Pancreas Transplantation

Anatomy and Physiology

The pancreas plays a key role in the digestion, absorption, utilization, and storage of energy substrates. It consists of 2 parts, the exocrine and endocrine pancreas, which are structurally distinct but functionally integrated glandular systems. Both parts arise from the primitive gut. Neural and hormonal signals control secretion by the exocrine pancreas through gastrointestinal peptides. Islet cells are interspersed in the exocrine pancreas.[8] The exocrine part is important for nutrient digestion, and the endocrine is critical for regulating glucose homeostasis. The endocrine portion consists only of 2% of the pancreas and comprises different types of endocrine cells called islets of Langerhans.  

Each islet has at least 5 types of cells, which are insulin-producing β-cells (65% to 80%), the glucagon releasing α-cells (15% to 20%), the somatostatin producing δ-cells (3% to 10%), pancreatic polypeptide-containing PP cells (1%), and the ghrelin containing ε-cells (<1%).[9] The exocrine pancreas comprises acinar and ductal cells, organized in lobular branched tissue architecture, which secrete and transport digestive enzymes into the duodenum.[10]

The human pancreas is a solitary organ, 14 to 18 cm long, 2 to 9 cm wide, and 2 to 3 cm thick, weighing 50 to 100 g, and can be divided into 3 major parts, which are the head, the body, and the tail with no clear-cut borders between these parts. The border between the head and the body is made by the left border of the superior mesenteric artery, whereas the midpoint of the body and tail combined marks the border between the body and the tail. Some authors distinguish a fourth and a fifth part, which are parts of the head. The uncinate process is located beneath the SMA, and the neck or isthmus, a thinned part, is situated over the SMA. The head of the pancreas is a C-shaped part aligned with the upper curvature of the duodenum. The flat body of the pancreas is situated behind the stomach, extending almost horizontally in the medial plane. The body of the pancreas crosses main vessels, including the abdominal aorta, inferior vena cava, portal vein, superior mesenteric artery, and superior mesenteric vein. The pancreatic tail lies in the hilum of the spleen. The pancreas is surrounded by a fibrous capsule that gives rise to connective tissue septa, which divides its parenchyma into lobes and lobules. Mesenchymal tissue of the pancreas makes up approximately 15% to 25% of the total pancreas volume and contains numerous fat cells.[11]

Indications

Various methods of pancreatic transplantation are:

1. Pancreatic transplant alone (PTA)
2. Simultaneous pancreas and kidney transplant (SPK)
3. Pancreas after kidney transplant (PAK)
4. Simultaneous deceased pancreatic donor and live kidney donor transplant [12] 

Indications for pancreas transplant alone are severe complications of diabetes mellitus with frequent and severe hypoglycemia or ketoacidosis. Poor quality of life despite insulin therapy. These patients have adequate renal function and no uremia. Patients with a glomerular filtration rate of 80 to 100 mL/min/1.73 m² are unlikely to need a kidney transplant. For the simultaneous pancreas-kidney transplant, the organs come from the same deceased donor. According to UK Transplant Kidney and Pancreas, Advisory Group indication for SPK is the patients with type 1 diabetes with end-stage renal failure on dialysis or requiring dialysis within 6 months. After a kidney transplant a pancreas transplant is performed after a previous kidney transplant from a different, living, or deceased donor. Indication for PAK is in patients who match the criteria for pancreas-alone transplant and also have previously working kidney transplants. It is also noted that the waiting time and mortality rate are reduced as compared to simultaneous pancreas-kidney transplant patients. The main benefit of a simultaneous deceased donor pancreas and live donor kidney is having a lower rate of delayed graft function than an SPK and significantly reduced waiting times, which results in improved outcomes compared to patients waiting for a simultaneous pancreas-kidney transplant.[12]

SPK is now the first choice of treatment in a patient with type 1 diabetes mellitus and related end-stage renal disease. Pancreas-alone transplants can be done in patients with preserved kidney function and hypoglycemic unawareness.[13] SPK is done in insulin-treated diabetic patients having end-stage renal disease with GFR < 20ml/min or on dialysis. There is increasing evidence that SPK is associated with improved quality of life, although it is never subjected to a randomized control trial. Kidney transplant alone for diabetic nephropathy has a poor prognosis. The decision in such patients is whether to do a kidney transplant alone with a subsequent pancreas transplant instead of a combined operation is dependent on several factors, eg, availability of potential living donor, the urgency to come off dialysis, waiting time for an SPK. Currently, SPK and PAK are offered to people with insulin-dependent diabetes (type 1 or type 2) with chronic renal failure.[7] 

SPKs are being increasingly performed in type 2 diabetes mellitus patients and in patients of advanced age, with excellent results.[14] One of the indications of pancreas transplantation is unstable glycemic control, particularly hypoglycemia unawareness.[7] PTA can be done in type 1 diabetes with preserved kidney function in case of hypoglycemic unawareness. PTA is also done in patients having frequent and severe episodes of hypoglycemia (more than 2 severe hypoglycemic episodes within the last 24 months) or assessed by diabetologists to have disabling hypoglycemia or significant impairment of quality of life due to diabetes. PAK is done in patients with insulin-treated diabetes who have a stable function after a previous renal allograft and meet the criteria for PTA.[14]

