The Use of Long‐Term Monthly Basiliximab Infusions as Rescue Maintenance Immunosuppression in Pancreas Transplant Recipients

ABSTRACT

This single‐center retrospective study was designed to evaluate the use of basiliximab as an alternative rescue maintenance immunosuppression in situations where standard maintenance immunosuppression is not tolerated after a pancreas transplant. All pancreas transplants performed between January 11, 2006, and January 6, 2022, were reviewed. All recipients received rabbit antithymocyte globulin (rATG) induction with tacrolimus + sirolimus maintenance for simultaneous pancreas and kidney (SPK) and additional low‐dose mycophenolic acid for pancreas transplant alone (PTA). Basiliximab 40mg IV q 4 weeks was either added to or in replacement of adjunct immunosuppression in cases of medication intolerance. All recipients who received ≥3 months of basiliximab with ≥1 year follow‐up were included. 29/557 (5.2%) recipients (5 SPK and 24 PTA) were identified. Median time to switch was 13 months. When compared 1:2 to matched controls on standard immunosuppression, there was no difference in pancreas rejection, allograft loss, or mortality. Eleven recipients had 13 episodes of pancreas rejection at a median of 28 months post conversion. Eight pancreas allografts failed at a median of 28 months post conversion, and there were five deaths—all occurring in PTA, 4/5 occurring ≥1 year after discontinuation of basiliximab. Renal allograft rejection occurred in one SPK and there was one renal allograft loss. Five PTA developed renal failure. Ten remain on basiliximab (2/5 SPK, 8/24 PTA) at a median of 44 months with good pancreas and kidney function; 4 pts > 4 years. Basiliximab can be considered an alternative rescue maintenance strategy in pancreas transplant recipients who failed other conventional agents.

Abbreviations

CMV

cytomegalovirus

CNI

calcineurin inhibitor

ESRD

end‐stage renal disease

MPA

mycophenolic acid

mTORi

mammalian target of rapamycin

PTA

pancreas transplant alone

rATG

rabbit antithymocyte globulin

Sir

sirolimus

SPK

simultaneous pancreas and kidney

Tac

tacrolimus

1. Introduction

Pancreas transplant has the potential to render select candidates with diabetes euglycemic without the requirement for the administration of exogenous insulin. This procedure requires a major abdominal operation and a lifelong commitment to immunosuppressionso it is currently most frequently offered as a treatment option to patients with diabetes that require another extra pancreatic transplant, usually a renal transplant for end‐stage diabetic nephropathy. These transplants can either be performed simultaneously from the same donor (simultaneous pancreas and kidney transplant [SPK] or sequentially if the candidate has a potential living donor for the kidney [PAK]) [1, 2]. Pancreas transplant is also offered as an isolated allograft for patients with potentially life‐threatening complications of diabetes such as hypoglycemia unawareness [1, 2].

Modern immunosuppression regimens for pancreas transplant recipients consist of a t‐cell‐depleting induction treatment followed by a maintenance regimen of a calcineurin inhibitor (CNI) in combination with an adjunct medication such as mycophenolic acid (MPA) (either MPA delayed release or mycophenolate mofetil) or mammalian target of rapamycin inhibitor (mTORi) with or without long‐term corticosteroids [3]. These regimens are associated with consistently low rejection rates and excellent graft and patient survival rates [4, 5, 6, 7, 8]. Despite these results, the side effects of the maintenance agents are considerable and can be challenging to manage. CNIs, for example, are commonly associated with nephrotoxicity and neurotoxicity. Nephrotoxicity can particularly be a problem when CNI is used in combination with an mTORi. Protocols  to minimize or avoid the use of corticosteroids are used in pancreas transplant recipients due to the undesirable well‐known side effects such as glucose intolerance, weight gain, hypertension, hyperlipidemia, osteoporosis, and cataracts [5, 9, 10]. MPA is associated with myelosuppression and dose‐limiting gastrointestinal side effects of nausea, vomiting, and diarrhea. This particular patient population tends to also consist of particularly brittle patients with diabetes where gastroparesis and other diabetes‐related bowel motility disorders may be quite common [11]. For this reason, full‐dose MPA may not be tolerated.

