Sequential protocol biopsies from renal transplant recipients show an increasing expression of active TGF beta

Abstract

Chronic allograft nephropathy (CAN) is a major cause of graft loss after renal transplantation. Implicated in the pathogenesis of this complication is overproduction of the cytokine transforming growth factor beta (TGF β). In this study we measured changes in CAN's expression in stable patients early after transplantation, and studied links with established risk factors for CAN, such as delayed graft function, acute rejection, and cyclosporine exposure. We took biopsies from 40 renal allografts at time of transplantation (pre‐perfusion), and then, using ultrasound guidance, at 1 week and 6 months after transplantation. An immunofluorescence technique was used to stain sections for active TGF β. These were then assessed by semi‐quantitative scanning laser confocal microscopy. There was very little variation in active TGF‐β expression among patients in their pre‐perfusion biopsies. Expression had increased by 1 week and then very significantly by 6 months (P<0.0001). Patients who suffered delayed graft function had increased TGF‐β expression at both time points. There was no difference regarding donor type, acute rejection, and immunosuppressive drug (cyclosporine or tacrolimus). There was no correlation between the amount of TGF‐β expression at any time‐point and isotope glomerular filtration rate (GFR) at 12 months. This study demonstrated that in a group of stable renal allograft recipients, TGF‐β expression in the kidney increased after transplantation. As the study used protocol biopsies, this increase is unlikely to be due to acute events, and probably represents a genuine increase.

Kidney Disease After Heart and Lung Transplantation

“…TGF‐β expression is induced in renal tissue by CyA in heart transplant recipients (29). In the absence of specific data in heart and lung transplant patients, extrapolation from studies involving protocol biopsies in kidney recipients suggests that renal expression of TGF‐β is similar in patients regardless of whether they are receiving CyA or Tac as their calcineurin inhibitor (30).…”

Plasma TGF‐β1 as a risk factor for gingival overgrowth

“…Interestingly, intra‐renal expression of TGF‐ β 1 was enhanced with both ciclosporin and tacrolimus therapy (Bicknell et al 2000, Jain et al 2002, Khanna et al 2002). However, quantitative analysis of the comparative levels of TGF‐ β 1 in biopsies from ciclosporin and tacrolimus‐treated patients have not revealed consistent results (Bicknell 2000, Mohammed et al 2000, Jain 2002, Khanna et al 2002). Furthermore, there are differences between the expression of latent TGF‐ β 1 and active TGF‐ β 1 which might be pathologically important (Mohammed et al 2000).…”

“…Tacrolimus seems to have effects similar to ciclosporin in terms of stimulating TGF-b1 synthesis and secretion in lymphoid and non-lymphoid tissues albeit through different biochemical mechanisms (Han et al 1995, Khanna et al 1999. Interestingly, intra-renal expression of TGF-b1 was enhanced with both ciclosporin and tacrolimus therapy (Bicknell et al 2000, Jain et al 2002, Khanna et al 2002. However, quantitative analysis of the comparative levels of TGF-b1 in biopsies from ciclosporin and tacrolimustreated patients have not revealed consistent results (Bicknell 2000, Mohammed et al 2000, Jain 2002, Khanna et al 2002.…”

Role of Integrin CD103 in Promoting Destruction of Renal Allografts by CD8+ T Cells

“…On the other hand, exposure of CD8 cells to bioactive TGF‐β subsequent to their progression to effector status induces expression of CD103 without compromising effector function (39). An additional factor to be considered is that rejecting renal allografts are associated with exceptionally high levels of TGF‐β (54–56). Moreover, TGF‐β activity is not normally systemic, but rather is localized to peripheral inflammatory sites (51).…”

“…An additional factor that limits the involvement of CD103 + CD8 + effectors is the availability of local TGF‐β activity. Rejecting renal allografts are associated with high levels of TGF‐β (54,55), and it is therefore possible that the renal environment is relatively unique in the capacity to induce CD103 expression by graft‐infiltrating CD8‐effector populations. In this regard, it is important to note that although we have reported that CD103 plays a critical role in rejection of pancreatic islet allografts (49), grafts in this study were transplanted into the renal subcapsular site, and it remains to be determined if CD103 plays an analogous role in destruction of islet grafts transplanted via the clinically relevant route (intraportally) or, for that matter, in vascularized renal allografts.…”