Pancreas Transplantation Alone (PTA) and Islet Cell Transplantation

Number: 0601


  1. Pancreas Transplantation Alone (PTA)

    Aetna considers pancreas transplantation alone (PTA) without kidney transplant medically necessary for members who meet the transplanting institution's selection criteria.  In the absence of an institution's selection criteria, Aetna considers PTA without kidney transplant medically necessary when all of the following general and disease specific criteria are met:

    1. General Criteria

      1. Absence of ongoing or recurrent active infections that are not effectively treated; and
      2. Absence of uncontrolled HIV/AIDS infection, defined as:

        1. CD4 count greater than 200 cells/mm3 for more than 6 months; and
        2. HIV-1 RNA (viral load) undetectable; and
        3. No other complications from AIDS, such as opportunistic infection (e.g., aspergillus, coccidioidomycosis, resistant fungal infections, tuberculosis) or neoplasm (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma); and
        4. On stable anti-viral therapy more than 3 months; and
      3. Documentation of compliance with medical management; and
      4. Member has adequate cardiac status (e.g., no angiographic evidence of significant coronary artery disease, ejection fraction greater than or equal to 40 %, no myocardial infarction in last 6 months, negative stress test); and
      5. Member has satisfactory kidney function (creatinine clearance greater than 40 ml/min); and
      6. No malignancy (except for non-melanomatous skin cancers or low-grade prostate cancer) or malignancy has been completely resected OR (upon medical review) malignancy has been adequately treated such that the risk of recurrence is small.
    2. Disease Specific Criteria

      1. Member has a history of labile (brittle) insulin-dependent diabetes mellitus (IDDM); and
      2. Member has recurrent, acute and severe metabolic and potentially life-threatening complications requiring medical attention, as documented by chart notes, frequent emergency room visits and/or hospitalizations. They may include:

        1. Hyperglycemia; or
        2. Hypoglycemia; or
        3. Hypoglycemic unawareness associated with high risk of injury; or
        4. Ketoacidosis; and
      3. Member has consistent failure of exogenous insulin-based management, defined as inability to achieve sufficient glycemic control (HbA1c of greater than 8.0) or recurrent hypoglycemic unawareness, despite aggressive conventional therapy including all of the following:

        1. Adjusting frequencies and amounts of insulin injected; and
        2. Measuring multiple blood glucose levels on a daily basis; and
        3. Modifying diet and exercise; and
        4. Monitoring HgbA1c levels.
  2. Pancreas Retransplantation after a Failed Primary Pancreas Transplant

    Aetna considers pancreas retransplantation after a failed primary pancreas transplant medically necessary when member meets the selection criteria stated above.

  3. Pancreas Retransplantation after 2 or more Prior Failed Pancreas Transplants

    Pancreas retransplantation after 2 or more prior failed pancreas transplants may be considered medically necessary upon individual case review.

  4. Contraindications

    1. Contraindications

      PTA is considered not medically necessary in members with prohibitive cardiovascular risk because the risks of PTA exceed the benefits.  Examples of prohibitive cardiovascular risk include, but are not limited to:

      1. Angiographic evidence of significant non-correctable coronary artery disease; or
      2. Ejection fraction less than 35 %; or
      3. Myocardial infarction within last 6 months; or
      4. Refractory uncontrolled hypertension
    2. Relative Contraindications

      Aetna considers pancreas transplant medically necessary for members with the following relative contraindications to pancreas transplant only if the requesting physician documents that these relative contraindications were considered, and has determined that the benefits of pancreas transplant outweigh the risks in these members.  Relative contraindications to PTA include the following:

      1. Ejection fraction 35 % to 40 %; or
      2. Severe peripheral vascular disease.
  5. Islet Cell Autotransplantation

    Aetna considers islet cell autotransplantation (i.e., transplantation of the member's own islet cells) medically necessary for members undergoing near-total or total pancreatic resection for severe, refractory chronic pancreatitis.

    Aetna considers islet cell allotransplantation (i.e., transplantation of islet cells from a donor) experimental and investigational.

  6. Partial Pancreas Transplant

    Aetna considers a partial pancreas transplant from a living donor an acceptable alternative to cadaveric transplant for persons who meet medical necessity criteria for pancreas transplant.

  7. Experimental and Investigational Interventions

    Aetna considers any of the following experimental and investigational because their safety and effectiveness have not been established in the peer-reviewed published medical literature.

    1. Pancreatic islet xenotransplantation; or
    2. PTA for increased longevity; or
    3. PTA primarily indicated for life-style issues, i.e., a desire to no longer take insulin.