It has become evident that not all recipients are able to tolerate a complete maintenance immunosuppression regimen consisting of a CNI with therapeutic dosing, and either sirolimus (Sir), an MPA, or azathioprine with appropriate levels or dosing. These patients are particularly vulnerable and would be considered at high risk for acute and chronic rejection and allograft loss. An alternative or supplemental long‐term maintenance immunosuppression for rescue in these cases is necessary and to date has not been well described. In recent years, some success using belatacept as rescue or as a CNI‐sparing strategy for pancreas transplant recipients has been described including three small case series of 2–8 pancreas transplant recipients and a randomized control trial [12, 13, 14, 15]. However, this strategy is limited as it is not an option for all recipients, particularly as this medication is contraindicated in Epstein–Barr virus seronegative patients. Our program has been using monthly infusions of basiliximab in these situations as it has the potential to supplement baseline immunosuppression, allow dosage reduction of CNIs, or completely replace the adjunct immunosuppression medications. Furthermore, this medication is well tolerated with limited toxicity and no known contraindications to its use. This study is a retrospective single‐center analysis of all recipients where basiliximab monthly infusion was used as rescue maintenance immunosuppression in addition to or as an alternative following pancreas transplant in scenarios where standard immunosuppression side effects or toxicities were not tolerated, and no alternative options were apparent. Please appreciate that in all cases, without adequate baseline immunosuppression, these recipients were perceived to be at great risk for allograft rejection or loss if not provided with some form of alternative adequate maintenance immunosuppression strategy, and all available alternatives had been exhausted. Basiliximab was initiated in all cases with the intention that this would serve as a long‐term component of maintenance immunosuppression and, in fact, many of the subjects were maintained using this strategy for years. This approach has not been previously reported by other centers.

2. Methods

The medical records for all adult deceased donor pancreas transplants performed at Indiana University between January 11, 2006 and January 6, 2022, were reviewed (n = 557). Following approval from the Indiana University Institutional Review Board, data were extracted from the comprehensive transplant recipient registry maintained at our center, individual written and electronic medical records, and the original donor medical history. Inclusion criteria for this analysis included all SPK, PAK, or pancreas transplant alone (PTA) recipients who received at least 3 months of basiliximab therapy with at least 1 year of follow up. As there was not a control cohort of patients who deviated from standard immunosuppression and who were not initiated on basiliximab rescue maintenance therapy, the study patients receiving basiliximab en‐lieu of standard therapy were compared to a group of recipients who tolerated standard immunosuppression using a 1:2 case‐control study methodology, which was designed to compare transplant outcomes including any rejection of the pancreas allograft, allograft loss, and patient death. Cases and controls were matched manually for transplant type (SPK or PTA), gender, age (±10 years), race, year of transplant (±5 years), donor age (±10 years), and donor cause of death. Statistical analysis of the groups was performed using chi‐square and analysis of variance with p value significant at the 0.05 level. The PTA and SPK groups were analyzed separately.

All recipients were listed for transplantation according to standard procedures and protocols as established by our own center and the Organ Procurement and Transplantation Network (OPTN). During the study period, in order to qualify for pancreas transplant listing at our institution, the potential recipient had to be insulin‐dependent, and the majority had a fasting serum C‐peptide level <2 ng/mL. For PTA, the recipients had to demonstrate preserved renal function, usually with a creatinine clearance of at least 50 mL/min/1.73m^2.

Pancreas allografts were procured following aortic flush with preservation solution and topical cooling with saline slush and prepared on the back bench with standard donor iliac artery Y‐graft reconstruction for arterial inflow as previously described [16, 17, 18]. The recipient operation was performed through a midline incision. The pancreas was routinely positioned with the tail toward the pelvis and the head and duodenum oriented superiorly in order to facilitate the enteric anastomosis. Systemic venous drainage was performed to the vena cava or to the right common iliac vein. Arterial perfusion of the allograft was routinely established from the right common iliac artery, although on rare occasions where this vessel was found to be diseased or had been the site for arterial anastomosis for a prior transplant, the inflow would be established either from the aorta or the left common iliac artery. All pancreas allografts were drained enterically using a stapled technique as described elsewhere [19]. For SPK, the pancreas and kidney were placed ipsilaterally on the right side as described previously [20]. Kidney allografts were placed on pulsatile perfusion until transplantation [21].

