New Approaches to Pathogenesis and Management of Hypertension

Upon the initiative of Smithwick and Thompson (1) of the Massachusetts General Hospital, resection of the splanchnic nerves through a posterior infradiaphragmatic approach plus removal of the sympathetic chain from the level of the eighth dorsal ganglion to the second lumbar ganglion had been used with relative frequency in cases of desperate hypertension at the time when antihypertensive medication was not yet available. In the hands of other investigators, the results were spectacular in a minority of patients but not quite satisfactory in many patients (2,3). Despite improvement of headache, reversal of papilledema in malignant hypertension, etc., the long-term reduction of BP was quite variable and the 5-yr mortality remained approximately 40% (2). A 10-yr follow-up compared 100 patients who were subjected to thoracolumbar sympathectomy with 1500 patients who received symptomatic therapy. Lasting BP reduction was seen only in one third of the patients (4). Whereas the average BP levels were reduced, occasional BP spikes were not. The average difference of preoperative to postoperative systolic BP values was 21 mmHg. The authors saw reduction of cerebrovascular accidents and less progression of proteinuria and renal dysfunction, but 10-yr mortality was still 41%. Against this background, once effective antihypertensive medication was available, this relatively crude procedure fell out of favor and remained a sleeping beauty. With today's better insight into the role of sympathetic activity in the genesis of hypertension and particularly the role of the kidney in sympathetic activation, there has been a renaissance in the interest of the renal sympathetic nervous system, including its role in primary hypertension—apart from its undoubted role in the hypertension of chronic kidney disease (5–10). Renal disease and, in animal experiments, even minor renal tissue damage such as injection of minute volumes of phenol, trigger afferent signals that ascend via the spinal cord to the posterior hypothalamus, resulting in increased efferent sympathetic activity (8,9). In the distant past, it had been assumed that sympathetic activation is restricted to advanced kidney disease and the presence of uremic toxins. Increased sympathetic activity had been documented by the methodologic gold standard of microneurography in end-stage kidney disease but later on also in earlier stages of chronic kidney disease (11,12). It is interesting that after renal transplantation BP decreases and microneurographic overactivity is normalized when the recipient's own anuric kidneys are removed by bilateral nephrectomy, clearly illustrating the important role of the kidney independent of its excretory function (13). A new twist has been introduced by the recognition that the kidney secretes a proform of an enzyme called renalase, which retards catecholamine breakdown (14). The complexity of sympathetic activation in chronic renal failure was recently reviewed by Schlaich et al. (10). There is little argument about Guyton and Coleman's postulate that “all forms of hypertension are ultimately a consequence of resetting of the pressure-natriuresis relationship” (15). This concept is supported by observations such as that transplantation of a kidney from a donor with normotension causes persistent normotension in the recipient, that high urinary albumin excretion precedes the onset of overt hypertension, that patients with essential hypertension have fewer nephrons, and that asymptomatic heterozygotic carriers of the Gitelman mutation have lower BP than the background population (Mendelian randomization) (16–19). Apart from these observations, however, there is good evidence that renal sympathetic activity is also crucial for the initiation and maintenance of systemic hypertension even in the absence of kidney disease (5,20,21). Young humans with borderline hypertension exhibit already increased norepinephrine spillover, an index of sympathetic nerve activity, in the kidney (22). Barajas and Muller (23) found in experimental studies that bilateral renal denervation prevented the development or attenuated the magnitude of hypertension. Sympathetic activity affects a great spectrum of renal functions, for example, increasing renal tubular sodium reabsorption independent of changes in GFR by releasing norepinephrine and stimulating postsynaptic α-1 adrenal receptors on the basolateral membrane of renal tubular epithelial cells (24). Hypertension control remains poor worldwide, and one particular problem is the management of “resistant hypertension” defined as hypertensive BP values despite use of three antihypertensive agents, including a diuretic (25). Past efforts to correct this condition included administration of the mineralocorticoid receptor antagonist spironolactone, which lowered BP on average by 21.9/9.5 mmHg in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study (26). As a procedure competing with the approach described next, carotid baroreceptor stimulation is under investigation as well (27,28). In view of the aforementioned important role of the renal sympathetic overactivity in the genesis of hypertension, this has recently again become a target for intervention. In a proof-of-principle study, Krum et al. (29) took up again the idea to eliminate the function renal sympathetic nerves. In contrast to the past nonselective surgical denervation riddled by numerous adverse effects, the authors adopted percutaneous selective renal denervation to eliminate the afferent and efferent sympathetic nerves that conveniently lie within and immediately adjacent to the wall of the renal artery. To this end, a catheter connected to a radiofrequency generator was introduced into the lumen of the main renal artery. The study comprised 50 patients at five Australian and European centers with expertise in catheter-based interventions. For assessment of the efficacy of elimination of sympathetic denervation, renal noradrenaline spillover was measured in a subgroup of patients, an elegant indirect method to assess the activity of the sympathetic nervous system (5). The spillover data documented substantial afferent renal denervation in almost all patients. Renal angiography as well as magnetic resonance angiography was performed early and late to exclude potential renovascular damage; renal artery aneurism or renal artery stenosis were not observed. In such expert hands, only one major complication—a renal artery dissection—occurred without long-term complications, but the safety in less expert hands awaits further evaluation. The effect on BP control was remarkable: Average office BP decreased progressively by 14 mmHg systolic and 10 mmHg diastolic at month 1 and by 27 mmHg systolic and 17 mmHg diastolic at month 12, but not all patients showed a response. One can even speculate that in the long run, interruption of sympathetic nerve traffic to and from the kidney may be beneficial by BP-independent effects (e.g., reduction of left ventricular hypertrophy) of insulin resistance and of vascular catastrophes. The progressive decrease of BP is remarkable because of the theoretical possibility of regrowth of sympathetic nerves as documented after renal transplantation. It is still early to assess the potential clinical role of this innovative therapeutic approach and, as the authors indicated, controlled prospective trials will be necessary. Several aspects in the study are not ideal. Office BP is far from ideal for assessing BP, and 24-h BP measurements would have been preferable. This proof-of-principle study did not have a control group. Furthermore, given the efficacy of spironolactone and reduction of dietary salt intake in several studies of resistant hypertension, it would have been desirable to assess the efficacy of the novel procedure in patients who did not respond to such proven interventional procedures (26,30). It is also of note that not all patients responded, suggesting heterogeneity of the role of sympathetic overactivity in the genesis of resistant hypertension. The challenge in the future will be to provide long-term controlled data on safety (particularly in less experienced hands) and quantification of the efficacy compared with proven treatments in resistant hypertension and to work out criteria to identify nonresponders (26,30).