No Difference in Degree of Interstitial Sirius Red–Stained Area in Serial Biopsies from Area under Concentration-over-Time Curves–Guided Cyclosporine versus Tacrolimus-Treated Renal Transplant Recipients at One Year

Abstract

Interstitial fibrosis is the main characteristic of chronic allograft nephropathy and long-term graft failure. Cyclosporin (CsA) is thought to be more fibrogenic than tacrolimus. In a prospective, randomized, multicenter trial using a calcineurin-sparing regimen, renal interstitial volume was compared in CsA-and tacrolimus-treated renal transplant recipients by image analysis of Sirius red (SR)-stained cortical areas in protocol biopsies obtained at 6 mo (n ‫؍‬ 94) and 12 mo (n ‫؍‬ 97) after transplantation. Immunosuppression consisted of CsA or tacrolimus, CD25 mAb, mycophenolate mofetil, and prednisolone. CsA therapy increased the 6-mo risk for subclinical rejection. The prevalence of subclinical rejection was 38.8% in the CsA-treated and 15.2% in the tacrolimus-treated patient group (P ‫؍‬ 0.012). Strikingly, no difference in the degree of interstitial SR-stained area was detectable between the two treatment groups. In particular, previous subclinical rejection episodes did not influence the degree of interstitial volume. Also, no difference in GFR occurred at 1 yr, when the mean GFR mounted 63 ml/min. No significant differences in the degree of interstitial SR-stained area could be observed at 6 and 12 mo between CsA-and tacrolimus-treated renal transplant recipients. Although CsA-treated patients developed significantly more subclinical rejections at 6 mo, this did not influence the degree of SR staining or the change in renal function at 1 yr.J Am Soc Nephrol 17: 305-312, 2006305-312, . doi: 10.1681 C hronic allograft nephropathy (CAN) is the leading cause of long-term graft failure. Its prevalence has been estimated at 50 to 94% at 1 yr (1,2). In concept, clinical CAN refers to kidney transplant disease with a slow decline rate in renal function that histologically can be characterized by interstitial fibrosis, tubular atrophy, fibrointimal hyperplasia of the vessels, and glomerulosclerosis. Because multifactorial processes are involved in the pathogenesis of CAN, a clear histopathologic distinction between different causes, such as chronic rejection, toxic effects of calcineurin inhibitors, hypertensive vascular disease, and infection, is not always possible in one single case (3).Recently, the histopathologic dynamics in the development of CAN were evaluated in retrospective studies of serial biopsies from kidney-pancreas transplant recipients using the Banff semiquantitative grading system (1,4,5). Two distinctive phases of injury were recognized. The early phase was characterized by tubulointerstitial damage that occurred during the first year and correlated with ischemia-reperfusion injury, immunologic factors such as severe acute rejection, and persistent subclinical rejection. The later phase consisted of chronic damage characterized by progressive arteriolar hyalinosis, ischemic glomerulosclerosis, and further interstitial fibrosis that was associated among others with long-term calcineurin-inhibitor nephrotoxicity. Regardless of the nature and dynamics of the underlying disease, the extent of fi...

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

“…We applied these Bayesian estimators to compare an exposure-controlled dosing strategy to prevent structural changes, quantified by morphometric analysis of nonpolarized Sirius red staining of 6-and 12-mo protocol biopsies. 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).…”

“…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).…”

Calcineurin Inhibitor Nephrotoxicity

“…Although cyclosporine and tacrolimus are not structurally related (and despite initial optimism), it has been demonstrated that tacrolimus has nephrotoxic properties similar to those of cyclosporine and induces similar histologic injury (83,199,200). In addition, in a study with 61 cyclosporine analogs, it was shown that the ability to induce nephrotoxicity in vivo correlates with the immunosuppression activity of these agents (201).…”