The induction immunosuppression protocol consisted of five daily doses of rabbit antithymocyte globulin (rATG) (1 mg/kg/dose) and a maintenance regimen of tacrolimus (Tac) and Sir initiated on postoperative day 1. Goal trough levels for Tac were 6–8 mCg/mL and Sir 3–6 mCg/mL [22, 23]. If Sir was not tolerated, full dosage MPA in the form of either mycophenolate mofetil (1000 mg po bid) or MPA (720 mg po bid) was used as a substitute. For PTA recipients, MPA in the form of either mycophenolate mofetil (500 mg po bid) or MPA (360 mg po bid) were added to the standard immunosuppression protocol [9]. On some occasions where MPA was not tolerated, azathioprine was used as an alternative. Steroids were used exclusively as a premedication for rATG and were discontinued following induction in all recipients. In situations where one of the standard maintenance immunosuppression medications was poorly tolerated or if augmentation of baseline immunosuppression seemed necessary, a monthly intravenous infusion of basiliximab (40 mg) was added. All recipients received routine perioperative antibiotics, prophylaxis against cytomegalovirus (CMV) with oral valganciclovir and prophylaxis against Pneumocystis jiroveci pneumonia with trimethoprim and sulfamethoxazole, unless contraindicated. Systemic anticoagulation was not routinely used unless the patient had a specific history of a coagulation disorder. All recipients were started on aspirin immediately postoperatively. Prophylaxis for deep venous thrombosis using heparin or enoxaparin was initiated on postoperative day 1. Sequential compression devices were maintained until prophylaxis was initiated.

Pancreas transplant biopsy was infrequently pursued. A diagnosis of pancreas rejection was made based on clinical parameters with elevated serum amylase and lipase in which other possible causes were ruled out. Recipients who had episodes of pancreas rejection were identified as those that had received treatment with either corticosteroid bolus and/or a t‐cell‐depleting agent outside of induction immunosuppression. SPK recipients in whom kidney rejection was suspected underwent a biopsy of the kidney allograft for diagnosis of rejection.

3. Results

Out of 557 pancreas transplants performed between January 11, 2006, and January 6, 2022, (325 SPK, 76 PAK, 156 PTA), 29 recipients (5.2%) received basiliximab maintenance immunosuppression. An additional four recipients were excluded from the analysis. Two patients were lost to follow‐up when they transferred their long‐term follow‐up to another center. One patient received a PTA and did not tolerate MPA, so basiliximab was initiated briefly (two doses) but ultimately discontinued when the patient tolerated azathioprine on a second attempt and is doing well with excellent allograft function at 7 years of follow‐up. Another recipient was tolerating their immunosuppression poorly in the first months after the transplant and received two doses of basiliximab as adjustments to maintenance immunosuppression were made. At 7 years of follow‐up, the pancreas allograft was still functioning well. Donor and recipient demographics for the 29 recipients studied are shown in Table 1. Of the 29 recipients, 24 received PTA and 5 underwent SPK. All had type 1 diabetes mellitus. Twenty recipients were female and nine were male. The median time to switch or addition of basiliximab was 13 months (range 1–119 months) following transplant. Reasons for switching or adding basiliximab are shown in Table 2. For the five SPK recipients, two recipients were maintained on basiliximab indefinitely due to issues with CNI toxicity (one due to thrombotic microangiopathy [maintained on basiliximab, low dose cyclosporine and Sir] and the other severe neurotoxicity [maintained on Sir, MPA, and basiliximab]) with preserved renal and pancreas allograft function at 3 and 4 years after basiliximab initiation, respectively. Basiliximab was added to the immunosuppression regimen for 6 months for one recipient who developed rejection due to the inability to reliably administer oral medications. Basiliximab was also added to the immunosuppression maintenance for two recipients that were switched from Tac and Sir maintenance to CNI sparing reduced dosage Tac with MPA in the setting of progressive nephrotoxicity. The basiliximab was discontinued in one of the recipients when they ultimately developed renal allograft failure following infection with COVID. The pancreas allograft is functioning well with resumed standard immunosuppression. The other recipient received therapy with basiliximab for 15 months, but this was discontinued due to poor compliance with the monthly infusions. Overall, the most common reasons for the switch in recipients of PTA transplants were intolerable MPA side effects (gastrointestinal or neutropenia) (n = 11 and 5, respectively), followed by Sir‐induced mouth ulcers (n = 6), nephrotoxicity (n = 5), wound healing (n = 2), and inability to achieve adequate levels (n = 1). Six of these patients had more than one primary reason for switching. See Table 2 for all of the indications for including monthly basiliximab infusions as a component of the maintenance immunosuppression. For Sir‐induced mouth ulcers, all cases were debilitating, impacted oral intake, and were resistant to interventions including oral hygiene, dose reduction, and topical corticosteroids prior to discontinuation of the medication [24, 25]. Basiliximab was well tolerated following the introduction; no patient discontinued basiliximab due to side effects or adverse events. Regimens post switch were Tac/Sir/basiliximab (n = 10), Tac/MPA/basiliximab (n = 8), Tac/Aza/basiliximab (n = 5), Tac/Sir/MPA/basiliximab (n = 3), Tac/Sir/Pred/basiliximab (n = 1), Tac/Pred/basiliximab (n = 1), and Sir/MPA/basiliximab (n = 1).

