The purpose of the prospective study was to determine the prevalence of subclinical toxicity of calcineurin inhibitors (CI) in repeated protocol renal allograft biopsies and to assess its impact on the development of chronic graft changes. A total of 424 biopsies were conducted in a cohort of 158 patients; of these biopsies, 158 were in the third week, 142 were in the third month and 124 were in the first year after transplantation. Histological signs of toxicity occurred in the third week in 33 (20.1%) patients, with persistence after CI dose reduction in the third month in 27 (19.0%) and in the first year in 23 (18.5%) patients. Of the toxic changes, 52% were clinically silent. At the end of the one-year follow-up, both subclinical and clinically manifest toxicity resulted in a similar progression of chronic changes quantified by Banff chronicity score and they significantly differed from the control group (P < 0.05). Subclinical toxicity affects a significant percentage of grafts; it occurs independently of dosage, blood level and type of applied CI. It is associated with the progression of chronic changes as early as in the first year after transplantation and represents an independent risk factor for chronic allograft damage. We report here our clinical approach to toxicity.

3rd Department of Internal Medicine and Nephrology University Hospital Olomouc Olomouc Czech Republic

Zobrazit více v PubMed

Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4:1289. PubMed

Rush D. Protocol transplant biopsies: an underutilized tool in kidney transplantation. Clin J Am Soc Nephrol. 2006;1:138. PubMed

Chapman JR, Nankivell BJ. Nephrotoxicity of ciclosporin A: short-term gain, long-term pain? Nephrol Dial Transplant. 2006;21:2060. PubMed

Naesens M, Lerut E, Damme BV, Vanrenterghem Y, Kuypers DR. Tacrolimus exposure and evolution of renal allograft histology in the first year after transplantation. Am J Transplant. 2007;7:2114. PubMed

Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Chapman JR, Allen RD. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation. 2004;78:557. PubMed

Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713. PubMed

Solez K, Colvin RB, Racusen LC, et al. Banff ‘05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’) Am J Transplant. 2007;7:518. PubMed

Rush DN, Nickerson P, Jeffery JR, McKenna RM, Grimm PC, Gough J. Protocol biopsies in renal transplantation: research tool or clinically useful? Curr Opin Nephrol Hypertens. 1998;7:691. PubMed

Viklicky O, Matl I, Voska L, et al. TGF-β1 expression and chronic allograft nephropathy in protocol kidney graft biopsy. Physiol Res. 2003;52:353. PubMed

Morath C, Ritz E, Zeier M. Protocol biopsy: what is the rationale and what is the evidence? Nephrol Dial Transplant. 2003;18:644. PubMed

Woywodt A, Bahlmann FH, De Groot K, Haller H, Haubitz M. Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol Dial Transplant. 2002;17:1728. PubMed

Koo DD, Roberts IS, Quiroga I, et al. C4d deposition in early renal allograft protocol biopsies. Transplantation. 2004;78:398. PubMed

Rowshani AT, Scholten EM, Bemelman F, et al. 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 zdar. J Am Soc Nephrol. 2006;17:305. PubMed

Hauser IA, Schaeffeler E, Gauer S, et al. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J Am Soc Nephrol. 2005;16:1501. PubMed

Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation. 2005;79:499. PubMed

Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int. 2005;18:22. PubMed

Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant. 2006;6:514. PubMed

Ekberg H, Grinyó J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant. 2007;7:560. PubMed

Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004;4:953. PubMed

Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials. Am J Transplant. 2005;5:1748. PubMed

Diekmann F, Budde K, Slowinski T, et al. Conversion to sirolimus for chronic allograft dysfunction: long-term results confirm predictive value of proteinuria. Transpl Int. 2008;21:152. PubMed

Tostivint I, du Montcel ST, Jaudon MC, et al. Renal outcome after ciclosporin-induced nephrotoxicity. Nephrol Dial Transplant. 2007;22:880. PubMed