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Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression

Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression
Literature review current through: Jan 2024.
This topic last updated: Mar 03, 2023.

INTRODUCTION — Combined pancreas-kidney transplantation is an established treatment for selected patients with diabetes and end-stage kidney disease (ESKD). In the United States, more than 85 percent of pancreas transplants are performed as simultaneous pancreas-kidney (SPK) transplants, with the remainder performed as either sequential pancreas after kidney (PAK) transplants or pancreas transplants alone (PTA) [1].

This topic reviews surgical considerations and immunosuppression for SPK or PAK transplantation in patients with insulin-requiring diabetes mellitus and ESKD. Other aspects of pancreas-kidney transplantation are discussed elsewhere:

(See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)

(See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation".)

(See "Pancreas allograft rejection".)

The roles of PTA and islet transplantation in patients with diabetes who do not have kidney failure are discussed separately. (See "Pancreas and islet transplantation in diabetes mellitus".)

SURGICAL CONSIDERATIONS — In the United States, the most common technique for simultaneous pancreas-kidney (SPK) transplantation consists of placing both organs intraperitoneally through a vertical lower-midline incision. This technique preserves all possible options for transplantation of the pancreas as well as simultaneous placement of the kidney. In general, midline incisions are associated with fewer wound infections, although the key concepts are taking advantage of the intraperitoneal lymphatic circulation and permeability for internal absorption of peripancreatic secretions in conjunction with preventing proximity between the healing wound and the reperfused pancreas [2]. Centers differ in regards to either contralateral or ipsilateral placement of the organs as well as the surgical management of the exocrine pancreas secretions and the venous outflow. The majority of pancreas transplants are placed on the right side of the pelvis and performed with enteric exocrine drainage (≥90 percent) and systemic venous drainage (ie, from the graft portal vein either to the right iliac vein or distal inferior vena cava), while a minority of cases are performed with bladder exocrine drainage, using the right external iliac artery and vein for vascularization [3].

Organ placement — Historically, the kidney was transplanted to the left and the pancreas to the right iliac vessels. Although some centers continue to practice this time-honored bilateral or contralateral technique, other centers have switched to placing the pancreas and kidney both on the right side with the pancreas transplanted first (to minimize cold ischemia time [CIT]) on the distal inferior vena cava/right common iliac vein and artery followed by the kidney transplanted more distally on the right external iliac vein and artery [4]. This ipsilateral technique preserves the left side for future transplantation and reduces operating time because the vascular dissection is localized to the right side only.

In planning for patients undergoing sequential pancreas after kidney (PAK) transplantation, it is preferable to transplant the kidney (either from a living or deceased donor) through an extraperitoneal approach on the left side (using a conventional kidney transplant incision) so that the right side remains available for subsequent PAK transplantation. However, similar to SPK transplantation, PAK transplantation is most commonly performed through a lower-midline intraperitoneal approach with the pancreas transplanted on the right side. For patients with a kidney transplant in situ on the right side, a PAK transplant can still be performed safely and successfully on the right side with the pancreas placed proximally and intraperitoneally while the kidney remains more distal and extraperitoneal on the right iliac vessels [5]. Because the inferior vena cava is on the right side and exposure of the right common iliac artery and vein is easier anatomically than isolating the left common iliac artery and vein, most surgeons prefer to place the pancreas on the right side irrespective of the position of the kidney transplant. Historically, there were data to suggest that placement of the pancreas on the left side had a higher rate of thrombosis, but little data exist in the past 20 years to either confirm or refute this observation, because nearly all pancreas transplants are placed on the right side.

Perioperative anticoagulation — Unlike a kidney, a pancreas is an inherently low-microcirculatory-flow organ with a blood supply based on collateral (splenic and mesenteric) circulation. Consequently, the risk of early thrombosis (usually venous thrombosis) is much higher for the pancreas compared with other solid organ transplants. For patients undergoing SPK transplantation in the presence of end-stage kidney disease (ESKD), the presence of uremia (with its corresponding antiplatelet and anticoagulation effects) is in part protective against early pancreas allograft thrombosis. However, in the setting of preemptive SPK transplantation or PAK transplantation (in the absence of uremia), the risk of early pancreas thrombosis is higher. In addition, patients with longstanding diabetes may have significant vascular disease as well as inherent hypercoagulable defects. Consequently, many centers have included thrombophilia screening in the pretransplant evaluation of SPK transplant candidates. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Hypercoagulability evaluation'.)

Accordingly, the judicious use of perioperative anticoagulation plays an important role in pancreas transplantation [6]. At a minimum, most centers use aspirin or other antiplatelet agents in the immediate perioperative and postoperative period. At a maximum, some centers administer full therapeutic anticoagulation for a specified duration (one to four weeks). In general, however, most centers use some form of perioperative anticoagulation prophylaxis for a limited period (usually one to two weeks). Because the risk of early thrombosis is inherently much higher in PAK and pancreas transplant alone (PTA) compared with SPK transplantation, either low-dose unfractionated or low-molecular-weight heparin is used routinely in this setting with or without subsequent conversion to consolidation therapy with an oral agent. However, wide variation exists in perioperative anticoagulation protocols, and the risk of bleeding resulting in relaparotomy is not trivial in protocols that involve full therapeutic anticoagulation for an extended duration.