Exogenous insulin is effective therapy for most diabetics.  Intensive insulin therapy with multiple daily injections or with a constant infusion pump has been shown to be an effective method of maintaining blood glucose and hemoglobin A1c at near normal levels.  Despite maximal medical therapy, a rare (less than 1%) number of non-uremic patients with insulin-dependent diabetes mellitus (IDDM) may experience frequent and unpredictable occurrences of severe hyperglycemia, hypoglycemia, ketoacidosis, and hypoglycemic unawareness, thus labeling them as brittle, labile and unstable.  This subgroup tends to have a life that is constantly disrupted by these disabling and life-threatening events, which cause a considerable burden on social and family resources due to multiple emergency room visits and/or hospital admissions.  Fortunately, in this small subset of patients, there is sufficient evidence in the medical literature to support performance of pancreas transplantation alone (PTA).

Initially, the reported results of solitary pancreatic transplantation in non-uremic diabetic patients were less favorable than simultaneous pancreas-kidney (SPK) transplantation or pancreas after kidney (PAK) transplantation because of high rates of rejection and difficulties in the diagnosis and treatment of these rejection episodes.  Because there was no marker for pancreas rejection with sensitivity similar to serum creatinine for kidney transplant rejection, detection and treatment of PTA rejection was often delayed.  Subsequently, outcomes of PTA have substantially improved due to technical refinements of the procedure, the introduction of new immunosuppressive regimens, and better selection of transplant candidates.  Unlike SPK and PAK, there is no adequate evidence that PTA can prevent or retard the development and/or progression of the long-term complications of diabetes; nor is there evidence that pancreas transplantation can prolong the life of patients with diabetes mellitus

Pancreas transplantation alone is contraindicated in patients with clinically significant cardiovascular disease.  Because of the high prevalence of microvascular disease, especially in the coronary arteries in patients with diabetes, it is especially important to evaluate patients for these risks before PTA surgery.  Indeed, one of the most frequent causes of pancreas transplant failure is death from myocardial infarction.  Therefore, accepted guidelines state that any substantial coronary artery disease needs to be corrected before transplantation is undertaken.

A history of coronary revascularization is no longer considered an absolute contraindication.  Nevertheless, coronary event rates remain greater among pancreas transplant recipients who have undergone coronary revascularization, than among individuals without pre-transplantation coronary artery disease.  The literature states that severe peripheral vascular disease is a relative contraindication to PTA since iliac atherosclerosis can complicate the technical procedure.  Other relative contraindications to pancreas transplantation include obesity, substance abuse, poorly controlled psychiatric illnesses, noncompliance, and any recent malignancy.

Although segmental grafts (consisting of only the pancreatic body and tail) were once common, the entire pancreas and its associated duodenal segment are now almost always transplanted (unless a living donor is used).  This advance provides more insulin-secreting cells.  The allograft is positioned laterally in the lower abdomen.  Vascular anastomoses in a pancreas transplant are the donor splenic and superior mesenteric artery and portal vein to the recipient iliac artery and vein, respectively.  This provides systemic rather than portal delivery of insulin with a resulting baseline fasting hyper-insulinemia.  The incidence of post-transplant graft thrombosis has been greatly reduced using this method.  Ligation or obliteration of the pancreatic duct was once commonly practiced, but these techniques have also been abandoned.  Instead, the pancreatic exocrine secretions are drained internally into either the small intestine or the bladder.  In general, immunosuppression is the same as that used for patients with kidney transplants.  Induction therapy and rejection treatment usually involves use of ALG or OKT3.  All in all, with excellent HLA matching, a graft survival rate of 80 %, comparable with the overall success rate of combined kidney-pancreas transplantation, can be achieved.

Indications for Pancreas Transplantation

The American Diabetes Association (2003) has developed established indications for pancreas transplantation: "In the absence of indications for kidney transplantation, pancreas transplantation should only be considered a therapy in patients who exhibit these 3 criteria:
  1. a history of frequent, acute, and severe metabolic complications (hypoglycemia, hyperglycemia, ketoacidosis) requiring medical attention;
  2. clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and
  3. consistent failure of insulin-based management to prevent acute complications."

Autologous islet cell transplantation is an alternative for persons undergoing total pancreatectomy for severe, refractory chronic pancreatitis.  Near total or total pancreatic resection can alleviate pain in patients with severe chronic resection.  Autologous islet cell transplantation can preserve islet cell function in patients undergoing this procedure.  The islet cell transplantation procedure involves the infusion of islet cells into the liver by portal embolization, where the cells function as a free graft.  The liver's dual vascular supply allows embolization of isolated pancreatic islets by cannulating the umbilical vein, a tributary of the mesenteric venous system, or by transcutaneous, transhepatic cannulation of the portal vein itself.  The terminal portal venule can be occluded without infarcting the transplant site.

