Renal denervation for patients with chronic kidney disease and resistant hypertension: effective and safe but still not the panacea

Hypertension is often difficult to control in patients with chronic kidney disease (CKD) and the prevalence of apparent resistant hypertension is particularly high in this patient group [1]. For example, in the Chronic Renal Insufficiency Cohort, which included and followed >3000 patients with CKD, the prevalence of apparent resistant hypertension was 40.4% [2]. However, the prevalence of true resistant hypertension was probably lower because poor adherence to therapy and white coat hypertension are also common in CKD patients. Resistant hypertension is associated with significant increases in cardiovascular and renal outcomes in the general hypertensive population as well as in CKD [1]. Therefore, early identification and intensive management of patients with true resistant hypertension should be a high priority in CKD patients and reaching the target blood pressure (BP) values defined by recent guidelines should be the main objective of antihypertensive therapy.

The pathogenesis of hypertension in CKD is complex, involving several mechanisms including increased sodium retention, volume expansion, high sympathetic nervous system activity, activation of hormonal systems such as the renin–angiotensin–aldosterone and endothelin systems and endothelial dysfunction. Among the various factors contributing to the elevation of BP in CKD, hyperactivity of the sympathetic nervous system plays an important role. Indeed, it is well recognized that efferent renal nerves contribute to the regulation of renin secretion, tubular sodium reabsorption and renal haemodynamics [3]. Moreover, CKD is associated with lower kidney renalase activity, reducing catecholamine clearance and thereby increasing the exposure of kidneys to catecholamines. Given the known role of increased sympathetic nerve activity in the development of hypertension and in the progression of CKD, there was a high scientific and clinical rationale to support the investigation of renal denervation as an effective means of lowering BP and to provide cardiovascular and renal protection in CKD patients with resistant hypertension.

Preliminary results from small, uncontrolled studies have shown that renal denervation is indeed effective in lowering BP in CKD patients [4, 5] and some data suggest that the procedure might even retard the deterioration of kidney function irrespective of the BP effect [6]. In the absence of specific randomized controlled trials, data from large registries are important to provide information on the long-term efficacy and safety of any new therapeutic strategies. In the present issue of NDT, Ott et al. [7] present the 3-year data of the global SIMPLICITY registry regarding the efficacy and safety of renal denervation in patients with and without CKD. The database included 475 patients with CKD [baseline estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² but ≥15 mL/min/1.73 m²] and 1505 patients without CKD (baseline eGFR ≥60 mL/min/1.73 m²). As already published by the same group [8], renal denervation induced significant decreases in office and ambulatory BP, which were greater in patients without CKD than in those with CKD. Regarding the decline in kidney function, although patients without CKD had a greater decrease in eGFR during the first year after the intervention, the decline in eGFR was comparable in the two groups at 3 years. Interesting new information presented in this paper is the 3-year incidence of major cardiovascular outcomes and side effects in both groups. The incidence of deaths, cardiovascular deaths (but not non-cardiovascular deaths) and all cardiovascular and renal events was significantly higher after renal denervation in CKD than in non-CKD patients. However, the incidence of renal artery re-interventions due to perforation or dissection and vascular complications was low and not more frequent in patients with CKD.

These data collected in the global SIMPLICITY registry deserve a few comments. Regarding the effect of renal denervation on BP, recent studies conducted in patients with hypertension and no antihypertensive therapy have now confirmed that this interventional approach to hypertension produces lower office and ambulatory systolic BP by about 6.5 and 3.9 mmHg, respectively [9]. The present data confirm that renal denervation is also effective in patients with CKD [8]. In these patients, office systolic BP decreased by 11.7 mmHg and ambulatory systolic BP decreased by 9.2 mmHg at 3 years. However, if one considers that baseline office and ambulatory systolic BP were at 162 and 153 mmHg, respectively, a substantial proportion of CKD patients was probably still uncontrolled 3 years after renal denervation. Unfortunately, the authors do not provide any information on the percentage of patients actually reaching office systolic BP targets as defined by recent guidelines, that is, <140 mmHg in Europe, <130 mmHg in North America and <120 mmHg (using non-attended BP measurements) according to 2021 Kidney Diesease: Improving Global Outcomes guidelines [10]. Thus renal denervation may be helpful in lowering BP in CKD patients with resistant hypertension, but it is evident that this technique by itself is not sufficient to control resistant hypertension in CKD. Therefore, intensive drug therapy, with all its limitations, will probably remain the cornerstone of the management of hypertension in CKD in order to reach recommended BP targets.

Regarding the impact of renal denervation on renal disease progression, preliminary studies were promising [5], but later results were less convincing and a meta-analysis of >50 renal denervation studies including all types of patients with resistant hypertension concluded that renal function does not significantly change up to at least 9 months after renal denervation [11]. The global SIMPLICITY registry data, which contain a significant group of CKD patients, are in line with this meta-analysis, suggesting no significant difference in kidney disease progression in patients with or without CKD. Yet, one has to mention that all renal denervation studies used the eGFR formula to monitor the changes in renal function over time. Recent data from a non-randomized study have found that measured GFR may provide different results than eGFR, suggesting that kidney damage may occur 1 or 2 years after renal denervation [12]. Therefore one needs more long-term data with measured GFR to conclude on the renal safety of renal denervation.

Finally, the SIMPLICITY registry demonstrates that the incidence of major cardiovascular and renal events is higher in patients with CKD than in those without CKD during the 3 years following renal denervation. In a way, this finding is not surprising, as patients with CKD have a very high cardiovascular and renal risk profile. However, it is unfortunate that due to the registry design and the absence of a sham control group, one cannot evaluate whether renal denervation actually reduces the incidence of cardiovascular events in CKD patients through BP-dependent and -independent mechanisms such as reducing left ventricular hypertrophy, improving glucose metabolism or reducing renal inflammation. Obviously, any significant reduction in BP should contribute to lowering cardiovascular outcomes in patients with hypertension with or without CKD and in this respect renal denervation will probably contribute to the reduction of cardiovascular and renal events in CKD. To demonstrate the benefits of renal denervation on cardiovascular and renal events in CKD patients, a large randomized prospective study with a sufficient follow-up is needed. When consulting the ClinicalTrials.gov site, no such trial is actually ongoing with specific attention to CKD patients. One large study that should include about 1000 patients is ongoing, with the aim to document the long-term safety and effectiveness of renal denervation in patients with hypertension and concomitant diseases characterized by elevated sympathetic activity including CKD, heart failure and diabetes (NCT01888315). The primary endpoint of this study is a combination of the effects of renal denervation on BP and on the number of adverse effects (death, stroke, myocardial infarction, new dialysis and congestive heart failure). Another interventional study is assessing the effect of renal denervation on BP in CKD patients and uncontrolled hypertension using a catheter-based device using ultrasound energy to ablate afferent and efferent renal nerves (NCT04264403). However, this study will not have sufficient power to investigate the impact on hard endpoints.

In conclusion, renal denervation represents a safe and effective approach to lower BP in CKD patients with resistant hypertension. In some circumstances, renal denervation will be helpful to achieve BP targets defined by recent guidelines [13]. However, today, renal denervation is not yet the panacea, as the quality of global control of hypertension appears to remain insufficient at 3 years in a large proportion of treated CKD patients with resistant hypertension. Therefore more work is needed to determine the precise role of renal denervation in the management of resistant hypertension in CKD.

CONFLICT OF INTEREST STATEMENT

The author declares no conflicts of interest.

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