Keys to managing early graft thrombosis include not only prevention but also risk stratification and early diagnosis. Many centers perform surveillance imaging immediately following SPK transplantation including duplex ultrasonography with contrast-enhanced ultrasonography or computed tomography scanning with intravenous (IV) contrast reserved for abnormal screening ultrasound examinations or clinical indications (either graft dysfunction or severe pancreatitis) [7-11]. Grading or scoring systems have been developed to quantitate not only the degree, severity, and location of thrombosis but also to guide decision-making with respect to nonoperative or operative management. Partial vascular thrombosis is not uncommon following SPK transplantation and can often be managed with anticoagulation alone or in combination with endovascular techniques.

Bladder versus enteric exocrine drainage — One important surgical consideration during pancreas transplantation is the method of drainage of the pancreatic ductal (exocrine) secretions. Historically, management of the exocrine pancreas secretions was most commonly accomplished by bladder drainage [12], whereby the allograft duodenum is anastomosed side-to-side to the recipient's bladder. This technique was developed primarily to reduce the morbidity associated with exocrine leaks and accounted for >90 percent of cases through 1995. However, since 1995, the preferred duct management technique has become enteric drainage with anastomosis of the donor duodenum to the recipient small bowel (either jejunum or ileum), with or without a diverting Roux-en-Y limb (used in approximately 15 percent of cases). A few centers use the recipient duodenum or even the stomach for exocrine drainage so that endoscopic surveillance and biopsy of either the allograft duodenum or pancreas can occur [13-17].

A major advantage of bladder drainage is the ability to use urine amylase to monitor for rejection in solitary pancreas transplants (either PAK or PTA). In PAK transplants, because the kidney transplant is performed from a different donor, the kidney cannot be used reliably as a marker for pancreas rejection. With SPK transplants from a single donor, the serum creatinine is used to monitor for kidney rejection, which may provide a surrogate marker for pancreas rejection. However, isolated rejection of the pancreas without kidney involvement (or isolated rejection of the kidney without pancreas involvement) may occur in SPK transplantation [18].

Patient and allograft survival rates appear to be similar with either bladder or enteric exocrine drainage. Enteric exocrine drainage is superior in terms of reducing the incidence of metabolic and bladder-related complications [13-15,19-25]. As an example, a survey of 102 articles of both SPK transplants and PTAs found that urological complications were significantly more frequent with bladder versus enteric drainage (62 to 63 versus 12 to 20 percent) [23]. In addition, a retrospective study of 71 SPK transplant patients found that, compared with bladder drainage, enteric drainage resulted in a significantly lower incidence of volume depletion (3 versus 34 percent), acidosis (0 versus 41 percent), pancreatitis (3 versus 40 percent), and urinary tract infection (27 versus 71 percent), although patient and pancreas allograft survival rates were similar [22]. According to the International Pancreas Transplant Registry (IPTR), in bladder-drained pancreas recipients performed between 2000 and 2004, enteric conversion (open re-operative "switching" from bladder to enteric exocrine drainage) was required in 9 and 17 percent at one and three years posttransplant, respectively [12].

In a registry study of the United Network for Organ Sharing (UNOS) database, patients who underwent pancreas transplantation with enteric exocrine drainage without a diverting Roux limb had increased long-term patient and graft survival rates compared with those who underwent either enteric drainage with a Roux limb or those who underwent bladder drainage [15]. Other studies of bladder drainage have reported long-term enteric conversion rates of 42 and 44 percent, respectively [24,25]. In the former study, kidney and pancreas graft survival rates were not affected by enteric conversion, whereas in the latter study, enteric conversion was associated with an increased risk of acute rejection but did not increase the risk of graft loss or mortality.

Portal versus systemic venous drainage — Another important surgical consideration during pancreas transplantation involves the location of venous drainage of the pancreas allograft. Venous drainage is important because venous thrombosis is the most common early technical complication of pancreas transplantation. In addition, the method of venous drainage determines the site where insulin is initially released into the circulation. As an example, if the portal vein of the pancreas allograft is anastomosed to the recipient's inferior vena cava or iliac vein, then "systemic hyperinsulinemia" occurs [26]. By contrast, with techniques of venous drainage that involve the recipient's splanchnic venous system (usually the superior mesenteric vein), then "portal hyperinsulinemia" occurs with subsequent "first-pass" hepatic degradation or elimination of insulin, which is more "physiologic" and mimics the native pancreas. Despite the theoretical concerns, in metabolic studies, systemic hyperinsulinemia associated with systemic venous drainage has not been shown to be a risk factor for either insulin resistance or the metabolic syndrome. Conversely, metabolic studies following portal venous drainage of the pancreas allograft have failed to show any consistent long-term benefit of this technique [13,14,27].