Rodriguez Rilo and associates (2003) reported on the results of autologous islet cell transplantation in a consecutive series of patients from one center who received total or near-total pancreatic resection for severe, refractory chronic pancreatitis.  From February 2000 to February 2003, a total of 22 patients, whose median age was 38 years, underwent pancreatectomy and autologous islet cell transplantation.  Sixty-eight percent of the patients had either a minor or major complication.  Major complications included acute respiratory distress syndrome (n = 2), intra-abdominal abscess (n = 1), and pulmonary embolism (n = 1).  All patients demonstrated C-peptide and insulin production indicating graft function.  Post-operatively, 41 % of subjects were insulin independent, and 27 % required less than 10 units of insulin per day, and the remaining 7 patients require between 15 and 40 units of insulin per day.  All patients had pre-operative pain and had been taking opioid analgesics; 82 % no longer required analgesics post-operatively.  The investigators concluded that pancreatectomy with autologous islet cell transplantation can alleviate pain for patients with chronic pancreatitis and preserve endocrine function.

Jie et al (2005) reported on outcomes of one center’s experience with 137 patients undergoing autologous islet cell transplantation for pancreatectomy since 1997.  Follow-up data was available in 120 patients; 63 % of the patients had complete relief from pain, 22 % experienced partial relief, and 15 % were unchanged.  Of patients with complete pancreatectomy since 1995 (n = 73), all but 1 pediatric patient (n = 22) transplanted with less than or equal to 2000 IEQ/kg islets required insulin post-pancreatectomy.  Of patients receiving more than 2000 IEQ/kg islets (n = 51), 47 % were completely insulin independent while 25 % were intermittently insulin-treated.  The investigators concluded that autologous islet cell transplantation should be considered in patients undergoing primary pancreatic resection for the treatment of refractory pain associated with small duct chronic pancreatitis.

Clayton and colleagues (2003) reported on a single center’s experience with autologous islet cell transplantation for total or partial pancreatectomy from September 1994 to July 2001.  Forty patients had been transplanted, with follow-up times range from 6 months to 7 years.  At 2 years post transplant, 18 patients had a median hemoglobin A1c of 6.6 % (5.2 to 19.3 %), fasting C-peptide of 0.66 ng/mL (0.26 to 2.65 ng/ml), and required a median of 12 (0 to 45) units of insulin per day.  Five patients with 6-year follow-up data had a median hemoglobin A1c of 8 % (6.1 to 11.1 %), fasting C peptide of 1.68 ng/ml (0.9 to 2.78 ng/ml), and required a median of 43 (6 to 86) units of insulin per day.  The investigators reported that these data demonstrate that up to 6 years after autologous islet cell transplantation, the grafts continue to function, but that over the time period studied, the level of function appears to be decreasing.  The investigators reported that the majority of patients no longer required opiate analgesia.

Allogeneic islet cell transplantation is being investigated as an alternative means of restoring normoglycemia, without the attendant morbidity of the whole-organ procedure, and potentially with significantly less need for immunosuppression than pancreas transplantation.  Experience with allogeneic islet cell transplantation has increased and incremental improvements in the islet cell isolation process have been achieved.  Islet cell transplantation has several advantages:
  1. the cells can be delivered easily into the recipient's portal circulation by umbilical vein cannulation without a major operation, and
  2. allogeneic islets can be cryopreserved.  Methods for treating allogeneic islet cells to reduce their immunogenicity are being studied.

Although considerable knowledge regarding allogeneic islet cell transplantation has been accumulated, both in the techniques of islet isolation and in preventing damage to the transplant by rejection or autoimmunity, research has not progressed much beyond experimental models.  Until recently, successful human islet transplantation has been exceedingly rare; human islet cell transplantations have been almost uniformly unsuccessful, if success is defined as restoration of normoglycemia with no dependence on exogenous insulin.  With continued improvements, allogeneic islet cell transplantation could eventually replace both insulin therapy and whole-pancreas transplantation as the optimal treatment for type 1 diabetes.  A number of immunologically privileged transplantation sites have been evaluated, including the anterior chamber of the eye, the brain, the pregnant uterus, the placenta, the testis, and the thymus.  Several of these sites have been shown to provide at least partial sanctuary for allogeneic islets while allowing normal physiologic function.  However, the technical considerations and potential morbidity of engraftment into these sites discourage their clinical use. 

