Graft Vasculopathy in Clinical Hand Transplantation

Abstract

Allogeneic hand transplantation is now a clinical reality. While results have been encouraging, acute rejection rates are higher than in their solid-organ counterparts. In contrast, chronic rejections, as defined by vasculopathy and/or fibrosis and atrophy of skin and other tissues, as well as antibody mediated rejection, have not been reported in a compliant hand transplant recipient. Monitoring vascularized composite allograft (VCA) hand recipients for rejection has routinely involved punch skin biopsies, vascular imaging and graft appearance. Our program, which has transplanted a total of 6 hand recipients, has experience which challenges these precepts. We present evidence that the vessels, both arteries and veins may also be a primary target of rejection in the hand. Two of our recipients developed severe intimal hyperplasia and vasculopathy early post-transplant. An analysis of events and our four other patients has shown that the standard techniques used for surveillance of rejection (i.e. punch skin biopsies, DSA and conventional vascular imaging studies) are inadequate for detecting the early stages of vasculopathy. In response, we have initiated studies using ultrasound biomicroscopy (UBM) to evaluate the vessel wall thickness. These findings suggest that vasculopathy should be a focus of frequent monitoring in VCA of the hand.

Facial transplantation: the first 9 years

“…One patient had to be switched from mycophenolate mofetil to sirolimus (in addition to tacrolimus and steroids) for nonresolving grade 2-3 rejection. 12 Chronic rejection or chronic allograft vasculopathy have not been reported; these disorders were previously considered possible and have become evident in human hand transplantation 44 and preclinical studies. 45 Hyperacute rejection from pre-formed antibodies has also not been reported.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…In particular, the intracellular signaling pathways leading to endomune factors also contribute to TV, the majority of renal allograft loss due to chronic rejection was associated with HLA DSAs (24, 164). Chronic rejection is also an important cause of late failure of vascularized CTA (165,166). Similarly, chronic damage and TV in heart (25), lung (95,167,168), pancreas (169), and liver (11, 28, 170) allografts are more common among patients with a history of biopsy-proven AMR and HLA DSAs.…”

Minimizing immunosuppression in hand transplantation

“…Aggressive and severe intima hyperproliferation was observed early post-transplant in two out of six of the recipients in their patient series. Of concern, standard monitoring techniques were inadequate to detect early potentially reversible stages of allograft vasculopathy in four out of the six recipients [94]. These data show that chronic rejection will be a topic in the next 5 years that requires due diligence and intense further investigation as we are expanding the number of transplants performed and about to develop novel treatment protocols for hand transplantation.…”

“…However, in experimental rat hindlimb transplantation models, changes such as intimal hyperproliferation and luminal narrowing/occlusion consistent with chronic rejection or allograft vasculopathy have been shown after repeated episodes of acute skin rejection and frequent lapses in maintenance immunosuppression [93]. Most recently, Kaufman et al reported some level of vasculopathy in all six of their hand transplant recipients with aggressive and severe intimal hyperplasia observed early post-transplant in two patients [94]. Of concern, in four of their patients standard techniques used for surveillance of rejection (protocol skin biopsies, DSA and conventional vascular imaging modalities) were obviously inadequate for detecting early, potentially reversible, stages of allograft vasculopathy.…”