Spontaneous Operational Tolerance in Kidney Transplant Recipients: Response

Abstract

To the Editor: We would like to thank Leventhal et al. (1) for bringing to our attention an inconsistency in Table 1 of our article (2). Due to an error, the time of immunosuppression for operationally tolerant kidney recipients was typed in years whereas it should have been typed in months. Thus, instead of a mean of mean 7 (range 3–12) years, the correct figures are mean 84 (range 36–144) months. The “2–13 years” reported in the text are a misprint. The correct data therefore are those described in Table 1 (we include here a correct version of the table). We apologize for these errors. Leventhal et al. also raised the question of whether kidney recipients requiring no immunosuppression but displaying donor-specific antibodies should ever be considered operationally tolerant. Our group first made the observation that a minority of operationally tolerant kidney recipients exhibits donor-specific antibodies in 2006 (3). In this case-report article, we described two patients with anti-HLA class II antibodies and normal kidney graft function 4 and 10 years after being off on all immunosuppressive drugs. A similar observation was made more recently by Newell et al. (4) in his report on the Immune Tolerance Network cohort of operationally tolerant kidney recipients, in which 1 of 20 recipients also had donor-directed anti-HLA antibodies. In the cohort of operationally tolerant kidney recipients described in this manuscript (2), only 3 of 12 recipients were HLA identical. The remaining nine recipients had one, two, three, three, three, four, four, four and five mismatches. Regarding the three patients with donor-specific antibodies, these were detected in the first case 10 years after transplantation and 9 years after drug withdrawal; in the second case 13 years after transplantation and 8 years after drug withdrawal and in the third case 16 years after transplantation and 2.5 years after withdrawal. To date the 3 recipients still display stable graft function. Unfortunately, we could not establish the relationship between the appearance of anti-HLA antibodies and the discontinuation of immunosuppressive drugs, because these patients were not prospectively followed from the date of transplantation. In any case, we have no data indicating that operationally tolerant kidney recipients bearing donor-specific antibodies have a greater risk of graft deterioration than those who do not. Altogether, the situation appears to be similar to what is observed in “conventional” kidney recipients under maintenance immunosuppression, in whom the pathogenic and clinical meaning of de novo anti-HLA antibodies is far from being clear (5). Until the prognostic value of anti-HLA antibodies is clearly defined in longitudinal studies, we therefore see no reason to exclude this subgroup of patients from studies attempting to characterize operational tolerance in kidney transplantation. We agree with Leventhal et al. that in the absence of kidney biopsies it is not possible to exclude the presence of graft histological abnormalities indicative of low-grade immune reactivity. This is a problem common to all studies that have attempted to characterize operationally tolerant kidney recipients. Nevertheless, we want to stress here that all recipients described in our article still display stable graft function and have done so during a very long period of time in the absence of any immunosuppressive therapy. Concerning our attempt to assess the stability of the circulating B-cell immunophenotype, sequential blood samples were collected from four recipients at the following posttransplant time points: 6 and 11 years after transplantation (4 and 9 years after drug withdrawal); 18 and 22 years after transplantation (5 and 9 years after withdrawal); 23 and 27 years after transplantation (13 and 15 years after withdrawal) and 17 and 18 years after transplantation (5 and 6 years after withdrawal). In this subgroup of patients, only one displayed donor-specific antibodies (detected 10 years after transplantation and 9 years after drug withdrawal). As stated in our article (2), the analysis of these sequentially collected samples revealed that the phenotype of circulating B cells was very stable over time. We are grateful to Leventhal et al. for their supportive comments on our article. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.