Decreased Numbers of Total CD19+ B Lymphocytes and the Presence of Monoclonal Proteins Are Frequent in Ultra-Long (30-43 Year) Renal Transplant Recipients: Implications for Allograft and Patient Survival

Abstract

Introduction: The B-cell signature of tolerance in kidney transplant recipients on no immunosuppression includes an increase in total CD19+ B cells (mean 287 cells/μL) (Newell et al. J Clin Invest. 2010;120:1836). The question is whether long-term renal transplant recipients on minimal immunosuppression have similar findings. Methods: Lymphocyte subsets were analyzed by flow cytometry. Monoclonal proteins were identified by immunofixation. Results: Among 44 renal transplant recipients whose primary immunosuppression was minimal daily doses of prednisone (≤10 mg) and/or azathioprine (≤100 mg) and whose initial graft functioned for 30-43 years, there was the opposite finding of low total CD19+ B lymphocyte numbers (< 60 cells/μL) in 65.9% (29/44). Mean B cell counts were 52.0 ± 65.2 cells/μL for all 44 recipients. Low CD4+ or CD8+ T cell counts (< 490 and < 265 cells/μL, respectively) occurred in 13.6% (6/44) and 20.5% (9/44), respectively, of these recipients. CD8+CD38+ T cells were low (< 192 cells/μL) in 59.1% (26/44) of patients. Monoclonal proteins (MP) were identified in 45.5% (20/44) of these same recipients. The mean age of the patients with and without MP was similar at 53.4 and 53.6 years, respectively, as was the time post-transplant at 28.7 and 28.0 years, respectively. The donor sources for patients with and without MP were: LRD (14 and 19, respectively, including HLA-Id 9 and 5, respectively) and DD (5 and 6, respectively). There were 15 patients with a single monoclonal gammopathy (SMG), primarily IgG lambda (7), and 5 patients with a double monoclonal gammopathy (DMG) who also had varying degrees of free light chains. In the 26 recipients with good/excellent renal function (eGFR >45 ml/min) (Group1), 12 had SMG, 13 no MP, and 1 DMG. Conversely, in the 18 patients with fair/failed function (eGFR < 40ml/min in 8 or ESRD after 30 years in 10) (Group 2), 3 had transient SMG or free light chains only, 11 no MG, and 4 DMG) (p=0.047). No myeloma has developed with MP follow-up to 10 years. Allograft biopsies in 5 patients with MP did not show changes of light chain or monoclonal pathology; amyloid staining was negative. Although speculative, it is possible that in recipients receiving minimal immunosuppression usually including azathioprine for more than 30 years a SMP could have, or be a marker for, a protective renal allograft effect, represent an epiphenomenon for another event, or simply be a toxic effect of long-term azathioprine. Neither depressed B cell number nor MP was significantly associated with mortality. Conclusion: Ultra-long renal transplant function for 30-43 years with minimal immunosuppression is associated with uncharacterized total low CD19+ B cell numbers in nearly 2/3 of patients, opposite to what has been reported in B-cell tolerance in patients on no immunosuppression. Preservation of renal function was associated with a single monoclonal gammopathy in certain patients. These findings warrant further investigation.