After procurement, the dual arterial supply of the pancreas is usually reconstructed with a Y-graft, derived from the donor iliac artery bifurcation [28,29]. The donor internal iliac or hypogastric artery is usually anastomosed end-to-end to the splenic artery, and the external iliac artery is anastomosed end-to-end to the superior mesenteric artery (or vice versa). The donor Y-graft is then anastomosed end-to-side to the recipient's right common or external iliac artery. In the majority of pancreas transplants, the graft portal vein is anastomosed to the recipient's iliac vein (either right external or common iliac vein) or distal inferior vena cava (systemic venous drainage). In approximately 10 to 20 percent of cases, the graft portal vein is anastomosed to the recipient's superior mesenteric vein (portal venous drainage) [13,26]. In 2015, 82 percent of SPK and 92 percent of PAK transplants in the United States were performed with systemic venous drainage [30].

Patient and allograft survival rates appear to be similar with either systemic or portal venous drainage [13,14,19,31-33]. Portal venous drainage does not appear to offer any significant metabolic or immunologic benefits and is associated with comparable outcomes [30].

Cold ischemia time — Preservation time of up to 20 hours in University of Wisconsin (UW) solution had no untoward effects on short- or long-term pancreas graft survival in earlier studies [34]. In a subsequent study, however, preservation time exceeding 20 hours was associated with a higher risk of early technical failure [35]. Many centers target CITs of less than 12 hours, given the association of longer CIT with the development of graft pancreatitis and early graft thrombosis. The "12-hour rule" was validated in a study that demonstrated a stepwise increase in early technical graft failures and decrease in long-term, death-censored pancreas graft survival associated with progressively longer CITs [36]. Consequently, in SPK transplantation, the pancreas is often transplanted before the kidney to minimize CIT.

Segmental pancreas donation — With segmental pancreas donation, a segment of pancreas (the body and tail) is donated by a living donor who is willing to undergo a hemipancreatectomy, and, in some countries, segments from cadaveric donors have been used. Live pancreas donation is associated with a finite risk of surgical and medical complications for the donors. Among 47 donors, 11 percent required transfusion, and 11 percent underwent splenectomy during the operation [37,38]. Postoperatively, 13 percent of donors developed a pseudocyst, and 9 percent had splenic infarct requiring splenectomy. In terms of medical complications, 26 percent developed new-onset diabetes requiring medication or insulin, 28 percent developed dyslipidemia, and 22 percent had hypertension at a median follow-up of 12 years.

In one case of living donation, a patient who had been diabetic for 17 years received a segment of pancreas from an identical twin [39]. No immunosuppressive therapy was given to prevent rejection. However, within two weeks, there was insulitis with lymphocytic infiltration of the beta cells in the grafted segment, indicative of recurrence of autoimmune diabetes in the transplanted tissue.

Robotic pancreas transplantation — An exciting innovation in pancreas transplantation is the description of laparoscopic pancreas transplantation under robotic assistance [40,41]. A report of the first three whole pancreas transplants performed with the assistance of the da Vinci Surgical System proved the feasibility of robotic-assisted laparoscopic surgery in pancreas transplantation [40]. In these cases, enteric drainage of the pancreas was created using an end-to-end circular stapler to anastomose the donor duodenum to the proximal small bowel of the recipient. However, the authors of this study have raised concerns regarding the effects of increased warm ischemia time on graft viability, although all three patients did well. Another study reported robotic-assisted pancreas transplants in 10 cases and concluded that this approach may have advantages in patients with diabetes and obesity [41]. Although numerous variations exist in the basic surgical techniques of pancreas transplantation and nuances continue to be described, current philosophy dictates that the most appropriate technique to be performed is the one with which the individual surgeon feels most comfortable based upon donor pancreas quality and recipient anatomic considerations.

IMMUNOSUPPRESSION — Immunosuppression regimens continue to change over time, with variations from center to center. The use of biologic agents for induction coupled with combinations of multiple agents with different mechanisms of action for maintenance therapy has become the standard of care in contemporary immunosuppression. These regimens accomplish the primary goals of immunosuppression, which are to achieve effective control of acute rejection while minimizing safety and tolerability risks for the patient and injury to the allograft(s).

Induction therapy — Most transplant centers advocate the use of induction therapy for all pancreas transplants [3,12,30-33,42-48]. Available agents for induction include T cell-depleting antibodies (such as polyclonal rabbit antithymocyte globulin [rATG]-Thymoglobulin and monoclonal alemtuzumab [anti-CD52 antibody]) and nondepleting antibodies such as interleukin (IL)-2 receptor antibodies (monoclonal basiliximab). According to the 2016 Organ Procurement and Transplant Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) Annual Data Report, 85 percent of pancreas transplants performed in 2016 used T cell-depleting agents for induction; fewer than 10 percent of transplants used IL-2 receptor antibodies or reported no induction agent [31].

Induction therapy tends to be similar for recipients of either a simultaneous pancreas-kidney (SPK) transplant or a pancreas after kidney (PAK) transplant with the caveat that PAK transplantation, by definition, represents a second transplant. We, and most other transplant centers, administer a T cell-depleting agent (either multi-dose rATG-Thymoglobulin or single-dose alemtuzumab) at the time of transplantation. We do not routinely use IL-2 receptor antibodies as induction therapy for SPK or PAK transplants due to concerns of a higher rate of acute rejection associated with pancreas transplantation in the absence of depleting antibody induction [49,50]:

If rATG-Thymoglobulin is given, we administer intravenous (IV) rATG-Thymoglobulin 1 to 1.5 mg/kg intraoperatively (through either central or peripheral venous access). This initial intraoperative dose of rATG-Thymoglobulin is followed by 1.5 to 2 mg/kg of rATG-Thymoglobulin per day for the next two to three days for a total cumulative induction dose of 4.5 to 6 mg/kg. rATG-Thymoglobulin is administered if, at presentation, the white blood cell count is greater than 2000/microL and the platelet count is greater than 75,000/microL. If rATG-Thymoglobulin cannot be given, we administer alemtuzumab.