TABLE 1.

Recipient and donor demographic data for 5 SPK and 24 PTA recipients who underwent transplant between January 1, 2007, and November 17, 2021, and subsequently received basiliximab as an adjunct maintenance immunosuppressant agent.

Recipient
Age, years, median (range)	40 (22–75)
Gender, female	20/29 (69%)
Race, white	25/29 (86%)
Body mass index, kg/m2, median (range)	24 (18–38)
Donor a
Age, years, median (range)	24 (6–39)
Body mass index, kg/m2, median (range)	22 (15–29)
Cold ischemia time, hours, median (range)	6 (4–10)
Cause of death	Gunshot wound to head	9
	Drug overdose	6
	Trauma	6
	Cerebrovascular accident/Stroke	4
	Anoxia/Drowning	3

^a Data unavailable for one donor.

TABLE 2.

Reasons for switching to basiliximab ^†

		SPK	PTA
Mycophenolic acid side effects	Gastrointestinal		11
	Neutropenia		5
Sirolimus side effects	Mouth ulcers		6
	Wound healing		2
CNI side effects	Unable to achieve goal trough levels	1	1
	Neurotoxicity	1
CNI + Sirolimus nephrotoxiciy		3	5

Abbreviation: CNI, calcineurin inhibitor.

^† Some recipients experienced more than one side effect.

Overall, there were 11 patients that experienced 13 episodes of pancreas rejection following the switch to basiliximab. All were PTA recipients. Rejection occurred a median of 28 months (range 1–100) post conversion. Five rejection episodes occurred within 6 months post conversion. The remaining rejections occurred 8, 28, 37, 46, 47, 52, 53, and 100 months following the switch. Two of the rejections required rATG treatment; the remaining were treated with corticosteroids. Eight of the 11 patients went on to lose their allografts with a median time to allograft loss of 28 months after basiliximab initiation (range 4–56 months). The time course to pancreas allograft loss is shown in Table 3. All but one of these patients were maintained on a triple‐drug regimen at the time of allograft loss (Tac/MPA/basiliximab n = 4, Tac/Sir/basiliximab n = 3, Tac/Aza/basiliximab n = 1, Tac/Sir/MPA/basiliximab n = 1). No other pancreas graft losses occurred in patients who did not have rejection. Three additional PTA recipients developed pancreatic rejection that did not result in allograft loss. These rejection episodes occurred >2 years post switch. Two recipients were converted from Tac/Sir/MPA to Tac/Sir/basiliximab for MPA‐induced gastrointestinal side effects at 28 and 53 months, respectively. One recipient was switched from Tac/Sir/MPA to Tac/Aza/basiliximab for Sir‐induced mouth ulcers and MPA‐induced gastrointestinal side effects. All three rejections were successfully reversed with corticosteroids. One pancreas allograft loss occurred in a patient who did not have prior rejection. Basiliximab was discontinued more than 1 year prior to allograft loss when the patient underwent a living donor renal transplant. Maintenance immunosuppression was switched from Tac/basiliximab /Pred to Tac/MPA.

TABLE 3.

Time to pancreas allograft loss (n = 8).

	Number of pancreas rejections	Time post transplant to first BAS dose (months)	Time post BAS to pancreas rejection (months)	Rejection treatment	Time from BAS to pancreas failure (months)	Immunosuppression regimen at graft failure
1	1	24	1	CS	4	Tac/MPA/Bas
2	2	11	46, 47	CS, CS	48	Tac/Sir/Bas
3	2	4	5, 37	CS, CS + rATG	48	Tac/MPA/Bas
4	1	60	8	CS, CS + rATG	47	Tac/MPA/Bas
5	1	2	52	CS	56	Tac/Sir/Bas
6	1	7	4	CS	4	Tac/Sir/MPA/Bas
7	1	38	6	CS	9	Tac/Sir/Bas
8	1	12	4	CS	6	Tac/Aza/Bas

Abbreviations: CS, corticosteroids; rATG, antithymocyte globulin, rabbit.

