessed before or after RDN in many randomized clinical trials (RCTs). The goals of such studies were usually to reduce BP, and several RCTs or observational studies in several centres were able to achieve this aim [4]. However, in some relatively small studies, other potential benefits of RDN were used as the treatment target, namely reduction of the clinical symptoms of sleep apnoea [5], improvement of blood glucose level [6], or a reduction of left ventricular hypertrophy [7] or atrial fibrillation [8]. In a few studies, RDN was performed in patients with chronic kidney disease (CKD) and significant reduction of the slope of kidney function deterioration or proteinuria was demonstrated [9]. Such an effect of RDN was, to some extent, expected as hyperactivity of the sympathetic nervous system is present in all patients with CKD and unquestionably participates in both the pathogenesis of elevated BP and the progression of CKD into end-stage kidney disease. There are several BP-dependent and BP-independent mechanisms by which hyperactivity of the sympathetic nervous system participates in the pathogenesis of CKD [10, 11]. It has already been documented that pharmacological treatment with drugs that decrease the activity of the sympathetic nervous system is effective in the reduction of progression of CKD in both experimental models [12] and clinical situations [13]. Widespread usage of RDN was rapidly reduced in 2014 when the results from a sham-controlled trial [14] and those concerning RDN were compared with active therapy [15], particularly the combination of mineralocorticosteroid receptor blockers [16]. Large meta-analyses recently reported the benefits of RDN to be less significant than previously thought [17]. It is difficult to explain the discrepancy between the results from the first RDN (not sham-controlled) studies and studies where a sham procedure served as the control group, but it seems that the selection of centres and/or patients in the early studies may not have been entirely appropriate [18]. In addition, there are still no clinically applicable methods that prove the effectiveness of renal nerve ablation, especially in situations where the anatomy of renal nerves was not taken into consideration when RDN was introduced into routine clinical practice [19, 20]. As a consequence of the negative studies described above, several trials with RDN were stopped and the development of new techniques and types of catheters slowed down. Since 2015, several National Societies of Hypertension have stopped recommending RDN as a therapeutic procedure in patients with resistant hypertension [21] and allow RDN only for appropriately prepared clinical trials. Additionally, the European Society of Hypertension recommends RDN trials only in very experienced centres with the use of a sham procedure, enhanced by additional factors like 24-h Ambularory Blood Pressure Measurement (ABPM), testing of the adherence to medical treatment and long-term assessment of the renal artery and renal function [22]. The question arises, is there a future for RDN? Certainly, in some well-selected patients with resistant hypertension (with confirmed good adherence for the medical treatment) where spironolactone is not effective, RDN can still be considered [23]. RDN can also be offered to patients with relatively benign forms of hypertension and results of the SPYRAL HTN-OFF study, which is currently investigating its use in subjects with stage 2 hypertension on no antihypertensive medication, will answer this question [24]. Interestingly, other indications for RDN, like reduction of kidney pain [25] or symptoms of sleep apnoea syndrome [26], are also very promising. Finally, for nephrologists, the dream of achieving renoprotection via RDN may become a real possibility, as relatively small prospective studies have shown that significant reductions of the slope of glomerular filtration rate (GFR) decline [9] or decreased proteinuria [27, 28] can be achieved. However, to date there have been few studies where kidney function after RDN has been systematically assessed over at least several months (in order to eliminate the effect of contrast media on GFR during the first weeks after RDN). In this issue of NDT, Sanders et al. report the results of a systematic search of the Embase and Medline databases to identify studies reporting on the effects of catheter-based RDN on renal outcome [29]. The main indication for performing RDN was hypertension (82.7% of RDN studies) and radiofrequency ablation was the predominant RDN method. From 1034 citations, 52 studies (389 cohort studies, 4 non-randomized comparative studies and 10 randomized controlled trials) reporting on 56 RDN cohorts were included in meta-analyses and another 14 studies in a qualitative review. In total, 2381 patients were eligible for determination of the change of GFR after RDN. It is important to stress that to increase the number of patients, the authors included not only RCTs but also observational follow-up studies, which are often larger and with longer follow-up duration. Assessment of kidney function was based on analysis of estimated GFR (eGFR) (by Modification of Diet in Renal Disease, MDRD; Cockcroft-Gault; or Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI formulas) because, according to the authors, ‘it is a reliable and frequently measured parameter of renal function’. Other objectives were quantification of the effect on serum creatinine, serum cystatin C levels and urinary protein concentrations [urine/albumin and/or protein concentration; urine albumin/creatinine ratio (ACR) or protein/creatinine ratio]. The pooled mean change in eGFR was 0.64 mL/min/1.73 m2 (95% confidence interval −0.47 to 1.76, P = 0.26) after a mean follow-up time of 9 months after RDN. Additionally, ACR significantly improved, based on five studies. Furthermore, younger age, lower body mass index and a greater reduction of the number antihypertensive drugs given after RDN had positive effects on the course of eGFR. The general conclusion from this study is that RDN is safe with respect to subsequent renal function up to at least 9 months after the procedure. These results are certainly interesting and important for nephrologists. As RDN was indicated for patients with resistant hypertension and in some studies also for patients with CKD, we can expect that the natural decline of GFR in a such a high-risk population will be greater [surprisingly enough the pooled mean eGFR was relatively high in this population (75.6 ± 23.0 mL/min/1.73 m2)] than 0.64 mL/min/1.73 m2, which means that RDN may be considered as a nephroprotective procedure. Such a conclusion was not expressed by the authors of this study because of a lack of comparable control group with natural changes of eGFR or information about changes of eGFR observed during the same period of time before RDN. Nevertheless, younger age, lower body mass index and a greater reduction of antihypertensive drugs given after RDN had a positive effect on the course of eGFR [29]. Our hope for a nephroprotective effect of RDN is supported by the positive results obtained in patients with CKD [27, 28] and the overall decline of albuminuria obtained in this current meta-analysis [29]. It is clear that large RCTs performed with the restrictions currently recommended by the European Society of Hypertension in proteinuric CKD patients are needed. The positive findings described certainly have a lot to do with recent improvements of RDN, namely the development of next-generation multi-electrode catheters. New methods of renal nerve ablation seem to be essential, as is a need for more comprehensive understanding of renal nerve localization, which will aid the development of clinically applicable methods for the assessment of renal nerve ablation. What reasons are there to perform RCTs with RDN in 2017? First, to document its effectiveness in appropriately selected hypertensive patients. The good news from this study is that RDN seems to be safe for renal function! Secondly, for potential new indications, as for patients with CKD and proteinuria, the study by Sanders et al. gives some hope that RDN may represent a new, effective nephroprotective procedure. It is interesting to observe how the indications for RDN may change to be different from those when it was initially developed. Hopefully, nephrologists will participate in the future of RDN and especially in these new indications. So, dear colleagues, please assume responsibility and get involved in this opportunity. None declared. (See related article by Sanders et al. Renal safety of catheter-based renal denervation: systematic review and meta-analysis. Nephrol Dial Transplant 2017; 32: 1440--1447)