If alemtuzumab is given, we administer alemtuzumab as a single IV (or subcutaneous) dose of 30 mg at the time of transplantation. We do not recommend administration of multiple doses of alemtuzumab, because this regimen has been associated with a high incidence of infection [50,51].

A lower rate of kidney allograft rejection following SPK transplantation has been observed with use of depleting induction agents [42,44,45,47,48,52,53]. As examples:

In one prospective, multicenter study, 174 SPK transplant recipients receiving tacrolimus, mycophenolate, and glucocorticoids for baseline immunosuppression were randomly assigned to induction (n = 87) or noninduction groups (n = 87) [44]. Any commercially available induction therapy could be used. At three years, kidney allograft survival was higher in the induction group compared with the noninduction group (92 versus 82 percent, respectively), and there was a trend toward increased biopsy-confirmed kidney rejection in the noninduction group compared with the induction group (28 versus 20 percent, respectively).

A randomized trial directly compared antithymocyte globulin, azathioprine, glucocorticoids, and delayed cyclosporine to azathioprine, glucocorticoids, and cyclosporine among 50 type 1 diabetic patients undergoing SPK transplant [42]. A lower incidence of acute kidney allograft rejection episodes was observed among those randomly assigned to the antithymocyte globulin regimen (36 versus 76 percent).

The following studies compared individual induction agents in pancreas transplant:

A retrospective analysis of 128 SPK transplants performed between 2001 and 2008 compared outcomes between basiliximab (20 mg x two doses, n = 49) and multi-dose rATG (cumulative total 5 mg/kg, n = 79) [49]. rATG was associated with a decreased risk of rejection both at three months (6 versus 21 percent) and one year (14 versus 27 percent) posttransplant. Despite higher rates of rejection in the basiliximab group, both pancreas and kidney graft survival rates were similar at one year. Similarly, a separate retrospective analysis of 97 SPK transplants showed that overall and early T cell-mediated (cellular) rejection were more common with basiliximab (n = 38) than rATG (n = 59; 30 versus 14 percent and 21 versus 6 percent, respectively). No significant differences in either patient or one-, three-, or five-year pancreas allograft survival rates were observed [54].

Alemtuzumab and rATG induction were compared in a randomized, single-center trial of kidney and pancreas recipients [55,56]. Of the 222 patients enrolled, 46 received an SPK transplant (28 alemtuzumab, 18 rATG), and four received a PAK transplant (all received alemtuzumab). There were no significant differences between the alemtuzumab and rATG groups in five-year patient survival (82 versus 89 percent), kidney graft survival (79 versus 72 percent), or pancreas graft survival (64 versus 56 percent). Rates of acute rejection were lower in patients receiving alemtuzumab than in those receiving rATG (21 versus 44 percent, respectively), although this difference was not statistically significant. Cytomegalovirus (CMV) infections were significantly lower with alemtuzumab compared with rATG (0 versus 17 percent, respectively). In patients with functioning grafts, five-year mean serum creatinine, glomerular filtration rate (GFR), glycosylated hemoglobin, and C-peptide were similar between groups.

In addition, in the multicenter study cited above in which 174 SPK transplant recipients were randomly assigned to induction or noninduction, the lowest incidence of biopsy-proven acute rejection occurred in patients receiving T cell-depleting antibody compared with IL-2 receptor antibody induction (11 versus 24 percent, respectively), but this difference was not statistically significant [44].

T cell-depleting agents are more commonly used in pancreas transplantation compared with kidney transplantation (ie, 85 to 90 percent among pancreas transplants versus 75 percent for kidney transplants) [3,31]. This difference in practice is because there is an intrinsically higher acute rejection rate and greater difficulty in diagnosing rejection among pancreas transplant compared with kidney transplant recipients. Thus, most pancreas transplant centers believe that a greater amount of frontloaded immunosuppression, which is provided by T cell-depleting agents, is warranted in this setting.

Maintenance therapy — Following induction with a T cell-depleting agent (see 'Induction therapy' above), we administer maintenance immunosuppression therapy to all SPK and PAK transplant recipients. Maintenance immunosuppression is given to help prevent acute rejection and loss of the pancreas and kidney allografts. Maintenance therapy is similar for patients receiving an SPK or PAK transplant and typically includes a calcineurin inhibitor, an antimetabolite, and generally a tapering dose of glucocorticoids [45-48]. This approach is generally preferred by most transplant centers, although practice may vary from center to center and some centers individualize therapy based upon immunologic risk [12,45-48].