Guidelines from the American Diabetes Association (Robertson et al, 2004) have concluded that "islet cell transplantation is an experimental procedure, also requiring systemic immunosuppression, and should be performed only within the setting of controlled research studies."

An assessment prepared for the Ontario Ministry of Health and Long-Term Care (2003) concluded that "[t]he current evidence on the use of islet transplantation for non-uremic type 1 diabetic patients is limited since it is based on studies with weak methodological design .… The effect of islet transplantation on restoring hormonal responses to hypoglycemia is inconclusive. Islet transplantation in non-uremic type 1 diabetic patients with hypoglycemia unawareness or uncontrolled diabetes is an evolving procedure with promising preliminary, but inconclusive final results."

An assessment prepared by the Alberta Heritage Foundation for Medical Research (Guo et al, 2003) reached the following conclusions about islet cell transplantation for type 1 diabetes: "Limited evidence suggests that ITA [islet cell transplantation] is effective in controlling labile diabetes and protects against unrecognised hypoglycemia in highly selected patients in the short term.  The long-term effects of ITA on metabolic control remain to be proven.  Follow-up studies are needed to determine the duration of this metabolic effect in order to assess its potential for preventing or arresting the development of chronic diabetes complications in non-uremic type 1 diabetic patients with severe hypoglycemia.  Future research is required to improve measures for islet mass/function in order to appropriately evaluate the effects of the ITA procedure."

An assessment by the National Institute for Clinical Excellence (2003) states: "Current evidence on the safety and efficacy of pancreatic islet cell transplantation does not appear adequate to support the use of this procedure without special arrangements for consent and for audit or research."  The assessment explained that "the identified studies did not compare blood sugar control or risks of diabetic complications for the treatment options (injected insulin versus pancreatic islet cell transplantation)."  The assessment also stated that there was a lack of long-term follow-up data.

An assessment of islet cell transplantation for type 1 diabetes prepared for the Agency for Healthcare Quality and Research (AHRQ) reached the following conclusions: "Evidence on outcomes of islet transplant is limited by small patient numbers, short followup, and lack of standardized reporting.  (These issues are being addressed by the NIH funded Collaborative Islet Transplant Registry.)  Of 37 patients from 3 centers, 28 (76 %) maintained insulin independence at 1 year (published evidence); similarly, 50 to 90 % of 104 patients from four centers were insulin independent (supplemental evidence).  Serious adverse events, including portal vein thrombosis and hemorrhage, occur infrequently.  Data are lacking on long-term durability of the procedure, effects on diabetic complications, or long-term consequences of immunosuppression.  Evidence is insufficient for comparison with whole-organ pancreas transplant."

An assessment by the Institute for Health Economics (Guo et al, 2008) of islet cell transplantation for type 1 diabetes concluded that there was insufficient evidence to consider islet cell allotransplantation as standard care in patients with non-uremic type-1 diabetes with severe hypoglycaemia and uncontrolled diabetes.  The assessment stated a number of implications for research, including the development of more sensitive methods to predict and detect graft loss, and the need for studies that were larger, prospective and had longer follow-up periods.  Studies of single donors with standardized immunosuppressive regimens and studies of patients with and without renal dysfunction were also recommended.

In a pilot study, Mineo and colleagues (2008) attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion.  A total of 6 patients with brittle type 1 diabetes mellitus received a single-donor allogeneic islet transplant (8611 +/- 2113 IEQ/kg) followed by high doses of donor HSC (4.3 +/- 1.9 x 10(6) HSC/kg), at days 5 and 11 post-transplant, without ablative conditioning.  An "Edmonton-like" immunosuppression was administered, with a single dose of infliximab added to induction.  Immunosuppression was weaned per protocol starting 12 months post-transplant.  After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 +/- 23 days).  No severe hypoglycemia or protocol-related adverse events occurred.  Graft function was maximal at 3 months then declined.  Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts.  Graft failure occurred within 4 months from weaning (478 +/- 25 days post-transplant).  Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 +/- 0.48 %), highly reduced at 1-year (0.20 +/- 0.08 %), and was undetectable at graft failure.  CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter.  Combined islet and HSC allotransplantation using an "Edmonton-like" immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.

In a review on pancreas retransplants, Humar et al (2000) concluded that pancreas retransplants can be performed with a minimal increase in surgical complications.  However, graft survival after retransplants is slightly inferior to that after primary transplants, probably for both immunological and non-immunological reasons.  Retransplants can be offered to suitable candidates, but they may require more aggressive monitoring for rejection.