One of the five SPK recipients developed Banff 1A rejection in the kidney allograft. Tac was changed to cyclosporine due to thrombotic microangiopathy early post transplant. Basiliximab was added to cyclosporine + Sir as the patient did not tolerate MPA due to severe gastroparesis. Rejection occurred 3 months post‐basiliximab initiation, which was successfully treated with corticosteroids.

One kidney allograft loss occurred on basiliximab therapy. Basiliximab was initiated 119 months post‐transplant to target lower Tac + Sir levels for elevated serum creatinine. Five months following conversion, the patient developed end‐stage renal disease. The pancreas graft is still functioning, and the recipient requires no insulin or oral antihyperglycemic medications.

End‐stage renal disease occurred in the native kidneys in 5/24 PTA recipients. Switch to basiliximab from MPA or Sir for severe intolerance occurred in 4/5 patients. Three patients have undergone successful kidney transplant. Basiliximab was continued until kidney failure in two patients at 31‐ and 41‐month post conversion. One patient with a history of severe gastroparesis developed ESRD 1 month post‐basiliximab switch from MPA due to gastrointestinal intolerance. This patient had significant renal dysfunction at the time of initiation. Basiliximab was continued for an additional 30 months until pancreas allograft failure. The remaining patient was switched from Sir to basiliximab at 30 months post‐transplant due to worsening renal function from the combination of Tac + Sir and subsequently developed ESRD 14 months later.

There were five deaths in patients who had received basiliximab occurring at 16, 24, 45, 66, and 102 months after the first dose of basiliximab. Causes of death were intestinal hemorrhage (n = 1), aspiration pneumonia (n = 1), diabetic ketoacidosis (n = 2), and cause unknown (n = 1). Basiliximab had been discontinued greater than 1 year prior to death in 4/5 patients. Three patients died with a functioning pancreas allograft, one of which was still receiving basiliximab in combination with Tac and Sir.

Two PTA patients developed CMV viremia while on basiliximab therapy at 8 and 64 months after therapy initiation; both resolved with treatment. One of these recipients also developed anal carcinoma in situ at 36 months after the first basiliximab dose. No patients developed BK virus infection or post‐transplant lymphoproliferative disease. Ten patients (10/29, 34%) remain on basiliximab therapy at a median of 44 (range 22–84) months following initiation. All recipients have been receiving basiliximab for at least 1 year; 1 year (n = 1), 2 years (n = 2), 3 years (n = 3), 4 years (n = 1), 6 years (n = 2), and 7 years (n = 1). Current immunosuppression regimens are described in Table 4. Recipients who remain on basiliximab (2/5 SPK, 7/23 PTA) have reached a median of 80 (range 27–99) months following transplant with good pancreas and kidney function.

TABLE 4.

Recipients continuing basiliximab therapy (n = 10).

	Transplant type	Time post transplant (months)	Duration of basiliximab therapy (months)	Current immunosuppression regimen
1	K/P	27	26	Tac/Sir/Bas
2	K/P	46	43	Tac/Aza Bas
3	PTA	96	80	Taz/Aza/Bas
4	PTA	99	27	Tac/MPA/Bas
5	PTA	99	22	Tac/Sir/Bas
6	PTA	87	84	Tac/Sir/Bas
7	PTA	83	43	Tac/MPA/Bas
8	PTA	76	73	Tac/Aza/Bas
9	PTA	76	53	Sir/MPA Bas
10	PTA	58	45	Tac/MPA/Bas