Maintenance regimen for SPK transplant recipients — For most simultaneous pancreas-kidney (SPK) transplant recipients, we and others administer a maintenance regimen consisting of triple immunosuppression therapy. This includes a calcineurin inhibitor (usually tacrolimus), an antimetabolite (mycophenolate), and prednisone [30-33,45-48]. Most clinicians prefer triple maintenance therapy in SPK transplant recipients because of a purported higher risk of acute rejection in this setting compared with kidney transplantation alone. In addition, patients with diabetes who undergo SPK transplantation may have difficulty either achieving or tolerating therapeutic doses of individual drugs because of gastroparesis, erratic absorption, and diabetic enteropathy. By endorsing a three-drug regimen, adequate cumulative immunosuppression can be attained without incurring major specific-drug toxicities.

Initiation of maintenance therapy — Maintenance immunosuppression is initiated postoperatively and continued indefinitely. Because recipients of a pancreas transplant are typically "nil per os" (ie, NPO) for the first few days after surgery, maintenance immunosuppression during this period is generally administered IV or per nasogastric tube (using liquid suspensions when available) until patients are able to take oral medications on their own. Alternatively, tacrolimus may be given sublingually as a powder.

In patients undergoing SPK and receiving induction therapy with rATG-Thymoglobulin or alemtuzumab, we initiate maintenance immunosuppression therapy as follows:

We administer tacrolimus on the evening of postoperative day 1 with immediate-release tacrolimus 1 to 2 mg twice daily, with doses adjusted to achieve a 12-hour trough level of 8 to 10 ng/mL for the first three months posttransplant and 6 to 8 ng/mL thereafter. Alternatively, some centers give extended-release tacrolimus tablets on postoperative day 1 at 0.08 mg/kg once per day, with doses adjusted to achieve the same 12-hour trough levels as with immediate-release tacrolimus. (See 'Selection of a calcineurin inhibitor' below.)

We administer mycophenolate mofetil (MMF) 1000 mg IV twice daily or MMF liquid suspension 1000 mg twice daily per nasogastric tube starting on postoperative day 1. When the patient is able to take oral medications by mouth (typically on postoperative day 2 or 3), we switch from IV or liquid suspension MMF to either enteric-coated mycophenolate sodium (EC-MPS) 720 mg orally twice daily or MMF capsules 1000 mg orally twice daily. Some centers may use three to four times daily dosing with either IV or oral formulations as part of a loading regimen. (See 'Selection of an antimetabolite agent' below.)

We administer either IV methylprednisolone at 7 mg/kg (maximum dose of 500 mg) or IV dexamethasone 100 mg in the operating room, followed by IV methylprednisolone 20 mg daily until the patient is able to take medications by mouth. We then switch to oral prednisone (20 mg once daily for the first week after transplantation, then tapered to 5 mg daily by one to two months posttransplant). Some centers give additional high doses of IV glucocorticoids as premedication for subsequent doses of rATG-Thymoglobulin or as part of a loading regimen. (See 'Dosing of glucocorticoids' below.)

Practice may vary from center to center with regards to selection and dosing of a calcineurin inhibitor, antimetabolite, and glucocorticoids. At some centers, mTOR inhibitors are used either in addition to or in place of any of the above agents. Other centers endorse early glucocorticoid withdrawal or use different glucocorticoid-tapering regimens. (See 'Less commonly used agents' below.)

Selection of a calcineurin inhibitor — Tacrolimus and cyclosporine selectively inhibit calcineurin, thereby inhibiting the transcription of IL-2 and several other cytokines in T cells. By inhibiting cytokine gene transcription, calcineurin inhibitors suppress T cell and T cell-dependent B cell activation. Tacrolimus is the most commonly used calcineurin inhibitor for maintenance therapy after SPK and PAK transplantation in the United States. In 2016, for example, tacrolimus was administered prior to hospital discharge in more than 95 percent of pancreas transplant recipients [31]. (See "Pharmacology of cyclosporine and tacrolimus".)

In most patients undergoing SPK transplant, we administer tacrolimus rather than cyclosporine because it is associated with equivalent or better pancreas survival, less acute rejection, less nephrotoxicity, and fewer cosmetic side effects [45-48,57-61]. A study that compared immediate to extended-release tacrolimus in stable SPK transplant recipients reported no differences in tacrolimus levels or outcomes [62]. The dosing of tacrolimus is discussed elsewhere in this topic. (See 'Initiation of maintenance therapy' above.)

We do not routinely give cyclosporine as a calcineurin inhibitor to SPK or PAK transplant recipients; however, cyclosporine may be used in patients who have a history of prior allergy or intolerance to tacrolimus. In addition, many transplant centers outside of the United States (including Europe) continue to administer cyclosporine. Cyclosporine is initiated with doses adjusted to achieve a 12-hour trough level of 250 to 350 ng/mL (or peak level of 1000 to 1200 ng/mL) in the first three months posttransplant and 150 to 250 ng/mL (or peak level of 600 to 800 ng/mL) thereafter [57-59].

Similar graft survival outcomes have been observed with tacrolimus- and cyclosporine-based maintenance regimens [58,59]. However, some data suggest that pancreatic graft survival is higher with tacrolimus [57]:

In the Euro-SPK 001 trial, 205 SPK transplant patients were randomly assigned to MMF plus glucocorticoids and either tacrolimus or cyclosporine [57]. At one year, both groups had similar patient and kidney allograft survival rates, with pancreas survival being significantly higher with tacrolimus (91 versus 75 percent). At three years, although patient and kidney survival rates were similar, pancreas survival remained significantly higher with tacrolimus (90 versus 72 percent), with pancreas allograft loss due to thrombosis being markedly increased with cyclosporine (10 versus 2 patients) [58]. In addition, an increased number of initial rejection episodes that were moderate or severe were observed with cyclosporine (28 versus 3 percent). Adverse events were largely similar between the two groups.

