Autoimmune Thyroid Disease After Renal Transplantation Using Depletional Induction with Alemtuzumab

To the Editor: Lymphocyte depletion is being used with increasing frequency as an induction strategy following renal transplantation (1Shapiro R Young JB Milford EL Trotter JF Bustami RT Leichtman AB Immunosuppression: evolution in practice and trends, 1993–2003..Am J Transplant. 2005; 5: 874-886Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). As an example, promising preliminary results have been reported from several centers using the CD52-specific monoclonal antibody alemtuzumab, an agent that induces profound lymphocyte depletion and appears to lessen the subsequent requirements for maintenance immunosuppression (2Calne R Friend P Moffatt S et al.Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients..Lancet. 1998; 351: 1701-1702Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 3Kirk AD Hale DA Mannon RB et al.Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody Campath-1H..Transplantation. 2003; 76: 120-129Crossref PubMed Scopus (396) Google Scholar, 4Knechtle SJ Pirsch JD H Fechner Jr, J et al.Campath-1H induction plus rapamycin monotherapy for renal transplantation: Results of a pilot study..Am J Transplant. 2003; 3: 722-730Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 5Shapiro R Basu A Tan H et al.Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath..J Am Coll Surg. 2005; 200: 505-515Crossref PubMed Scopus (160) Google Scholar, 6Axelrod D Leventhal JR Gallon LG Parker MA Kaufman DB Reduction of CMV disease with steroid-free immunosuppression in simultaneous pancreas-kidney transplant recipients..Am J Transplant. 2005; 5: 1423-1429Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The mechanism by which alemtuzumab reduces the need for maintenance drugs has not been established, although it is clear that the post-depletional immune repertoire differs significantly from that of non-depleted individuals. Specific differences include a generalized activation of residual cells undergoing homeostatic repopulation, alterations in peripheral cell phenotypes and acute reductions in the number of cells with a potential regulatory phenotype (7Pearl JP Parris J Hale DA et al.Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion..Am J Transplant. 2005; 5: 465-474Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar). As these effects appear to be general, both allo- and auto-specific immunity could be anticipated to be altered. Autoimmune diseases have been reported in patients undergoing profound T-cell depletion with alemtuzumab as a treatment for multiple sclerosis (MS) (8Coles AJ Wing M Smith S et al.Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis..Lancet. 1999; 354: 1691-1695Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar). Thyroid disease became clinically apparent 1–3 years after depletion. We have now seen a first case of autoimmune hyperthyroidism in a transplant patient treated with alemtuzumab induction. As this patient is the third index patient treated in North America with alemtuzumab induction, we would recommend that others using depletional induction strategies be vigilant in surveying for this potential complication.1 The patient presented for transplantation at age 30. Her cause of renal failure was tubulointerstitial nephritis associated with drug toxicity. Her thyroid function at transplantation was normal with a triiodothyronine of 82 ng/dL (82–179 ng/dL), a free thyroxine of 1.0 ng/dL (0.7–1.8) and a thyroid stimulating hormone of 2.3 uIU/mL (0.4–4.0 uIU/mL) at transplant. She received a live unrelated donor graft, with alemtuzumab induction (1.2 mg/kg in four preoperative doses) and no maintenance immunosuppression as previously described (3Kirk AD Hale DA Mannon RB et al.Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody Campath-1H..Transplantation. 2003; 76: 120-129Crossref PubMed Scopus (396) Google Scholar). She had a steroid sensitive rejection on postoperative day 15 and was transitioned to monotherapy sirolimus. Her creatinine has been remarkably stable since (current serum creatinine 1.0 mg/dL) with ultrasound evidence of physiological compensatory hypertrophy. She is currently on sirolimus, 1mg daily as her only maintenance immunosuppression. Four years following transplantation, she developed clinical hyperthyroidism with a triiodothyronine of 368 ng/dL, a free thyroxine of 2.3 ng/dL and a thyroid stimulating hormone 0.020 uIU/mL. Additionally, her free T3 was markedly elevated at 720 pg/dL (230–420), her reverse T3 was 131 ng/dL (11.7–33.2), her thyroxine was 21.7 mcg/dL (4.5–12.5) and she had concomitant evidence of autoimmune thyroiditis including an elevated thyroid stimulating antibody index 2.8 (0–1.8), an elevated thyrotropin-binding inhibitory antibody of 59.6% (0–10% inhibition), with diffusely elevated uptake on thyroid scan. Her absolute lymphocyte count at the time of diagnosis was 913 cells/μL, with low but proportionate numbers of CD4+ and CD8+ T cells (235 and 151 cells/μL, respectively). As with previously reported cases of autoimmune thyroiditis following T-cell depletion in MS patients, this case was sensitive to therapy with carbimazole. It is not clear whether the apparent association with alemtuzumab and autoimmune thyroid disease reflects a specific property of CD52 targeted therapy, or is, as we suspect, a more general phenomenon related to profound lymphocyte depletion with alemtuzumab being uniquely effective at achieving exceptionally low cell counts. It is important to point out that our patient received a relatively high dose of alemtuzumab, similar to that seen in the MS study and two to four times higher than that reported in most transplant trials (2Calne R Friend P Moffatt S et al.Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients..Lancet. 1998; 351: 1701-1702Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 4Knechtle SJ Pirsch JD H Fechner Jr, J et al.Campath-1H induction plus rapamycin monotherapy for renal transplantation: Results of a pilot study..Am J Transplant. 2003; 3: 722-730Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 5Shapiro R Basu A Tan H et al.Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath..J Am Coll Surg. 2005; 200: 505-515Crossref PubMed Scopus (160) Google Scholar, 6Axelrod D Leventhal JR Gallon LG Parker MA Kaufman DB Reduction of CMV disease with steroid-free immunosuppression in simultaneous pancreas-kidney transplant recipients..Am J Transplant. 2005; 5: 1423-1429Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). She also had minimal post-depletional maintenance immunosuppression, which could be permissive for autoimmunity. Thyroid dysfunction occurred late in this patient compared to the MS associated cases and this may reflect that although the patient’s maintenance immunosuppression was low relative to the standard of care, she was on chronic immunosuppression, which could have delayed the course of her disease. As with all isolated cases, it is also possible that this is a sporadic case unrelated to therapy. Nevertheless, we would suggest that clinicians be aware of potential autoimmune sequelae in the setting of profound lymphocyte depletion regardless of the induction agent and particularly when minimal maintenance regimens are being employed.