Patients with type 1 diabetes who are appropriate candidates for a pancreas transplantation may be simultaneously evaluated for suitable living segmental pancreas donors (Barr et al, 2006).  Potential donors may undergo either segmental pancreas donation alone (for non-uremic or post-uremic recipients) or simultaneous segmental pancreas and unilateral kidney donation (for uremic recipients).  Once identified, potential donors will be subject to a thorough medical, metabolic and psychosocial screening.  ABO and HLA cross-match compatibility is preferred but not manditory (Barr et al, 2006).  A segmental donor pancreatectomy can also be applied for islet isolation and allotransplantation.  Donor segmental pancreatectomy (tail) can be done open or laparoscopically.

The largest reported experience with living donor pancreas transplants has been reported from the University of Minnesota (Barr et al, 2006).  At the University of Minnesota, there have been 130 live donor pancreas transplants performed between 1977 and 2005.  The distribution of these transplants was as follows: 40 % PTA; 25 % pancreas after kidney (PAK); and 35 % simultaneous live donor pancreas and kidney transplants (SPK).  There are 20 PTA and PAK live donor grafts functioning between 10 and 30 yeaars following transplantation.  There are 3 living donor SPK transplants with  function greater than 10 years.  There have also been 2 live donor islet cell transplants after kidney transplantation early in the center experience.

Other centers have also reported their experience with living donor pancreas transplantation.  At the University of Illinois, Chicago, 9 living-donor simultaneous kidney and segmental pancreas bladder-drained transplants were performed between 1997 and 2004 (Barr et al, 2006).  Eight out of 9 pancreas grafts and all the kidney grafts are reported to be working for 1 to 8 years following transplantation.  There was no report of a donor death.

As of 2005, there had been 5 live donor segmental pancreatectomies performed in Japan, 1 case of live donor islet cell transplantation in Japan, and 2 live donor segmental pancreatectomies performed in Korea (Barr et al, 2006).

Tan et al (2008) evaluated the safety and effectiveness of simultaneous islet and kidney transplantation in patients with type 1 diabetes and end-stage renal disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction.  A total of 7 patients with type 1 diabetes and end-stage renal failure were transplanted with allogenic islets and kidneys procured from brain-dead donors.  To prevent organ rejection, patients received alemtuzumab for induction immunosuppression, followed by sirolimus and tacrolimus.  No glucocorticoids were given at any time.  The median duration of follow-up was 18.3 months (range of 13 to 31).  Kidney survival was 100 %.  Four patients became insulin independent at 1 year; the other 3 reduced insulin use to less than 25 % of the amount required before transplantation.  Serum C-peptide levels were significantly greater post-transplant in all patients, indicating continued islet function.  No major procedure-related complications were observed.  The authors concluded that these findings demonstrated that a steroid-free immunosuppressive regimen consisting of alemtuzumab, sirolimus, and tacrolimus is feasible for simultaneous islet and kidney transplantation.  The question of whether this induction regimen is superior to more standard induction deserves large studies.

Halban et al 92010) stated that beta cell mass and function are decreased to varying degrees in both type 1 and type 2 diabetes.  In the future, islet cell replacement or regeneration therapy may thus offer therapeutic benefit to people with diabetes, but there are major challenges to be overcome.  These researchers performed a review of published peer-reviewed medical literature on beta-cell development and regeneration.  Only publications considered most relevant were selected for citation, with particular attention to the period 2000 to 2009 and the inclusion of earlier landmark studies.  Islet cell regenerative therapy could be achieved by in situ regeneration or implantation of cells previously derived in vitro.  Both approaches are being explored, and their ultimate success will depend on the ability to recapitulate key events in the normal development of the endocrine pancreas to derive fully differentiated islet cells that are functionally normal.  There is also debate as to whether beta-cells alone will assure adequate metabolic control or whether it will be necessary to regenerate islets with their various cell types and unique integrated function.  Any approach must account for the potential dangers of regenerative therapy.  The authors concluded that islet cell regenerative therapy may one day offer an improved treatment of diabetes and potentially a cure.  However, the various approaches are at an early stage of pre-clinical development and should not be offered to patients until shown to be safe as well as more effective than existing therapy.