In one study, 33 SPK transplant patients were randomly assigned to either tacrolimus or cyclosporine, each given in combination with basiliximab (for induction therapy), glucocorticoids, and MMF [59]. With a median follow-up of approximately 16 months, one-year patient, pancreas, and kidney survival rates were each 94 percent with cyclosporine and 100 percent with tacrolimus.

Tacrolimus may be associated with an increased incidence of diabetes compared with cyclosporine, which has been noted in nondiabetic recipients of kidney allografts (see "Kidney transplantation in adults: Posttransplantation diabetes mellitus"). However, no obvious diabetogenic effects of tacrolimus have been documented in pancreas recipients [58,60-64]. As an example, among 136 type 1 diabetics who underwent successful SPK transplant and received either a cyclosporine- or tacrolimus-based regimen, glycemic status was the same in both groups as determined early (three months) and late (three years) after transplantation [63]. In a separate study of 674 pancreas transplant recipients, the incidence of redevelopment of diabetes at 10 years was not increased in those receiving tacrolimus compared with cyclosporine [64]. The possibility of glucocorticoid sparing or minimization with tacrolimus compared with cyclosporine may counteract some of the purported diabetogenic effects of tacrolimus.

As previously mentioned, the addition of induction therapy to a tacrolimus-based regimen may improve pancreas allograft survival [44]. However, it may also increase the risk of CMV viremia and syndrome. In addition, there has also been a reported 4 percent incidence of posttransplant lymphoproliferative disorder in pancreas transplant recipients [12,60]. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Several drugs may interfere with the metabolism of tacrolimus or cyclosporine, thereby causing either overdosing, with deterioration of kidney function, or underdosing, with an increased incidence of rejection. These issues are discussed in more detail elsewhere. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)

Selection of an antimetabolite agent — Antimetabolite agents interfere with the synthesis of nucleic acids and inhibit the proliferation of both T and B cells. MMF or EC-MPS is the antimetabolite agent used in 94 percent of pancreas transplant recipients in the United States; azathioprine is rarely used as primary therapy [31]. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Pharmacology' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacology and biologic effects'.)

Most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolite agent to SPK recipients rather than azathioprine. MMF, compared with azathioprine in both cyclosporine- and tacrolimus-based regimens, has been associated with more than a 50 percent reduction in the incidence and severity of acute T cell-mediated rejection [43,65-69].

There is also evidence that MMF results in enhanced graft survival [66,67,69]. A retrospective study evaluated the outcomes of 358 consecutive SPK transplant patients who received either MMF or azathioprine in combination with a cyclosporine-based regimen [67]. At two years after transplantation, superior survival rates were observed among the MMF group for both the kidney (95 versus 86 percent) and pancreas allografts (95 versus 83 percent).

However, many patients discontinue MMF due to gastrointestinal intolerance. In one series of 120 patients, the frequency of conversion (principally because of gastrointestinal toxicity) from MMF to azathioprine at one year after transplantation was 14, 26, and 39 percent in those who had undergone SPK transplant, PAK transplant, and pancreas transplant alone (PTA), respectively [68]. Most centers manage the purported synergistic gastrointestinal toxicity of the tacrolimus and MMF combination with either stepwise dose reduction of each agent, changing MMF interval dosing to three to four times daily, or separating the time of administration of tacrolimus and MMF by one to two hours. In another study, however, the administration of high-dose mycophenolate (1000 mg three-times daily versus twice daily) was associated with improved pancreas graft survival, although dose reductions because of tolerability were common in both groups [69].

The formulation of EC-MPS delays the release of mycophenolate acid until the small intestine [70]. EC-MPS shows fewer gastrointestinal side effects, and conversion from MMF [70] to EC-MPS has been associated with improved gastrointestinal tolerability in kidney and SPK transplant recipients [71-73]. Thus, conversion to EC-MPS is a reasonable option and should be considered first, before switching to azathioprine, if none of the above maneuvers are successful. However, because of gastroparesis and diabetic enteropathy, it is not uncommon for SPK and PAK transplant recipients to have problems tolerating therapeutic doses of the drug combination of tacrolimus and MMF/EC-MPS because of gastrointestinal side effects. In addition, MMF/EC-MPS dose reductions may occur in the setting of infection or cytopenias. Some data suggest that dose changes or reductions in either tacrolimus or MMF/EC-MPS (independent of conversion to another immunosuppressant) may be associated with a higher incidence of acute rejection. For this reason, some centers prefer to continue glucocorticoids long term (or add an mTOR inhibitor) to provide an adequate level of chronic immunosuppression in the setting of dose reduction of the primary immunosuppressants.