Patients receiving basiliximab were compared with those receiving and tolerating standard immunosuppression with full demographics and results shown in Table 5. Among the PTA group, there were 24 patients included in the basiliximab conversion study group, with 48 matched controls. The two groups were similar with regard to all matching variables. The basiliximab conversion group had a rejection rate at any time of 46%, compared to 29% for the control group (p = 0.16). Any graft loss was also similar for the two groups (basiliximab 50% and standard immunosuppression 42% (p = 0.50)). The mortality rates did not differ (basiliximab conversion at 21% and control group at 21% (p = 1.00)). Among the SPK patients, there were five in the basiliximab group and 10 in the standard immunosuppression group. The two groups were similar with regard to all matching variables. Pancreas graft rejection was rare, with only one patient in the control group having rejection (0% vs. 20%, p = 0.28). Rejection of the kidney was more common in the basiliximab group (60% vs. 20% in the control group [p = 0.12]). Among the basiliximab conversion group, there were no pancreas graft losses, one kidney graft loss and no deaths. This is compared to the standard control group, which had 30% pancreas graft loss, 40% kidney graft loss, and 20% death. These results did not reach statistical significance in this small study group.

TABLE 5.

Case‐control comparison (1:2) of patients receiving basiliximab conversion (n = 20) to those remaining on standard immunosuppression (n = 58).

	Pancreas transplant only			Simultaneous kidney and pancreas
	Basiliximab conversion	Standard immunosuppression	p value	Basiliximab conversion	Standard immunosuppression	p value
Number	24	48		5	10
Demographics
Gender			0.85
Male	6 (25%)	13 (27%)		60%	60%	1.00
Female	18 (75%)	35 (73%)		40%	40%
Race			1.00			1.00
White	24 (100)%)	47 (98%)		40%	40%
Black	0 (0%)	1 (2%)		60%	60%
Age at transplant
Mean/median (SE)	38/40 (1.7)	39/39 (1.4)	0.81	41/34 (8.7)	40/34 (4.5)	0.84
Recipient body mass index
Mean/median (SE)	26.4/25.1 (1.0)	25.0/24.3 (0.7)	0.25	23.4/22.9 (1.2)	26.0/26.2 (1.5)	0.34
Donor age
Mean/median (SE)	24/24 (1.7)	24/23 (1.2)	0.94	34/36 (3.4)	28/29 (2.5)	0.22
GFR at transplant
Mean/median (SE)	85/90 (2.5)	87/90 (1.4)	0.46	Dialysis	Dialysis
Outcomes
Any rejection of pancreas	46%	29%	0.16	0%	20%	0.28
Any rejection of kidney	n/a	n/a		60%	20%	0.12
Pancreas graft loss	50%	42%	0.50	0%	30%	0.51
Kidney graft loss	n/a	n/a		20%	40%	0.60
Patient death	21%	21%	1.00	0%	20%	0.52

4. Discussion

Early outcomes following pancreas transplantation have improved dramatically in the new millennium as a result of improvements in surgical and preservation techniques, postoperative management, and immunosuppression, however achieving long‐term allograft survival remains challenging [3, 20, 21, 22]. The pancreas allograft is more difficult to monitor for signs of rejection than other abdominal organs because monthly labs that include amylase and lipase may fail to capture episodes of inflammation or rejection, elevated fasting glucose and HBA1C are late and possibly terminal signs of deteriorating function, and the placement of the pancreas in the back of the abdomen makes it difficult to access for protocol biopsy [23]. Newer technologies including monitoring for the development of de novo donor‐specific antibody or for cell‐free DNA are approaches that may ultimately prove to be helpful in detecting subclinical rejection and maintaining or improving pancreas allograft longevity [26, 27], but currently these assays remain in the early investigative phase and are not readily or widely accessible for all recipients. Ultimately, the current standard for avoiding late allograft loss consists of close laboratory and clinical follow‐up in order to monitor for acute and/or chronic allograft rejection at a time when intervention may still be impactful, and constant vigilance in maintaining adequate immunosuppression. In terms of maintaining immunosuppression, the side effects of the different medications may be poorly tolerated long‐term, particularly in this patient population with diabetes, leading us to seek acceptable alternatives [26]. In this study, we described our experience with using basiliximab as an adjunct rescue maintenance immunosuppressant for pancreas transplant recipients who were not able to tolerate standard maintenance immunosuppression.

