Should Belatacept Be the Centrepiece of Renal Transplantation?

Monika Huber; Stephan Kemmner; Lutz Renders; Uwe Heemann

Disclosures

Nephrol Dial Transplant. 2016;31(12):1995-2002. 

In This Article

Discussion

The available clinical trials comparing belatacept versus a CNI-based immunosuppressive maintenance regimen indicate improved patient and graft survival in BENEFIT after 7 years of follow-up and similar outcomes for patient and graft survival in the other studies with shorter follow-up periods. With belatacept, renal function was significantly better in all trials despite the higher incidence and grade of early acute rejections.

However, although these data are very promising, they are far from conclusive. First of all, in the trials utilizing belatacept for induction and maintenance therapy, only patients with a low immunological risk were included. Thus, whatever we may conclude from the published trials is valid only for a limited number of patients. Furthermore, as we all know, CNIs, CsA more than TAC, lowers the GFR. Therefore, belatacept may not be better than CNIs, as in none of the initial studies was the decline of GFR between months 3 and 12 statistically significant between the groups. This tendency became obvious only in the extension of the follow-up period.[15,29]

When we consider the benefit 7-year results, it is hard to understand why a GFR should improve over time. This is certainly contradicting general nephrological experience in the treatment of patients. Furthermore, age is a factor in the calculation, thus, even if the real GFR remains constant, the eGFR would decrease. So how can we explain this finding? One possible explanation is the dropout rate. Those who lose their grafts might have had a worse GFR. If you eliminate them from the equation, the average GFR increases. One other explanation would be hyperfiltration of the single transplant kidney, because the GFR is not reduced by CsA. Whether this effect is as harmful to the kidney graft as assumed for diabetes- and obesity-induced hyperfiltration is unknown and difficult to prove.

Although this is one of the best long-term studies ever done in the field of transplantation, with a very high follow-up rate (79%), it has to be mentioned that only 447 of 660 patients were followed for 7 years, which limits the value of the study.

The data for patient and graft survival also have to be viewed with a great deal of caution. What happened to those who could not be followed? Why was the difference not apparent in other trials? As the advantage is based on a rather small number of individuals, a small number of dead patients among those who could not be followed might hamper the results. The authors claim a reduction in mortality of 43%, which is certainly impressive. However, at 7 years, 16 of the patients treated with LI belatacept had died (8.2%; n = 10 non-cardiovascular or unknown) compared with 25 (14.4%; n = 14 non-cardiovascular) in the CsA group. This is a rather small number of patients and, based on the large amount of patients who were not followed, although a strong indicator, it is not proof. Furthermore, it is unclear why belatacept should interfere with non-cardiovascular deaths, despite lower infection rates because of presumably lower immunosuppression or unclear death, which might be attributed to sudden cardiac death. Thus, the difference is 6 versus 11 in ~130 patients per group, and 5 patients in the cyclosporine group died during the first 6 months, a period unlikely to be affected by long-term risk factors.

So what can we safely conclude from these long-term observational studies? First of all, there are a number of patients who can be safely treated with a drug unlikely to cause diabetes and hypertension. Although we cannot be sure that patient and graft survival is improved, the suggestion is rather strong.

Is this drug better than conventional immunosuppression with TAC? At present we do not know. TAC is certainly more potent in the suppression of acute rejection episodes than CsA. Thus the difference in rejection rate between belatacept and TAC is certainly more pronounced.[30] However, the rejection episodes observed with belatacept resolved remarkably well, making it unlikely that permanent damage was induced. While we cannot fully exclude this possibility, the long-term tendency even when comparing belatacept with CsA and not TAC does not suggest a major problem. Whether, however, overall patient survival would differ from TAC is an open question.

The real benefit of belatacept seems to be the great adherence of patients. The very limited side effects in comparison to CsA garner an acceptance rate much higher than in cyclosporine. While >60% of the initial patients were still treated with belatacept, this percentage was much lower in the CsA arm (47%). Adherence will also be higher with belatacept due to the control of drug infusion in the centre. If the patient misses a dose it will be noted and steps can be taken to ensure timely administration.

In all trials, belatacept had a favourable profile in lowering cardiovascular and metabolic risk factors. Systolic and diastolic blood pressures were significantly lower, with less antihypertensive therapy, the lipid profile was less atherogenic by trend and in BENEFIT-EXT the incidence of NODAT was reduced.

An obvious benefit of belatacept is the significantly reduced production of donor-specific antibodies. This may explain, at least in part, the likewise reduced chronic renal damage in protocol biopsies and might be even more pronounced in the later stages of chronic allograft damage, where no protocol biopsies were acquired.

Since only a few of our patients have a low immunological risk, only a few would be suitable for belatacept treatment. The more attractive option is a switch from a CNI after a limited period of time, such as 3–6 months.

Based on the switching trials, an interesting approach could be to administer a CNI-based regimen during the initial phase of transplantation to reduce the risk of early acute rejections. Unfortunately, this use is off-label so far, but studies are under way (NCT02213068 and NCT01837043). In long-term maintenance therapy, a conversion to belatacept might preserve renal function and possibly improve long-term graft and patient survival. Late conversion to belatacept after a diagnosis of chronic allograft nephropathy and CNI toxicity might be a beneficial option to prevent allograft loss as well. This has to be confirmed in larger prospective randomized trials, particularly for patients at a higher immunological risk.[31]

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