Renal Allograft Sympathetic Reinnervation and Possible Impact on Cardiovascular Risk Profile and Graft Function

See Clinical Research on Article 106597

In the article by Ohki et al.,¹ the authors present a study entitled “Sympathetic reinnervation is associated with antihypertensive treatment burden and interstitial fibrosis after kidney transplantation.”

The design of the study is intriguing. The authors used serial kidney graft biopsies in 50 living donor renal transplant recipients, at 3 months, 1 year, and 3 years after transplantation. The authors assessed demographic data, cardiovascular risk factors such as blood pressure, and antihypertensive treatment in the patients and correlated the results with sympathetic reinnervation of the graft assessed using tyrosine hydroxylase immunostaining. In addition, they measured interstitial fibrosis in the biopsy specimen and related the extent of interstitial fibrosis to tyrosine hydroxylase immunostaining. To our knowledge, this is the first human study imaging sympathetic nerve fibres in serial kidney graft biopsies.

However, nearly half (n = 23) of the transplant recipients could not be analyzed with this study design because tyrosine hydroxylase immunostaining remained positive 3 months after transplantation and thereafter. Twenty-nine kidney grafts turned tyrosine hydroxylase immunostaining negative 3 months after transplantation, becoming positive 1 year after transplantation with variable staining at the follow-up biopsies. Six kidney grafts remained tyrosine hydroxylase negative throughout all protocol biopsies.

The group of patients with reestablished tyrosine hydroxylase immunostaining tended to be more hypertensive, tended to require more antihypertensive drugs, and showed a tendency toward higher interstitial fibrosis in the grafts than the group of patients without tyrosine immunostaining from the months on after transplantation. It should be noted though, that patients with positive tyrosine hydroxylase immunostaining throughout the whole study showed similar characteristics as the patients losing tyrosine hydroxylase immunostaining positivity 3 months after renal transplantation and regaining it thereafter.

For these reasons, the results do not permit the conclusion that sympathetic reinnervation of the kidney graft promotes hypertension and graft interstitial fibrosis in the recipients. Baseline differences between the 3 groups probably account for most of the differences observed. For example, patients with tyrosine hydroxylase immunostaining negative grafts from 3 months after transplantation onwards did not have hypertension or diabetes as cause of renal failure—in contrast to the other groups—and were hypertensive or diabetic to a much lesser degree than the other groups.

Hypertension after kidney transplantation affects the large majority of graft recipients and blood pressure level after kidney transplantation is a stronger predictor of long-term graft failure than ABO compatibility.²

Mechanisms promoting hypertension after kidney transplantation are complex; important factors are preexisting vascular damage, impaired graft function, the use of calcineurin inhibitors, steroids, and tonic sympathetic activation arising from damaged native kidneys³ (Figure 1).

Figure 1.

Interaction between the kidneys and the sympathetic nervous system. RAAS, renin-angiotensin-aldosterone system.

In this context, sympathetic reinnervation of the kidney graft may be of importance. Efferent sympathetic reinnervation of the kidney graft may promote sodium and water retention and activation of the renin-angiotensin-system. Afferent sympathetic reinnervation of the graft may promote increased sympathetic tone in case of graft damage (via chemoreceptor-activation or mechanoreceptor deactivation).⁴

Renal sympathetic activation is an important mechanism promoting hypertension and hypertensive end-organ damage. Following kidney transplantation, the graft is denervated. There is equivocal evidence of whether sympathetic reinnervation of the kidney graft occurs following transplantation.

Several studies have provided evidence of some sympathetic reinnervation of kidney grafts several months to years after transplantation. In animal studies tyrosine hydroxylase staining is a widely used tool to assess efferent renal sympathetic nerves.⁵ Calcitonin gene-related peptide staining may be used to assess afferent renal sympathetic nerves.⁵ Furter methods to study sympathetic reinnervation have been published (e.g., ubiquitin-C-hydroxylase or tissue norepinephrine content).⁶

To our knowledge, tyrosine hydroxylase staining patterns have not been established in human native or transplant kidney biopsies. Renal pathologists do not pay attention to nerves in routine sign-out of diagnostic biopsies. The 1 study looking at tyrosine hydroxylase staining in human kidneys,⁷ showed staining results only close to the renal artery, which (fortunately) is not sampled in a kidney biopsy. Therefore, a meaningful analysis will have to establish the normal and abnormal (e.g., in hypertensive kidney disease) patterns first.

However, even if there is renal sympathetic reinnervation following kidney transplantation, there is no evidence that this sympathetic reinnervation is functional. For example, Rousselle et al.⁸ observed renal sympathetic reinnervation of swine kidneys following renal denervation by radiofrequency ablation. However, the architecture of the sympathetic nerve sprouts was highly disrupted, making a functional sympathetic reinnervation unlikely.

Another issue is whether sympathetic reinnervation of kidney grafts ensues hypertension and hypertensive damage of the graft. To address this question, the study of Ohki et al.¹ was performed. Mauriello et al.⁷ studied 3 renal transplant patients after death occurring between 5 months and 11 years after transplantation. In all patients, hypertensive kidney damage was the main cause of kidney failure before transplantation. All patients showed substantial sympathetic nerve tissue around the graft renal artery and in the graft. Four controls with non–hypertension-related kidney failure served as controls. These patients had their kidney grafts removed between 10 months and 7 years after transplantation to recurrence of the primary disease (focal segmental glomerulosclerosis) or graft rejection. Their grafts only showed a modest amount of sympathetic nerve tissue. As observed by Ohki et al.,¹ and by Mauriello et al.⁷ different pretransplant characteristics of the studied patients may have accounted for the observed differences with respect to hypertensive graft damage, rather than different degrees of sympathetic innervation of the kidney grafts. In a rat model, Grisk et al.⁹ were able to demonstrate sympathetic renal reinnervation after kidney transplantation over time in rats; however, the development of hypertension in these rats was independent of sympathetic reinnervation of the kidney graft.

In conclusion, the issue of sympathetic efferent and afferent reinnervation of kidney grafts after transplantation and the role of sympathetic reinnervation for the development of hypertension and hypertensive vascular damage of the graft recipient remains an important issue. The design of the study presented by Ohki et al.¹ is innovative. Their study does not prove that functional sympathetic reinnervation of the kidney grafts occurs and ensues hypertension and other adverse cardiorenal effects, but the study is hypothesis-generating. If there was functional efferent and afferent sympathetic reinnervation of transplanted kidneys, this could cause a vicious cycle leading to reduced graft survival (Figure 1). Further studies are warranted to address the importance of functional sympathetic reinnervation of kidney grafts for the development of hypertension and hypertensive vascular damage.

Disclosure

All the authors declared no competing interests.