Mycophenolate is teratogenic, and its use is contraindicated in pregnancy. In female recipients of childbearing age, we administer mycophenolate as the antimetabolite agent and counsel them against getting pregnant for at least one to two years posttransplant. After this time, if patients wish to conceive, we switch them to azathioprine, which does not seem to have a detrimental effect on fertility or pregnancy [74]. Practice may vary at other transplant centers, and some clinicians do not use mycophenolate in any female recipients of childbearing age unless they are on long-acting contraception, have undergone surgical sterilization procedures, or have absolute infertility.

The dosing of MMF and EC-MPS is discussed above. (See 'Initiation of maintenance therapy' above.)

Dosing of glucocorticoids — There is no consensus on the optimal dose or maintenance schedule of glucocorticoids following SPK transplantation. As part of a triple-agent regimen, we administer IV methylprednisolone at 7 mg/kg (maximum of 500 mg) in the operating room, followed by IV methylprednisolone 20 mg daily until the patient is able to take medications by mouth. Other centers may prefer to use IV dexamethasone (up to 100 mg) perioperatively followed by IV and then oral methylprednisolone. We then switch to oral prednisone 20 mg once daily for the first week after transplantation. The daily dose is then tapered every week by 5 mg, resulting in 15 mg daily for one week, 10 mg daily for one week, and then 5 mg daily. In the absence of acute rejection, we generally reduce glucocorticoids to a dose of 5 mg daily by one month following SPK transplant. Dosing and tapering of glucocorticoids may vary among transplant centers.

The use of long-term glucocorticoids may also vary from center to center, and some centers prefer early glucocorticoid withdrawal in some SPK recipients. In this setting, some centers may use an mTOR inhibitor as a third maintenance immunosuppressive agent while others manage patients long term with dual (tacrolimus and mycophenolate) therapy. According to the OPTN/SRTR Annual Data Report from 2016, approximately 73 percent of pancreas transplant recipients were on glucocorticoid maintenance at one year posttransplant [31].

There is insufficient evidence for the benefits and harms of continued glucocorticoids in pancreas transplantation [75]. However, a number of centers have reported success with either glucocorticoid elimination or rapid glucocorticoid withdrawal in SPK transplant recipients, particularly in the setting of depleting antibody induction therapy [76-80].

Less commonly used agents

mTOR inhibitors – The use of mTOR inhibitors (sirolimus, everolimus) at the time of pancreas transplantation has been steadily decreasing over the past decade, from approximately 20 percent in 2006 to 10 percent in 2016. A similar trend is noted in the number of recipients who are receiving mTOR inhibitors at one-year follow-up [31]. The mechanism of action of mTOR inhibitors is inhibition of protein kinase-mediated signaling pathways, which regulate cell growth, proliferation, and cell cycle progression. In addition to immunosuppressive effects, mTOR inhibitors have anti-tumor, anti-viral, and anti-fungal properties. The mTOR inhibitors function through a targeting pathway that is unique from either calcineurin inhibitors or antimetabolites, which represents another rationale for their use. Sirolimus is administered once daily because of a long half-life, and everolimus is administered twice daily; both agents are dosed to achieve target trough levels of 3 to 8 ng/mL:

A single-center study reported one-year kidney and pancreas survival rates of 100 percent among 20 SPK transplant patients administered a tacrolimus/sirolimus maintenance regimen after induction therapy that also included rATG-Thymoglobulin and a rapid glucocorticoid taper [76].

In one study of 59 SPK transplant recipients, two prednisone-free tacrolimus-based regimens were compared [77]. Both groups received rATG-Thymoglobulin induction. At six years posttransplant, patients who received tacrolimus plus sirolimus (n = 37) had a lower rate of kidney survival compared with those who received tacrolimus plus MMF (n = 22; 71 versus 91 percent), although the difference was not statistically significant. Rates of death-censored pancreas survival and biopsy-proven acute T cell-mediated rejection were similar between both groups.

A United Network for Organ Sharing (UNOS) registry study spanning 1986 to 2016 stratified 25,387 pancreas or SPK transplant recipients into two groups according to those who either received mTOR inhibitors (at any time posttransplant; n = 4174) or those remaining (n = 21,663) who were managed exclusively with non-mTOR inhibitor-based immunosuppression [78]. The use of mTOR inhibitors was associated with a 7 percent risk reduction in allograft failure and higher patient survival rates up to 10 years. By contrast, randomized, controlled trials comparing mTOR inhibitors with standard immunosuppressive regimens have yielded conflicting results [81-83].

The available data suggest that the role of mTOR inhibitors may be better suited to replace an antimetabolite rather than a calcineurin inhibitor, which may then permit glucocorticoid weaning and withdrawal.

Adverse effects including poor wound healing, edema, lymphocele formation, proteinuria, and dyslipidemia as well as synergistic nephrotoxicity when combined with calcineurin inhibitors, which may limit the utility of mTOR inhibitors in diabetic transplant recipients. A common theme in most studies with mTOR inhibitors has been a high incidence of drug-related side effects resulting in either dose reductions or discontinuation with conversion to another agent. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors".)

BelataceptBelatacept is a soluble fusion protein that selectively blocks a T cell costimulation pathway, thereby limiting T cell activation. Although studied extensively in kidney transplantation, there are limited data in SPK transplantation. An open-label, multicenter, randomized trial of belatacept in SPK transplantation as a de novo maintenance agent (in combination with rATG induction and mycophenolate) in order to achieve calcineurin inhibitor and glucocorticoid withdrawal was stopped prematurely because of a high incidence of pancreas allograft rejection [84]. Previous attempts to attain calcineurin inhibitor and glucocorticoid withdrawal following SPK transplantation have likewise been met with difficulty [51].

