Sympathetic Reinnervation is Associated With Antihypertensive Treatment Burden and Interstitial Fibrosis After Kidney...

Sympathetic reinnervation after kidney transplantation has been demonstrated histologically and functionally, but its clinical and molecular consequences remain unclear.

In this single-center retrospective study, 50 adult living-donor kidney transplant recipients were evaluated. Based on tyrosine hydroxylase (TH) immunostaining at 3 months and subsequent biopsies, recipients were categorized into the following: regeneration group (TH-negative at 3 months and TH-positive thereafter), nonregeneration group (persistently TH-negative), and a histologically nonevaluable group (TH-positive from 3 months onward). Cortical interstitial fibrosis was quantified by Sirius Red morphometry, and fibrosis-related gene expression was assessed using NanoString Human Fibrosis V2 Panel.

Although all grafts showed TH-positive fibers immediately after transplantation, 58% became TH-negative at 3 months (29/50). Among these, 79% later demonstrated sympathetic reinnervation (23/29), whereas 6/29 remained persistently TH-negative. Antihypertensive agent use transiently decreased at 3 months but subsequently increased, predominantly in regeneration group. At 1 and 3 years, regeneration group required more antihypertensive medications than nonregeneration group (1 year: P = 0.066; 3 years: P = 0.012). Interstitial fibrosis progressed significantly in the regeneration group (7.78% to 10.56%, P = 0.037) but remained stable in nonregeneration group. Transcriptomic analysis showed upregulation of periostin (POSTN) and plasminogen activator inhibitor-1 (PAI-1), factors associated with sympathetic activation and senescence-associated secretory phenotype (SASP) (analysis performed in 8 selected cases).

Sympathetic reinnervation was observed together with higher antihypertensive medication burden and greater interstitial fibrosis over time, along with transcriptomic signatures consistent with SASP-related fibrogenic pathways. However, given limited size of the nonregeneration subgroup and lack of functional validation, these findings should be interpreted cautiously and regarded as hypothesis-generating.