Cantarelli et al (2013) noted that advances in islet transplantation research have led to remarkable improvements in the outcome in humans with type 1 diabetes.  However, pitfalls, mainly linked both to early liver-specific inflammatory events and to pre-existing and transplant-induced auto- and allo-specific adaptive immune responses, still remain.  In this scenario, research into pancreatic islet transplantation, essential to investigate new strategies to overcome open issues, needs very well-designed pre-clinical studies to obtain consistent and reliable results and select only promising strategies that may be translated into the clinical practice.  These researchers discussed the main shortcomings of the mouse models currently used in islet transplantation research, outlining the main factors and variables to take into account for the design of new pre-clinical studies.  Since several parameters concerning both the graft (i.e., islets) and the recipient (i.e., diabetic mice) may influence transplant outcome, the authors recommended considering several critical points in designing future bench-to-bedside islet transplantation research.

Pancreatic Islet Allotransplantation

Tekin and colleagues (2016) evaluated short-term and long-term results of the pancreatic islet allotransplantation.  Subjects underwent pancreatic islet cell allotransplantation using the Edmonton Protocol; they were followed-up for 10 years after initial islet transplant with up to 3 separate islet infusions.  They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus.  A total of 9 patients received a total of 18 islet infusions; 5 patients dropped-out in the early phase of the study.  Greater than 50 % drop-out and non-compliance rate resulted from both poor islet function and recurrent side effects of immunosuppression.  The remaining 4 (44 %) subjects stayed insulin-free with intervals for at least over 5 years (cumulative time) after the first transplant.  Each of them received 3 infusions, on average 445,000 islet equivalent per transplant.  Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects.  In the long-term follow-up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients.  Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant.  Results of metabolic tests including hemoglobin A1c (HbA1c), arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function.  The authors concluded that only a small fraction of patients presenting for evaluation were suitable candidates for islet transplantation.  Despite thorough patient screening and selection, the drop-out rate was high and was due to combination of poor initial islet graft function and extensive side effects of sirolimus.  They stated that immunosuppressant medications must be frequently adjusted to facilitate long-term islet survival and overall health of the islet transplant recipients.  Insulin independency was achieved by multiple infusions without detecting PRA.  They noted that in properly selected subjects with type 1 DM and severe hypoglycemia with hypoglycemic unawareness, pancreatic islet allotransplantation offered a chance for long-term excellent glycemic control and prevention of progression of diabetic complications, including nephropathy, retinopathy, and neuropathy.

Pancreatic Islet Xenotransplantation

Marigliano et al (2011) stated that the therapy of type 1 diabetes is an open challenging problem.  The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy.  Even if successful, this approach poses a problem of scarce tissue supply.  Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application.  Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets.  Several studies in the pig to non-human primate model demonstrated the feasibility of successful pre-clinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts.  Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies.  Nonetheless, the authors concluded that further efforts are needed to generate additional safety and efficacy data in non-human primate models to safely translate these findings into the clinic.

Samy et al (2014) stated that type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution.  Both whole organ pancreas and islet allo-transplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population.  Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allo-transplantation, and several pre-clinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems.  These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. 

Matsumoto and associates (2016) noted that while islet allotransplantation has become a viable option for the treatment of unstable type 1 diabetes (T1DM), donor shortage and the necessity of the immunosuppressive drugs are 2 main obstacles.  To solve these issues, these researchers performed islet xenotransplantation using encapsulated neonatal porcine islets without immunosuppressive drugs.  Two different doses (approximately 5,000 IEQ/kg and 10,000 IEQ/kg) of encapsulated neonatal porcine islets were transplanted twice (total approximately 10,000 IEQ/kg and 20,000 IEQ/kg) into 4 T1DM patients in each group (total 8 patients).  In the higher dose group, all 4 patients improved HbA1c.  This was maintained at a level of less than 7 % for greater than 600 days with significant reduction of the frequency of unaware hypoglycemic events.  These investigators did not evaluate the maturity of neonatal islets before transplantation, however; they plan to evaluate the maturity of neonatal islets before transplantation for the next clinical trial.  The authors concluded that encapsulated neonatal porcine islet xenotransplantation could maintain HbA1c less than 7 % with significant reduced hypoglycemic events without immunosuppression greater than 600 days.  They believed this study is the prologue for the clinical xenotransplantation to solve the issue of donor shortage.

