Sympathoexcitation in calcineurin inhibitor-induced hypertension: villain or innocent bystander?

Immunosuppressants are widely used in autoimmune disease and play a particular role in organ transplantation. Although these drugs are indispensable to avoid rejection of the donated organ, their side effects can pose a threat not only to long-term survival of the transplant but also to the overall prognosis of the individual receiving the transplant. The relatively unselective inhibition of the immune system, particularly with older drugs such as calcineurin inhibitors, results in reduced resistance to infections and the potential spread of malignant cells with an increased risk of malignancies. In addition, they can also increase the risk of cardiovascular disease through other frequently seen adverse effects such as hypertension, dyslipidaemia, hyperglycaemia and kidney injury. Interference with the action and metabolism of other drugs can further aggravate the situation. Although efforts to develop more selective immunosuppressants with fewer and less severe side effects have been partly successful, it is of clinical relevance to unravel the mechanisms and pathways by which currently used immunosuppressants induce these side effects. Calcineurin inhibitor and adrenergic function In the current issue of the Journal of Hypertension, Klein et al. [1] provide important data on the potential involvement of sympathetic nervous system activation in calcineurin inhibitor-induced hypertension. Indeed, previous studies have indicated that neural mechanisms might be in play and act as mediators of the blood pressure (BP) rise associated with this class of immunosuppressants, particularly cyclosporine. Although the incidence and severity of the hypertensive effect of calcineurin inhibitors is widely recognized as being related to the dose and duration of treatment [2], it also depends on the patient populations studied, which makes it difficult to unravel the exact mechanisms underpinning the BP rise. Accordingly, several potential mechanisms other than sympathetic activation have been suggested to be involved including vasoconstriction of the renal vascular bed, enhanced sodium retention and thereby increased plasma volume, direct nephrotoxicity, as well as central effects [3]. In view of this dilemma, Klein et al. [1] are to be commended for their efforts to study the effect of acute and sustained cyclosporine or tacrolimus administration in standard and high-dose regimens on muscle sympathetic nerve traffic, directly recorded via the microneurographic technique. Importantly, they have chosen to perform their study in a small group of young, male, healthy volunteers rendering this study unique in that healthy individuals are devoid of potentially important confounding factors such as preexisting comorbidities and concomitant medication, thereby allowing direct assessment of the effects of cyclosporine and tacrolimus on indices of sympathetic nerve activity and other parameters. On the contrary and aside of potential ethical implications, this approach inherently carries the risk of masking the potential influence of the internal milieu of a given disease state on calcineurin inhibitor-induced alterations in BP, for example, altered salt sensitivity, impairment of baroreflex control and others. Another caveat not being accounted for in healthy volunteers is the potential interaction with other concomitant medications that may influence the response to cyclosporine/tacrolimus. Furthermore, the number of participants studied is relatively small and muscle sympathetic nerve recordings could not be obtained in all patients at the various time points studied. However, given the high intraobserver and interobserver reproducibility of the method provided, this may not be of major concern. Unfortunately, plasma volume and sodium excretion have not been measured in the current study, making it difficult to pin down the sequence of events potentially underlying the main findings of the study as summarized below. Finally, assessment of adrenergic drive via microneurography encompasses a major, but unavoidable, limitation, that is, the fact that the results provided are limited to the neural district explored and, thus, not necessarily represent the behaviour of sympathetic activity in other cardiovascular areas such as the coronary or the renal circulation [4]. Sympathetic function and calcineurin: present findings and future investigations With all the above-mentioned limitations in mind, the authors provide convincing evidence for a dose-dependent effect of acute cyclosporine administration on both increasing muscle sympathetic nerve traffic and BP, sustained elevation of BP with continuous use of cyclosporine in the presence of suppressed sympathetic neural drive and the absence of an effect of acute tacrolimus on either BP or sympathetic neural drive and even reduced adrenergic activity with unchanged BP during sustained tacrolimus. Can we resolve this Gordian knot? Perhaps not, but based on the available evidence presented in this study and elsewhere, the following sequence of events appears as a reasonable explanation: cyclosporine when given acutely triggers an increase in muscle sympathetic nerve traffic either by direct central postsynaptic excitation mediated by modulation of glutaminergic neurotransmission [4] or by increased renal afferent signalling through cyclosporine-induced vasoconstriction of the renal vascular bed, thereby leading to increased central sympathetic outflow [5] as measured by microneurographic technique. As a consequence of increased efferent sympathetic drive to the kidneys, sodium retention occurs resulting in increased intravascular volume (not measured), mild increase in body weight, reduction of plasma renin activity (as demonstrated during sustained cyclosporine treatment), perhaps via baroreflex activation and suppression of muscle sympathetic nerve activity, as illustrated with sustained cyclosporine. Interestingly, tacrolimus administration neither acutely (bolus injection) nor continuously (long-lasting infusion) had an effect on BP in these healthy volunteers and suppressed adrenergic cardiovascular drive when given continuously, but not acutely. The data provided are not sufficient to even take an educated guess on the mechanisms underlying this particular observation but at least allows to conclude that the BP rise accompanied by acute cyclosporine treatment is likely to be mediated in part by activation of the sympathetic nervous system and sympathetic activation does not appear to be of major importance in long-term BP rises associated with either cyclosporine or tacrolimus. Consequently, specific inhibition of the sympathetic nervous system to reduce BP in patients with calcineurin inhibitor, although useful, may not provide benefits beyond those that could be obtained with any other antihypertensive drug class in this scenario. The question whether central or renal afferent mechanisms may account for the acute rise in sympathetic tone with cyclosporine treatment may be answered in the not too distant future by applying a catheter-based renal denervation approach, thereby potentially allowing to discriminate between the two components [6,7].