Kidney transplant recipients face a lifelong balancing act between short-term ease and long-term risk in their immunosuppressive regimen. Flavio G. Vincenti, MD, examines the trade-offs between calcineurin inhibitor–based and calcineurin inhibitor–free approaches to kidney transplant maintenance therapy and discusses why the easier short-term choice may not always be the better choice long-term.

Tacrolimus-based immunosuppressive regimens are the standard of care for kidney transplant maintenance. The combination of tacrolimus, mycophenolic acid, and steroids has substantially reduced acute rejections, from approximately 20% to 30% with earlier regimens down to the low double or even single digits when combined with induction therapy, such as the IL-2R monoclonal antibody basiliximab or the T-cell–depleting agent thymoglobulin. This combination is very effective at reducing acute rejection, enables the early discharge of patients, and results in improved graft survival. These agents are generally safe and easy to use, and, due to the many studies conducted on this treatment combination, clinicians are also very familiar with it. So, it is not surprising that its role in transplant immunosuppression has been solidified.

However, many problems persist with calcineurin inhibitor–based immunosuppression over the long-term. For one, calcineurin inhibitors are associated with various toxicities. These include nephrotoxicity, which can be difficult to diagnose because these changes can also be observed with other causes of allograft dysfunction, such as hypertension and rejection; neurotoxicity, ranging from minor tremors to more severe cognitive impairment (eg, brain fog); and metabolic effects, since tacrolimus impairs insulin secretion from the pancreas, increasing the risk of hyperglycemia and new-onset diabetes after transplant. These toxicities can be managed, but they come at the expense of long-term consequences and increased health care burden on patients.

Moreover, while calcineurin inhibitors are excellent at suppressing T-cell–mediated rejection early on, they are, perhaps, not as good at suppressing humoral alloimmune response long-term. When tacrolimus was compared with the noncalcineurin inhibitor belatacept, patients on belatacept showed a stable or improving estimated glomerular filtration rate slope over time, while the slope for patients on tacrolimus deteriorated over time. Additionally, over time, 15% to 20% of patients taking calcineurin inhibitors also develop donor-specific antibodies, which are associated with an increased risk of chronic antibody-mediated rejection and graft loss. Adding to this, to minimize toxicities, we tend to reduce dose levels (to ≤5 ng/mL), and I think that this level of immunosuppression is not adequate long-term to suppress donor-specific antibodies.

Belatacept is not without its own trade-offs, however. One of its weaknesses is a higher rate of acute cellular rejection early on, which has discouraged some health care professionals from using it more extensively. However, very little rejection occurs beyond the first 6 to 12 months, which is when belatacept may carry a higher rejection rate; with tacrolimus, a little rejection can occur every year. Additionally, belatacept is associated with very low rates of donor-specific antibodies long-term. It is currently the only available option for a calcineurin inhibitor–free regimen. Future costimulation blockade biologics are hoped to be as good as or better than belatacept, but this has not been determined yet.

Whether to concentrate on the short-term or treat patients with a view toward the long-term is a real conundrum for clinicians. Clinicians will often say that they are treating for the long-term; however, in practice, the opposite is happening. For example, the vast majority of patients who are being treated with immunosuppression are on a tacrolimus-based regimen rather than a calcineurin inhibitor–free one.