Molecular Comparison of Calcineurin Inhibitor–Induced Fibrogenic Responses in Protocol Renal Transplant Biopsies

Abstract

The calcineurin inhibitor cyclosporine (CsA) induces a fibrogenic response that may lead to scarring of the renal allograft. This study investigated whether tacrolimus, a novel calcineurin inhibitor, exerts fibrogenic effects to a similar extent. Sixty patients were enrolled in a randomized study: 29 received CsA, and 31 received tacrolimus. Patients were subjected to tailored exposure-controlled calcineurin inhibitor regimens. Protocol biopsies were obtained at the time of transplantation and 6 and 12 mo after transplantation. Cortical TGF-␤ and collagens ␣1(I) and ␣1(III) mRNA steady-state levels were determined with real-time PCR. The extent of protein deposition of TGF-␤, ␣-smooth muscle actin, and interstitial collagens in the renal cortex was quantified with computer-assisted image analysis. The extent of interstitial collagen deposition measured with Sirius red and the accumulation of ␣-smooth muscle actin and TGF-␤ protein after 6 and 12 mo were similar for both immunosuppressive regimens. mRNA levels of TGF-␤ and collagens ␣1(I) and ␣1(III) were not significantly different in the treatment groups either. It is concluded that the fibrogenic response in renal allografts is similar in patients who receive CsA-based regimens and patients who receive tacrolimus-based regimens.

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

“…The lack of heterogeneity for the most important analyses in this report suggests that the results are consistent across immunosuppression regimens and individual agents. Indeed this is consistent with data showing comparable outcomes for the calcineurin inhibitors ciclosporin and tacrolimus (when used at comparable levels of exposure) in terms of histologic damage, 69,70 graft survival in clinical trials 17 and registry analyses. 71 Another limitation is the inability to clearly distinguish drug concentrations between comparator groups, especially important in the context of CNI minimization study comparisons.…”

Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

“…In a previous study, we found no difference in the profibrogenic effect as measured by Sirius red staining of either of the currently available CNI in biopsies that were obtained 6 and 12 mo after renal transplantation (19). At the molecular level, no differences were found in the extent of protein deposition of TGF-␤ and interstitial collagens, as well as cortical mRNA levels of TGF-␤ and collagens ␣1(I) and ␣1(III) (20). The histologic features of CAN, although most often mild, may occur early after renal transplantation, with a reported prevalence up to 40% in surveillance biopsies performed as early as 3 mo after transplantation (21,22).…”

“…Laminin ␤2 and TGF-␤ mRNA levels in the renal cortex, however, allow for distinguishing chronic CNI toxicity from chronic rejection with high sensitivity and specificity (43). The nephrotoxic potential of CsA and tacrolimus is indistinguishable clinically (6,44), histologically (19), or at the renal molecular level (20). Six months after implantation, no significant differences were found in the extent of protein deposition as well as cortical mRNA levels of TGF-␤, but a wide variability within both treatment groups (20).…”

“…The nephrotoxic potential of CsA and tacrolimus is indistinguishable clinically (6,44), histologically (19), or at the renal molecular level (20). Six months after implantation, no significant differences were found in the extent of protein deposition as well as cortical mRNA levels of TGF-␤, but a wide variability within both treatment groups (20). TGF-␤ expression in biopsies that were performed 3, 6, and 12 mo after transplantation was associated with a significant increase in interstitial fibrosis (45).…”

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

“…Some clinicians also feel that TAC may exhibit less nephrotoxicity; supporting this opinion are studies where pathological evidence of decreased fibrogenicity were noted with TAC (8,9). However, such evidence remains controversial as other studies have not reported any differences in profibrogenic effects of CsA and TAC at either the renal or molecular level, and the effects of adjunctive therapies cannot be separated easily from the primary effects of CsA or TAC (8,10).…”