Pancreas Transplantation With Exocrine Drainage Through a Duodenoduodenostomy Versus Duodenojejunostomy

Lindahl and colleagues (2018) noted that until recently, pancreas transplantation has mostly been performed with exocrine drainage via duodenojejunostomy (DJ).  Since 2012, DJ was substituted with duodenoduodenostomy (DD) in the authors’ hospital, allowing endoscopic access for biopsies.  This study assessed safety profiles with DD versus DJ procedures and clinical outcomes with the DD technique in pancreas transplantation.  DD patients (n = 117; 62 simultaneous pancreas-kidney [SPKDD ] and 55 pancreas transplantation alone [PTADD ] with median follow-up of 2.2 years) were compared with DJ patients (n = 179; 167 SPKDJ and 12 PTADJ ) transplanted in the period 1998 to 2012 (pre-DD era).  Post-operative bleeding and pancreas graft vein thrombosis requiring re-laparotomy occurred in 17 % and 9 % of DD patients versus 10 % (p = 0.077) and 6 % (p = 0.21) in DJ patients, respectively.  Pancreas graft rejection rates were still higher in PTADD patients versus SPKDD patients (p = 0.003).  Hazard ratio (HR) for graft loss was 2.25 (95 % confidence interval [CI]: 1.00 to  5.05; p = 0.049) in PTADD versus SPKDD recipients.  The authors concluded that compared with the DJ procedure, the DD procedure did not reduce post-operative surgical complications requiring re-laparatomy or improve clinical outcomes after pancreas transplantation despite serial pancreatic biopsies for rejection surveillance.  It remains to be seen whether better rejection monitoring in DD patients translates into improved long-term pancreas graft survival.

Pantoprazole plus Sitagliptin for Restoration of Insulin Independence in Islet Transplant Recipients with Early Graft Insufficiency

Senior and associates (2017) stated that resuming insulin use due to waning function is common after islet transplantation.  Animal studies suggested that gastro-intestinal (GI) hormones, including gastrin and incretins may increase β-cell mass.  In a single-center, uncontrolled, open-label, pilot study, these researchers tested the hypothesis that pantoprazole plus sitagliptin (pantoprazole 40 mg twice- plus daily sitagliptin 100 mg daily for 6 months), would restore insulin independence in islet transplant recipients with early graft insufficiency and determined whether this would persist after a 3-month washout.  After 6 months of treatment, 2 of 8 participants (25 %) achieved the primary end-point, defined as HbA1c of less than 42 mmol/mol (6 %), fasting plasma glucose of less than 7.0 mmol, C-peptide of greater than 0.5 nmol and no insulin use.  There was a significant reduction in mean insulin dose, but no change in HbA1C or weight.  There were no changes in the acute insulin response to arginine, the mixed meal tolerance test or blinded continuous glucose monitoring.  After the washout, no participants met the primary end-point and HbA1C increased from 45 ± 8 mmol/mol (6.3 ± 0.7 %) to 51 ± 6 mmol/mol (6.8 ± 0.6 %) (p < 0.05); 2 participants had mild-moderate transient GI side effects.  There were no episodes of hypoglycemia.  The authors concluded that sitagliptin plus pantoprazole was well-tolerated and safe and may restore insulin independence in some islet transplant recipients with early graft insufficiency, but this was not sustained when treatment was withdrawn.  They stated that a larger, controlled trial is needed to confirm the effectiveness of this combination to achieve insulin independence and to confidently exclude any persistent benefit for graft function.

Total Pancreatectomy with Islet Autotransplantation for the Treatment of Chronic Pancreatitis

Berman and co-workers (2019) noted that painful chronic pancreatitis (CP) is the main indication for analgesic pancreatectomy with simultaneous islet autotransplantation to prevent post-operative diabetes mellitus (DM). However, advanced CP may lead to insulin secretion disorders and DM. There are doubts as to whether islet autotransplantation in such cases is an appropriate procedure. These researchers analyzed the findings of islet autotransplantation in patients with CP with already diagnosed with DM.  Between 2008 and 2015, at the Department of General and Transplantation Surgery, patients with CP and unsatisfying pain treatment with positive fasting C-peptide (greater than 0.3 ng/ml) level were qualified for simultaneous pancreatectomy and islet autotransplantation; 8 procedures were performed.  In 5 cases, patients had DM diagnosed prior to the procedure (DM group n = 5); 3 patients without DM diagnosed prior to surgery were the control group (n = 3).  There were no cases of procedure-related deaths in either group. Pain relief without analgesics was reported by all patients. Good islet function was observed in 80 % (4/5) of the DM group versus 100 % (3/3) in the control group (p = ns). Brittle diabetes was diagnosed in 1 patient in the DM group as a result of islet primary non-function.  The authors concluded that patients with CP-related severe pain and DM patients with positive C-peptides should be considered for pancreatectomy and islet autotransplantation.