Basiliximab was introduced as maintenance immunosuppression in 29 recipients, which could be further subcategorized by type of transplant into five SPK, where basiliximab was primarily introduced due to immunosuppression‐related nephrotoxicity as an approach to spare CNI exposure, and 24 PTA recipients, where basiliximab was added to replace a poorly tolerated immunosuppression medication. This latter group is characterized by a baseline higher rate of chronic rejection leading to allograft loss than other pancreas transplant subcategories, leading our program to pursue a more intense three‐drug maintenance regimen [9]. The rationale for using three agents with different mechanisms of action for maintenance immunosuppression for PTA recipients is to achieve synergistic immunosuppressive effects while utilizing lower doses of each individual agent. With this regimen, we were able to achieve 91% 1‐year and 68% 5‐year allograft survival [9] which is why we feel strongly that a maintenance immunosuppression consisting of three agents is important. Despite efforts to minimize toxicities, many recipients will still develop intolerable immunosuppressant‐related side effects requiring the cessation of one of the three medications—in which case monthly basiliximab infusion was started as an alternative third agent. PTA recipients have a higher incidence of gastrointestinal issues such as gastroparesis and diabetic bowel motility disorders, which makes the addition of MPA drugs problematic [11]. This was observed in our cohort of patients as 41% of patients required a switch from MPA to basiliximab due to gastrointestinal side effects. PTA recipients frequently present with some degree of renal impairment from years of diabetes prior to transplantation, which can be worsened with the use of Tac and Sir. Tac and Sir are both associated with nephrotoxicity. We also observed that conversion from Sir was required in 21% of patients due to nephrotoxicity. Overall, despite the change in immunosuppression, 12/24 PTA allografts were ultimately lost. This high rate of pancreas allograft loss was similar to the control group. It is important to note that this study includes all recipients that were initiated on basiliximab monthly infusion therapy. In some instances, it was a late decision to change or augment the immunosuppression with basiliximab and failure may have already been inevitable. All allograft losses were associated with prior rejection episodes.

Two other alternative immunosuppressants include azathioprine and belatacept. Azathioprine has largely been replaced by MPA as it is not as effective in preventing rejection and is associated with significant hematologic side effects such as anemia and thrombocytopenia as well as the potential to cause pancreatitis [26]. Nonetheless, this medication may be associated with less gastrointestinal side effects than MPA and is worth trying in this setting. Belatacept has been approved for the prevention of acute rejection following renal transplantation [27]. However, data to support its use in pancreas transplant recipients are limited to three small case series of 2–8 pancreas transplant recipients and a randomized control trial [12, 13, 14, 15]. The phase 2 multicenter randomized trial sponsored by the National Institute of Health conducted in SPK recipients was halted early as belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing Tac withdrawal and those who remained on belatacept with low dose Tac experienced higher rates of opportunistic infections [15]. Belatacept is also contraindicated in recipients who are EBV IgG negative due to the potential risk for post‐transplant lymphoproliferative disease [27]. Since the introduction of this medication, our current practice is now to use belatacept in similar situations where we had previously used basiliximab, unless contraindicated or if there are concerns of overimmunosuppression with the combination of belatacept, Tac and/or Sir, or MPA.

The strength of this manuscript is that this is a previously undescribed use of basiliximab as a rescue maintenance immunosuppression medication for pancreas transplant recipients who are unable to tolerate standard immunosuppression and have exhausted most other alternatives. The weakness of the study is that failure to tolerate standard immunosuppression was rare, so the cohort presented was relatively small and heterogeneous with respect to type of transplant, and indication for and timing of the change. In an attempt to include all patients who were switched to a maintenance protocol that included basiliximab, a mixture of SPK and PTA recipients were included. Furthermore, the limitations of retrospective single‐center analysis methodology apply here, although the surgical approach and immunosuppression strategy and philosophy have been consistent throughout the study period leading to consistency in most other aspects of management other than the intervention. Finally, an ideal control group consisting of pancreas recipients who did not tolerate standard immunosuppression, yet did not receive rescue basiliximab as an alternative, was not available, requiring comparison to recipients who tolerated standard immunosuppression. Nonetheless, this study is the first description of basiliximab as a maintenance immunosuppression medication for pancreas transplant recipients who are unable to tolerate standard immunosuppression with a demonstration of similar allograft and patient survival compared to patients receiving standard therapy.

In conclusion, basiliximab is generally safe and well tolerated in pancreas transplant recipients. Advantages to basiliximab over other immunosuppressants include a once‐monthly administration as well as a favorable side effect profile as it does not cause nephrotoxicity, gastrointestinal, or bone marrow suppression. Basiliximab is an acceptable long‐term alternative rescue maintenance immunosuppressant that can be considered in combination with CNI when other options have been exhausted in pancreas transplant recipients.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.