Is Accelerated Renal Calcification a Reason for the Failure of Renal Denervation to Lower Blood Pressure in Chronic Kidney Disease?
There is a current surge in research investigating renal denervation as a potential treatment for resistant hypertension, as an overactive renal sympathetic system is known to exert an influence on the underlying pathophysiology of both hypertension and CKD. In a uraemic rat model, Campese et al. have shown in subtotally nephrectomised rats that BP rapidly increases after surgery, which was abolished by afferent denervation.50 Interestingly, renal afferent denervation has also prevented the progression of renal disease in this model.51 They have also showed that a small lesion in one kidney by an intrarenal phenol injection, not affecting kidney function, increases sympathetic activity and leads to a long-term increase in noradrenaline secretion and to hypertension. These effects are also abolished by afferent denervation. In humans, it has been show that the activity of the sympathetic nervous, assessed by microneurography, increases as renal function declines.52 Taken together, these results indicate that the sympathetic nervous system is a logical target for intervention. Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic BP reductions. Prior unblinded studies have suggested that catheter-based renal artery denervation reduces office BP in patients with resistant hypertension;41 the results of the SYMPLICITY HTN-3 study, a single-blind, randomised, sham-controlled trial, failed to show a significant reduction of systolic BP six months after renal artery denervation as compared with a sham control.53 Interestingly, subgroup analysis suggested that patients with eGFR <60 ml/min/1.73 m2 were less responsive (between-group difference in change in office BP 0.54 [-8.29–9.37, 95 % CI]) than patients with eGFR ≥60 ml/min/1.73 m2 (between-group difference in change in office BP -5.22 [-10.51–0.06, 95 % CI]).54 The effect of renal function in response to renal denervation is consistent with an earlier report showing that higher baseline creatinine was associated with lower probability of 24 hour BP improvement (odds ratio for each 20 μmol/L increase, 0.60; p=0.05). The degree of renal artery calcification may limit the efficacy of renal denervation; however, this remains to be proven. Recently, a study was conducted to investigate the proportion of patients eligible for renal denervation and the reasons for non-eligibility at 11 expert centres participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD).55 The most frequent cause of ineligibility (approximately half of cases) was BP normalisation after treatment adjustment by a hypertension specialist. These results highlight that hypertension centres with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.56 Further evaluation in rigorously designed clinical trials will be necessary to bring evidence that renal denervation may a therapeutic option for CKD patients.
In conclusion, the burden of hypertension in CKD patients is high. These patients are at increased risk of target organ damages and CV events. Vascular lesions due to hypertension-induced remodelling and vascular calcifications play an important role in the development of CV and renal complications. In the absence of specific treatment of arterial stiffness and calcifications, reduction of BP using non-pharmacological or/and pharmacological interventions is crucial to reduce these risks. Most of the time, several drugs are necessary to reach the targeted BP. Today, the combination of drugs including a blocker of the RAS and a calcium channel blocker appear to be one of the most effective associations in high-risk patients.