Response to: De Novo Kidney Transplantation Without Use of Calcineurin Inhibitors Preserves Renal Structure and Function at 2 Years

To the Editor: We appreciate the comments by Dr. Abbott regarding our randomized prospective comparison of cyclosporine-based (CNI treated) and sirolimus-based (CNI free) immunosup-pression in kidney transplantation. We refer him to the initial report of the clinical results to answer several of his questions (1; reference 19). This study was not powered to detect differences in patient and graft survival, but was intentionally powered to detect, using a power of 0.90 and an alpha of 0.05, a difference in mean creatinine of 0.25 ± 0.15 mg/dL and calculated creatinine clearance of 15 ± 10 cc/min. We agree that blood pressure (BP) among kidney transplant recipients is important, and as previously reported at 6 and 12 months, respectively, there were no significant differences in mean systolic and diastolic BP nor the number of anti-hypertensive agents (including diuretics) between the sirolimus-treated and the CNI-treated patients (1Flechner SM Goldfarb D Modlin C et al.Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine..Transplantation. 2002; 74: 1070-1076Crossref PubMed Scopus (375) Google Scholar).Analysis at the time of the 2- year biopsies demonstrated mean ± SD BPfor CNI-treated versus sirolimus, respectively, Systolic 147.2 ± 18.5 versus 134.6 ± 16 and Diastolic 80.7 ± 9.4 versus 75.5 ± 9.9 mmHg. The difference in the means for systolic BP was significant (p = 0.0074), using a 2-tailed t-test assuming equal variances. The difference in the means for diastolic BP was marginally significant (p = 0.051). There was no significant difference in ACE inhibitor use, as 39% (11) of sirolimus-treated and 36% (10) CNI-treated patients were receiving a converting enzyme inhibitor. The mean number of BP drugs per patient (including diuretics) was greater for the CNI treated 2.46 than the sirolimus treated 2.04, but the difference was not significant, row mean score (CMH test, p = 0.332). These findings may reflect small sample sizes. Since the prevalence of Banff-scored CAN in our 2-year biopsies for CNI-treated patients mirrors previous reports (3Solez K Vincenti F Filo RS Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group..Transplantation. 1998; 66: 1736-1740Crossref PubMed Scopus (348) Google Scholar,4Nankivell BJ Borrows RJ Fung CL et al.The natural history of chronic allograft nephropathy..N Engl J Med. 2003; 349: 2326-2333Crossref PubMed Scopus (1687) Google Scholar), it is most likely that the reduction of CAN is due to the different immunosuppressive maintenance regimens employed. A similar degree of protection from CAN was reported in biopsies of kidneys treated with sirolimus and steroids, after cyclosporine elimination at 3 months (5Mota A Arias M Taskinen E et al.Sirolimus based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function..Am J Transplant. 2004; 4: 953-961Crossref PubMed Scopus (209) Google Scholar). Whether the reduction of CAN is directly due to the com-bination of sirolimus-mycophenolate-steroids or rather the absence of a CNI drug is open to conjecture, but may likely represent a contribution from both. It is also likely that 2–3 years of follow-up is insufficient for differences in graft survival to emerge, even though CNI-free patients have markedly improved renal function. However, a graft survival advantage for CNI-free patients and/or a lack of advantage for those on continuous CNI therapy has been reported as follow-up is observed beyond 4–5 years (6Marcen R Pascual J Teruel JL et al.Outcome of cadaveric renal transplant patients treated for 10 years with cyclosporine: is chronic allograft nephropathy the major cause of late graft loss?.Transplantation. 2001; 72: 57-62Crossref PubMed Scopus (57) Google Scholar, 7Kreis H Oberbauer R Campistol JM et al.Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal..J Am Soc Nephrol. 2004; 15: 809-817Crossref PubMed Scopus (221) Google Scholar, 8Gallagher MP Hall B Craig J et al.A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients: 15-year results..Transplantation. 2004; 78: 1653-1660Crossref PubMed Scopus (78) Google Scholar). Our series awaits this longer interval of time. Lastly, treatment impli-cations from our data should not be projected to long-term damaged grafts with biopsy-confirmed CAN. This remains a distinct problem that is best addressed by prospective controlled investigation.

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