Prolonged CD4 T Cell Lymphopenia Increases Morbidity and Mortality after Renal Transplantation

Abstract

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts Ͻ300/mm 3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for Ͼ1 year (24.1 versus 7.6%; P Ͻ 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P ϭ 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3 ϩ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P ϭ 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P ϭ 0.013). In summary, prolonged polyclonal anti-thymocyte globulin-induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections. Broad T cell depletion by polyclonal anti-thymocyte globulins (ATG) has been used for many years as a part of immunosuppressive treatment in transplantation. These polyclonal antibodies are a complex mixture of antibodies with multiple specificities directed to both T and non-T cells. 1,2 These antibodies produce profound T cell depletion via complement-dependent lysis and Fas/Fas ligand-mediated apoptosis. 3,4 Although T cell regeneration generally occurs in the months after ATG administration, Muller et al. 5 reported that ATG may induce persistent changes in T cell subsets characterized by a low CD4 T cell count and a CD8 T cell expansion.

In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia

“…13 In our ATG-treated patients, the most prevalent complications were infections: one hATG patient and eight rATG patients went "off study" due to recurrent life-threatening systemic infections not adequately controlled with antimicrobials, in the setting of progressive pancytopenia. CD4 + T cell lymphopenia might contribute to this complication, adding to susceptibility from the more severe and prolonged neutropenia with rATG.…”

Polyclonal Antithymocyte Globulin and Cardiovascular Disease in Kidney Transplant Recipients

“…We also reported an increased incidence of cardiovascular events in patients with ATG-induced persistent CD4 T-cell lymphopenia. 8,9 Unfortunately, all of the patients had received ATG and the lack of a control group did not enable to demonstrate a direct effect of ATG on atherosclerosis.…”

Progressive Multifocal Leukoencephalopathy After Allogeneic Bone Marrow Transplantation for Acute Myeloid Leukemia

“…In Case 2, it is probable that ATG was a significant contributor to the patient's prolonged T-cell lymphopenia, a well-described phenomenon in the solid organ transplant literature. 35,36 However, it is generally difficult to implicate a single immunosuppressive agent as the inciting reason for the development of PML, because most patients who develop PML after allogeneic BMT are exposed to more than one immunosuppressive drug. 37 Although immunosuppression is an unavoidable risk in patients undergoing allogeneic BMT, the present cases highlight the potential fatal complications of the resultant impaired cellular immunity and T-cell lymphopenia that occurs with time.…”