Belatacept and Long-Term Outcomes in Kidney Transplantation

Riella LV, Gabardi S, Azzi J.

N Engl J Med. 2016 Jun 30;374(26):2599-600. doi: 10.1056/NEJMc1602859#SA4.

To the Editor:

We congratulate Dr. Vincenti and colleagues for their manuscript reporting 7-year outcomes of the BENEFIT trial, one of the longest-term follow-up studies in transplantation. However, understanding its limitations will help define belatacept’s role in modern immunosuppressive regimens. Firstly, the major limitation is cyclosporine as the comparator. Tacrolimus is standard-of-care based on results of the Symphony trial, which demonstrated its superiority over cyclosporine in graft survival and function (1). Secondly, the continuous rise of eGFR throughout the study in belatacept-treated patients may potentially reflect the shortcomings of creatinine in assessing renal function. Alternatively, a component of adaptive hyperfiltration could be present (2). If available, measurements of direct renal function and proteinuria are vital in clarifying this issue. While Vincenti, et al. show low rates of de novo donor-specific antibodies in belatacept-treated patients, it’s essential to note that cyclosporine reduces exposure to mycophenolate (3), a known suppressor of B-cell maturation (4). Lastly, low-dose belatacept had significantly higher graft loss due to infections (24%) versus cyclosporine (0%). Enlightenment of the details of infections leading to graft loss is necessary.

1. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562-75. PubMed PMID: 18094377.
2. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012 May;8(5):293-300. PubMed PMID: 22349487.
3. Gregoor PJ, de Sevaux RG, Hene RJ, Hesse CJ, Hilbrands LB, Vos P, et al. Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation. 1999 Nov 27;68(10):1603-6. PubMed PMID: 10589962.
4. Karnell JL, Karnell FG, 3rd, Stephens GL, Rajan B, Morehouse C, Li Y, et al. Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation. Journal of immunology. 2011 Oct 1;187(7):3603-12. PubMed PMID: 21873529. Pubmed Central PMCID: 4180087.