Kempeneers and associates (2019) stated that the rationale for total pancreatectomy in painful, treatment refractory CP is pain control. Concomitant islet cell autotransplantation could prevent the loss of islet cell function. In a systematic review and meta-analysis, these researchers examined the impact of total pancreatectomy with islet autotransplantation (TPIAT) on pain and quality of life (QOL). This meta-analysis was carried out according the Meta-analyses of Observational Studies in Epidemiology guideline. The Cochrane Library, PubMed, and Embase were searched for the following terms (1990 through April 2018): total pancreatectomy and chronic pancreatitis. Studies were included when addressing TPIAT for chronic pancreatitis in adults. Studies that reported no data on pain, endocrine function, or QOL were excluded. Quality was assessed using the Newcastle-Ottawa scale for evaluation of all studies. These investigators included 15 observational studies evaluating 1,255 patients, of whom 28 % had had endoscopic and 23 % operative therapy. One year after TPIAT, the opioid-free rate had improved from between 0 % and 15 % to 63 % (95 % CI: 46 to 77), and the insulin-free rate had decreased from between 89.5 % and 100 % to 30 % (95 % CI: 20 to 43). An alcoholic etiology was associated with a lesser insulin-free rate after TPIAT; QOL improved statistically after TPIAT.  Publication bias was present for both opioid and insulin outcomes.  The authors concluded that in selected patients with painful, treatment refractory CP, evidence showed that TPIAT was effective for pain control in almost 2/3 of patients, whereas the insulin-free rate was relatively low.

Abu-El-Haija and colleagues (2020) noted that advances in the understanding of TPIAT have been made.  These investigators defined indications and outcomes of TPIAT. Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address 6 questions selected by the writing group as high priority topics.  A consensus was reached by voting on statements generated from the review.  Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve QOL, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact DM outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery.  The authors concluded that agreement on TPIAT indications and outcomes has been reached through this working group; further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

48160 Pancreatectomy, total or subtotal, with autologous transplantation of pancreas or pancreatic islet cells
48550 Donor pancreatectomy (including cold preservation), with or without duodenal segment for transplantation
48551 Backbench standard preparation of cadaver donor pancreas allograft prior to transplantation, including dissection of allograft from surrounding soft tissues, splenectomy, duodenotomy, ligation of bile duct, ligation of mesenteric vessels, and Y-graft arterial anastamoses from iliac artery to superior mesenteric artery and to splenic artery
48552 Backbench reconstruction of cadaver donor pancreas allograft prior to transplantation, venous anastamosis, each
48554 Transplantation of pancreatic allograft
48556 Removal of transplanted pancreatic allograft

CPT codes not covered for indications listed in the CPB:

0584T Islet cell transplant, includes portal vein catheterization and infusion, including all imaging, including guidance, and radiological supervision and interpretation, when performed; percutaneous
0585T     laparoscopic
0586T     open

Other CPT codes related to the CPB:

80069 Renal function panel
82947 Glucose; quantitative, blood (except reagent strip)
82948     blood, reagent strip
82950     post glucose dose (includes glucose)
82962 Glucose, blood by glucose monitoring device(s) cleared by the FDA specifically for home use

HCPCS codes not covered for indications listed in the CPB:

G0341 Percutaneous islet cell transplant, includes portal vein catheterization and infusion
G0342 Laparoscopy for islet cell transplant, includes portal vein catheterization and infusion
G0343 Laparotomy for islet cell transplant, includes portal vein catheterization and infusion
S2102 Islet cell tissue transplant from pancreas; allogeneic

ICD-10 codes covered if selection criteria are met:

E08.649 Diabetes mellitus due to underlying condition with hypoglycemia without coma
E10.10 - E10.9 Type 1 diabetes mellitus
E11.00 - E11.9 Type 2 diabetes mellitus
E15 Nondiabetic hypoglycemic coma
E16.0 - H16.2 Hypoglycemia
E79.0 Hyperuricemia without signs of inflammatory arthritis and tophaceous disease
E87.2 Acidosis
E89.1 Postprocedural hypoinsulinemia
K86.0 - K86.1 Chronic pancreatitis
R78.71 Abnormal lead level in blood
R78.79 Finding of abnormal level of heavy metals in blood
R78.89 Finding of other specified substances, not normally found in blood
R79.0 Abnormal level of blood mineral
R79.9 Abnormal finding of blood chemistry, unspecified
Z79.4 Long term (current) use of insulin
Z90.410 Acquired total absence of pancreas
Z90.411 Acquired partial absence of pancreas

The above policy is based on the following references:

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