Maintenance regimen for PAK transplant recipients — At the time of pancreas after kidney (PAK) transplantation, patients are already receiving maintenance immunosuppression to prevent rejection of the previous kidney allograft. If the patient is already on a triple immunosuppression regimen consisting of tacrolimus, MMF or EC-MPS, and prednisone, we typically do not modify the maintenance regimen if kidney allograft function is stable and the patient is tolerating the maintenance regimen without significant adverse effects.

However, given the higher immunogenicity of the transplanted pancreas, many patients may require a modification of their maintenance regimen to augment immunosuppression following pancreas transplant. As examples:

In patients who are on tacrolimus and are being maintained at 12-hour trough levels of 3 to 7 ng/mL, we adjust the dose to target higher trough levels of 8 to 10 ng/mL for the first three months following PAK transplant, then 6 to 8 ng/mL thereafter.

In patients who are receiving reduced doses of MMF (ie, 500 mg twice daily) or EC-MPS (ie, 360 mg twice daily), we increase to full dose (ie, 1000 mg twice daily for MMF or 720 mg twice daily for EC-MPS).

Patients receiving cyclosporine, rather than tacrolimus, as a calcineurin inhibitor do not need to switch to tacrolimus if they have stable kidney allograft function and are not experiencing significant adverse effects. However, some clinicians prefer tacrolimus and will advise their patients to switch from cyclosporine to tacrolimus at the time of PAK transplant unless the patient is taking cyclosporine because of intolerance to tacrolimus. If cyclosporine is continued following PAK transplant, then higher levels (similar to those following SPK transplant) are targeted for the first few months posttransplant.

In patients who are already on glucocorticoids, we initiate a "steroid recycle" at the time of PAK transplant (IV high-dose glucocorticoids perioperatively, then prednisone 20 mg daily with a taper to 5 mg daily by one to two months posttransplant).

However, similar to SPK transplantation, many variations exist on dosing and target levels of all of the above immunosuppressants based upon center practice patterns and individualized immunological risk.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

General principles – Combined pancreas-kidney transplantation is an established treatment for selected patients with diabetes and end-stage kidney disease (ESKD). Pancreas transplants are performed as simultaneous pancreas-kidney (SPK) transplants (most common), sequential pancreas after kidney (PAK) transplants, or pancreas transplants alone (PTAs). (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Introduction'.)

Surgical considerations – In the United States, the most common technique for SPK transplantation consists of placing both organs intraperitoneally through a vertical midline incision. Centers differ in regards to either contralateral or ipsilateral placement of the organs as well as the surgical management of the exocrine pancreas secretions and the venous outflow. The majority of pancreas transplants are placed on the right side and performed with enteric exocrine drainage (≥90 percent) and systemic venous drainage (ie, from the graft portal vein either to the right iliac vein or distal inferior vena cava). (See 'Surgical considerations' above.)

Induction immunosuppressive therapy – Among patients receiving either an SPK or PAK transplant, we recommend induction immunosuppression therapy that consists of an antibody plus standard triple immunosuppressive therapy (Grade 1B). In recipients of an SPK or PAK transplant, we suggest administration of a T cell-depleting agent (either rabbit antithymocyte globulin [rATG]-Thymoglobulin or alemtuzumab) rather than a nondepleting interleukin (IL)-2 receptor antagonist (Grade 2C). (See 'Induction therapy' above.)

Maintenance immunosuppressive therapy

SPK transplant recipients – In patients receiving an SPK transplant, we and most transplant centers administer a maintenance immunosuppression regimen consisting of triple immunosuppression therapy with a calcineurin inhibitor, an antimetabolite, and tapering doses of glucocorticoids (see 'Maintenance therapy' above):

-Among the available calcineurin inhibitors, we suggest the administration of tacrolimus rather than cyclosporine (Grade 2B). (See 'Selection of a calcineurin inhibitor' above.)

-Among the available antimetabolite agents, we suggest the administration of mycophenolate (mycophenolate mofetil [MMF] or enteric-coated mycophenolate sodium [EC-MPS]) rather than azathioprine (Grade 2C). (See 'Selection of an antimetabolite agent' above.)

-For most patients, we administer glucocorticoids. We use oral prednisone tapered to 5 mg daily by one to two months after transplantation. (See 'Dosing of glucocorticoids' above.)

PAK transplant recipients – At the time of pancreas transplantation, most recipients of a PAK transplant are receiving maintenance immunosuppression to prevent rejection of the kidney allograft. If the patient is already on a triple immunosuppression regimen consisting of tacrolimus, MMF or EC-MPS, and prednisone, we typically do not modify the maintenance regimen if kidney allograft function is stable and the patient is tolerating the maintenance regimen without significant adverse effects. However, given the higher immunogenicity of the transplanted pancreas, many patients may require a modification of their maintenance regimen to augment immunosuppression following pancreas transplant. (See 'Maintenance regimen for PAK transplant recipients' above.)

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Topic 118566 Version 8.0

References

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