Renal Denervation 101: Understanding Hypertension and RDN

Hypertension is the leading cause of death worldwide, but a permanent cure is on the way.

Hypertension is the number one risk factor of death globally, and responsible for some 10 million deaths every year. This isn’t surprising given the condition’s prevalence. According to the WHO’s 2023 Global Health Estimates, 1.9 billion adults worldwide have hypertension – that’s 40% of all adults. Alarmingly, nearly half of them are unaware of this, and only 21% have it under control.

Despite being a significant non-communicable disease burden globally, hypertension has no permanent cure yet. Instead, the condition can only be managed through lifelong medication, as well as lifestyle adjustments such as dietary changes and exercise.

A breakthrough is in sight though. Renal denervation, a one-time procedure, may soon be commonly available as a lasting solution for lowering blood pressure. The challenge lies in developing the technology to perform it safely, effectively, and across a broad segment of the patient population. Some 30 medtech device companies are variously doing so right now; success will mean a paradigm shift in how hypertension is treated, as well as improved patient outcomes for millions worldwide.

What is hypertension?

Hypertension, or high blood pressure, is a chronic medical condition where a patient’s blood exerts a consistently elevated force against the artery walls. Clinically, normal blood pressure is defined as systolic and diastolic blood pressures below 120mmHg and 80mmHg respectively i.e. a measurement lower than 120/80mmHg. In contrast, hypertensive patients have blood pressures that are consistently above 140/90mmHg, with some revised guidelines adjusting this threshold down to 130/80mmHg for better risk stratification within patient populations.

Classification of blood pressure ranges for hypertension diagnosis

Hypertension is broadly categorised as either primary or secondary hypertension. Primary hypertension, seen in an estimated 90-95% of cases, has no single identifiable cause. Rather, it is the result of a complex interplay of factors: genetic predisposition, high sodium intake, obesity, physical inactivity, and increased sympathetic nervous system activity. In contrast, secondary hypertension has clearly identifiable causes such as endocrine disorders and medications (NSAIDs, oral contraceptives, etc).

Persistent hypertension increases the workload on the heart and the arterial walls that causes structural and functional changes in the vascular system. These, in turn, increase the risk of cardiovascular disease, stroke, renal failure, organ failure, and various other conditions. Reducing a hypertensive patient’s blood pressure is thus essential to prevent further health complications.

Managing hypertension

Given the prevalence of primary hypertension and its lack of a single, definitive cause, however, broad strategies are typically employed. For a start, pharmaceuticals such as ACE inhibitors and beta-blockers can be prescribed – often in different combinations specific to a patient’s needs. This is typically done in conjunction with lifestyle interventions. Patients may need to reduce their sodium intake, for instance, as well as to lose weight, lower their alcohol intake, and have regular aerobic exercise.

Lifestyle interventions such as increasing one's exercise volume are an important part of hypertension management – but require lifelong discipline

The challenges with the above are multifold. For one, pharmacological and lifestyle interventions are both lifelong in nature. There simply is no permanent cure for hypertension through these means, so patients must have sustained discipline over their lifetimes. Patient adherence is also an issue. After all, interventions are only as effective as a patient’s ability to abide by what they have been prescribed. A third limitation concerns side effects: they can limit a patient’s tolerability towards some pharmacological solutions, which narrows the options available.

Efficacy is an issue too; a significant subset of hypertensive patients do not respond adequately to the above interventions. For those with resistant hypertension, blood pressures remain uncontrollable despite a combination of three or more medications. Refractory hypertension, an even more severe condition, describes high blood pressure that cannot be managed even with five or more drugs. Such cases point to a different causal mechanism – often an overactive sympathetic nervous system – and highlight the need for additional therapeutic options.

The sympathetic nervous system’s role in hypertension

The sympathetic nervous system (SNS) is part of the autonomous nervous system, and responsible for governing the body’s “fight or flight” response. Its stimulations are normally temporary – once a “threat” has passed, the SNS’s activity reverts to baseline levels to normalise the body’s autonomic outputs, such as heart rate and blood pressure.

When there’s persistent overactivity in the SNS, however, hypertension can occur. This involves the kidneys, which regulate the body’s haemodynamics – the movement and flow of blood – that directly affect blood pressure. A chronically overactive SNS has higher levels of sympathetic nervous activity, which leads the kidney to keep blood pressure elevated. The long-term result is hypertension.

Medication cannot fully manage hypertension if the root cause is an overactive sympathetic nervous system

What’s important to note is that the kidneys aren’t just responding passively to the SNS. Instead, they actively amplify and sustain elevated blood pressure levels through a few different mechanisms – it is this two-way, afferent-efferent feedback loop that makes the condition self-sustaining. Because no drug is capable of directly severing this system, pharmaceutical interventions have limited impact here. There is, however, an alternative: renal denervation.

What is renal denervation? 

Renal denervation (RDN) is the process of ablating (i.e. surgically removing) the nerves running on the outside of the renal arteries, which supply the kidneys with blood. This directly reduces the kidney’s sympathetic nervous activity to achieve lowered blood pressure for the patient. Crucially, the procedure is capable of disrupting both afferent signalling and efferent drive between the kidneys and the central nervous system to, essentially, sever this bidirectional relationship between the two components.

RDN’s mechanism of action is well-understood, with the original idea of removing parts of the central nervous system dating as far back as the 1940s. The procedure showed much promise in early trials, but subsequent studies delivered mixed results due to design flaws, which raised doubts about its efficacy. Thanks to subsequent improvements to surgical techniques, patient selection, and device technology, however, RDN has seen a resurgence of interest in the last decade. Recent trials have demonstrated significant reductions in blood pressure for patients that have undergone RDN – both with and without concomitant medication(s).

What is the current status of renal denervation?

As a procedure, renal denervation isn’t subject to regulatory approval. Rather, the medical devices that perform RDN are individually approved by regulatory authorities worldwide. On that front, just two devices are currently approved by the FDA: Medtronic’s Symplicity Spyral and ReCor Medical’s Paradise. Both are catheter-based solutions that perform RDN by advancing a catheter through the femoral or radial artery to reach the renal artery, where they then deliver RF and ultrasound energy respectively to ablate the renal nerves.

Medtronic's Symplicity Spyral, a catheter-based medical device cleared by the FDA for RDN

The catheter-based approach is minimally invasive, but faces some technical limitations. For example, it has limited suitability for patients with smaller arteries and/or complex arterial structures, as the catheters may be unable to reach the necessary locations to carry out denervation. Risk of injuries is another concern. As the catheter is inside the artery, it must deliver energy through the arterial wall to reach and ablate the renal nerves running along the exterior of the renal artery. This means that surgeons may need to make the tradeoff between incomplete denervation and the risk of damaging the artery wall.

Despite the limitations associated with current RDN devices, the procedure remains a promising treatment option for patients. Elsewhere, various other companies are engaged in R&D to develop different iterations of the technology. Interestingly, most of them are developing catheter-based solutions as well, albeit with varying approaches in a bid to overcome the technical limitations discussed. The one exception is DeepQure – in lieu of a catheter, we have opted to develop HyperQure, which uses a laparoscopic approach that performs extravascular RDN, with none of the inherent issues faced by catheters.

DeepQure's HyperQure performs renal denervation using an extravascular approach – the only such medical device under developnment so far

For now, renal denervation is still an adjunct therapy for resistant and refractory hypertension, as well as an option for patients who are intolerant to antihypertensive medications. As this procedure and its associated technologies continue to mature, however, RDN has the potential to become a mainstream, device-based solution for hypertension – one that can permanently lower blood pressure, no less.