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Dear Editors,
Belatacept has proven its efficacy as maintenance therapy in kidney transplant recipients (KTR), allowing a reduction in calcineurin inhibitor (CNI) allograft injuries. Despite being of interest for pancreas transplant recipients due to the β-cell toxicity of the CNI, data on the subject are scarce and suggest a high risk of pancreas rejection when used
We report our experience with 8 pancreas transplant recipients converted to belatacept (5 mg/kg day 1, 15, 28, and then monthly) during their follow-up, because of pancreas dysfunction (i.e., hyperglycemia not requiring insulin,
Summary of pancreas transplant recipients who underwent belatacept conversion.
| Patient | Sex | Age at transplant | Category | Indication for conversion | Immunosuppressive regiment before belatacept | Time from belatacept introduction (months) | Total duration of belatacept at last follow-up (months) | Associated immunosuppression | eGFR at conversion (mL/min) | βcell function at conversion (Igls criterion) | Oral antidiabetics | Insulin | eGFR at 1 year (mL/min) | βcell function at 1 year (Igls criterion) | Occurrence of rejection and/or DSA | Infectious complication |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 28 | SPK | Pancreas | CsA + low MPA | 80 | 3 | Low CsA + low MPA | 87 | Good | DPP4 inh | None | NA | NA | None | None |
| 2 | M | 36 | SPK | Pancreas | CsA + low MPA + steroids | 10 | 36 | Low mTOR inh. + low MPA | 51 | Marginal/Good | Metformin + GLP1-a | None | 77 | Optimal | None | None |
| 3 | F | 35 | PTA | Kidney | Tac + low MPA | 9 | 20 | Low Tac + low MPA | 44 | Optimal | None | None | 55 | Optimal | None | None |
| 4 | F | 34 | SPK | Kidney | Tac + low MPA | 20 | 22 | Low Tac + low MPA | 49 | Optimal | None | None | 105 | Optimal | None | None |
| 5 | M | 47 | SPK | Kidney | Tac + low MPA | 150 | 4 | Low MPA + low steroids | 5 | Optimal | None | None | NA | NA | None | None |
| 6 | M | 53 | PTA | Kidney | Tac + Steroids | 48 | 40 | Low mTOR inh. + low MPA | 26 | Optimal | None | None | 39 | Optimal | None | None |
| 7 | F | 27 | SPK | Kidney | Tac + Aza + Steroids | 43 | 28 | Low Tac + low MPA | 24 | Optimal | None | None | 25 | Optimal | None | None |
| 8 | F | 49 | SPK | Kidney | Tac + low MPA | 1 | 30 | Low Tac + low MPA | 5 | Good | None | None | 18 | Optimal | None | None |
SPK, simultaneous pancreas kidney; PTA, pancreas transplant alone; CsA, cyclosporine; MPA, mycophenolic acid; Tac, tacrolimus; Aza, azathioprine; DPP4 Inh, DPP4 inhibitors; GLP1-a, GLP1-agonists.
Two patients were converted to belatacept in order to preserve β-cell function (Patient 1 and Patient 2). For Patient 1, Belatacept was interrupted 3 months later due to the patient’s convenience (refusal of injections). Patient 2 had a marginal β-cell function 2 years after transplantation related to the donor’s characteristics, persisting despite a switch from tacrolimus to CsA and addition of oral antidiabetics (metformin + GLP agonists). At belatacept conversion, CsA was withdrawn and replaced with low dose mTOR inhibitors in addition to low dose Mycophenolate Acid (MPA, 360 mg twice daily). At 2 years’ follow-up, we observed a significant improvement in fasting glycemia in addition to improvement in the kidney allograft function. HbA1c level decreased from 7.7% to 6% 2 years after conversion to belatacept, without any other medication modifications (and notably no change in his oral antidiabetic drugs).
Among the six patients converted for nephroprotection, there were 2 Pancreas Transplant Alone (PTA) and 4 Simultaneous Pancreas Kidney (SPK). Two SPK patients were on dialysis when initiating belatacept, (Patient 5 and Patient 8). Belatacept was interrupted after a few months in Patient 5 due to a poor renal prognosis and massive glomerulosclerosis and fibrosis on kidney biopsy. Causes of kidney impairment in other patients were CNI toxicity added to previous diabetic nephropathy in the PTA patients (Patient 3 and Patient 6), thrombotic microangiopathy related to CNI (Patient 4), sequelae of kidney allograft rejection (Patient 7) and kidney infarction in the immediate post-transplantation period (Patient 8). Associated immunosuppression was low tacrolimus (trough level between 3 and 5 ng/mL) plus low MPA (360 mg twice daily) in 4/6 patients and low everolimus (trough level between 3 and 5 ng/mL) plus low MPA in one patient. No steroids were used except for one patient who received neither CNI nor mTOR inhibitors.
Apart from Patient 5 who presented severe chronic injuries, belatacept conversion improved kidney allograft function in all patients. Notably, interruption of dialysis was allowed for Patient 8 who presented a primary non function following SPK transplantation due to ischemic complication. One year after conversion, the average improvement of estimated glomerular function (eGFR) was 20 mL/min (median = +13 mL/min),
Importantly, during the complete follow-up (at least 18-month), we did not observe any suspicion of pancreas and/or kidney rejection nor appearance of donor specific antibodies (DSA). In our institution, patients are usually followed-up monthly following conversion, and pancreas rejection is suspected when unexplained significant elevation in lipasemia associated with glycemic imbalance. DSA were monitored yearly. Additionally, no serious infections were observed (notably no CMV/BKV), despite the use of low tacrolimus/mTor inhibitor in addition to belatacept.
Impairment of kidney function is not unusual in pancreas transplantation and might require CNI reduction. Even though mTOR inhibitors have been validated in a clinical trial conducted by our group, their use is associated with a wide range of side effects often leading to treatment interruption [
Importantly, no rejection episodes were observed among our patients. Even if we assume that the low number prevents any definitive conclusion, late conversion to belatacept may carry a lower risk of rejection compared to the
In conclusion, our series highlights the feasibility of belatacept in pancreas transplant recipients. Whilst a larger dataset is obviously required, belatacept does allow CNI reduction (and even withdrawal), thus leading to improvement in kidney and pancreatic allograft functions. Importantly, we did not observe any pancreas/kidney rejection nor infectious complications, providing promising insights regarding its use in pancreatic and potentially islets transplantation.
The original contributions presented in the study are included in the article/
The studies involving humans were approved by Commission nationale de l’informatique et des libertés numéro 914184. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
DC elaborated the design and research project, supervised analysis, helped in writing the manuscript and critically revised it. CM collected and analyzed the data and wrote the manuscript. All authors participated in writing and revising the manuscript. All authors contributed to the article and approved the submitted version.
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
SPK, simultaneous pancreas-kidney; PAK, pancreas after kidney; PTA, pancreas transplantation alone; CNI, calcineurin inhibitors; CsA, cyclosporin A; MPA, mycophenolate acid; eGFR, estimated glomerular filtration rate.