The number of pancreas transplants has decreased in the past decade, but the outcomes have improved for all groups of pancreas transplants, mainly due to improvements in immunosuppression, surgical technique, and donor-recipient selection. The decrease in pancreas transplants in the past decade can be due to improved insulin delivery systems, concerns about outcomes after solitary pancreas transplants, and a renewed interest in islet transplants. The most noticeable decrease is noted in the PAK and PTA groups, possibly due to decreased donors.[2] Pancreas survival after PAK is less than the pancreas survival in SPK.[15] As non-surgical diabetes management has improved, whether patients benefit from PTA has become unclear.[2] The need for chronic immunosuppression and the risk of surgical complications make pancreas transplant an option only for a selected group of diabetic patients who have chronic renal failure, extrarenal complications, or struggle against difficult metabolic indices control.[16]

Contraindications

Absolute contraindications for pancreas transplant include:

• Age over 65
• Major cardiovascular risk is defined as uncorrectable significant coronary artery disease
• Myocardial infarction within 6 months
• Left ventricular ejection fraction <30%, pulmonary artery systolic pressure over 50mm Hg
• Incurable malignancy except localized skin cancer, low-grade prostate cancer
• Active sepsis
• Peptic ulcer disease
• Immune suppression
• A major psychiatric history which can result in nonadherence to the treatment
• Any inability to withstand surgery

Relative contraindications for pancreas transplant include:

• Cerebrovascular accident with long-term impairment
• Active infection of hepatitis B or C virus
• Body mass index >30 kg/m
• Insulin requirements >1.5 units/kg per day
• Extensive aorta/iliac and/or peripheral vascular disease
• Continued abuse of alcohol, tobacco, or drugs [7]

Preparation

The donor selection criteria are more strict for pancreas transplantation as compared to other organs, thus limiting potential donors. The donor organ may be rejected due to alcohol intake, a family history of diabetes, or elevated serum amylase. Pancreas with fibrosis or fat deposition upon retrieval is discarded because they are associated with severe reperfusion pancreatitis, resulting in morbidity and mortality. Donors with a body mass index >30 kg/m² are declined for donation. Pancreas from young donors is preferred, up to the age of 60 years, for solid organ transplantation. The pancreas is very vulnerable to sustaining an injury during retrieval, which leads to higher discard rates.[7]

To obtain better results, the selection of deceased donors is made as close as possible to match the ideal donor criteria. Therefore, adequate maintenance of the potential brain death donor is necessary to avoid hemodynamic instability. Blood compatibility in the ABO system and negative crossmatching, and an age range between 5 and 50 years is required for the donors. If the pancreas is retrieved without the liver, the donor should weigh between 30 and 50kg and >50kg if both pancreas and liver are procured. Signs of acute pancreatitis, glandular edema, hematoma, fatty infiltration, and hardened consistency are considered in the macroscopic evaluation of the pancreas as such factors increase the risk of post-transplant complications. Type 1 diabetes, pancreatic disease, prior surgery of the duodenum, pancreas, or splenectomy, malignant tumor, positive serology for infectious diseases (acquired immunodeficiency syndrome, hepatitis B and C), chronic liver disease, body mass index >40kg/m², and history of chronic alcohol abuse are other factors that might determine the exclusion of donors.[6]

 Transplant teams have extended their donor criteria due to the increasing lack of availability of transplant organs and high graft demand, and this has led to the inclusion of more high-risk groups. However, this can result in high rates of graft rejection and low graft survival after transplantation. The pre-procurement pancreas allocation suitability score (P-PASS) has been used within the Eurotransplant area to identify suitable donors. The Eurotransplant Pancreas Advisory Committee designed  P-PASS, a calculated score based on 9 donor-specific clinical parameters. These specific clinic parameters include patient age, body mass index, the occurrence of cardiac arrest, serum levels of sodium, amylase, lipase, adrenaline, and dopamine, and the length of stay in the intensive care unit. The preoperative donor risk index (DRI) was initially used for quantification of the risk of liver graft failure after liver transplantation. The pancreas donor risk index (pDRI) is a modified form of the DRI specific for pancreas transplantation, and it is used to help predict outcomes after a pancreas transplant. The pDRI, like DRI used for the liver, consists of the specific donor characteristics that include gender, body mass index, serum creatinine, height, age, race, cause of death, donation after cardiac death, and the parameter of pancreas preservation time. P-PASS and pDRI are used to know whether or not an organ is acceptable for transplantation. The Eurotransplant now recommends that pancreas grafts from donors with a P-PASS score of <17 should be considered for organ transplantation because they have a 3-times higher acceptance rate as compared to grafts with a P-PASS score of  ≥17.[17]

The number of new candidates on the pancreas waiting list kept increasing until 2000, after which it started decreasing until 2011, when only 1,005 candidates were added to the waiting list as active candidates. A new patient is put 1 of the 3 lists (SPK, PTA, PAK) in the given year without being listed in the previous year. Patients listed in more than one list or at multiple centers are counted once.[18] The waiting list for pancreas transplants is growing in many countries. The NHS Blood and Transplant showed that over 250 patients were waiting for transplantation in March 2015.[12] More recent data from around the world suggests swelling waiting lists.

Technique or Treatment

A pancreas and a kidney can be transplanted serially or simultaneously. The procedure takes 3-4 hours when the pancreas alone is transplanted, while if combined with the kidney, it takes 6-8 hours. The kidney is placed on the left of the abdomen, while the pancreas is on the right. The native pancreas and kidneys are left in place. The blood vessels of the new pancreas are connected to the iliac vessels. The pancreas has 2 arterial supplies, so a ‘Y’ graft is created using donor arteries, which allow both to be supplied from a single arterial anastomosis. A connection between the small intestine and the pancreas is made so that the digestive juices produced by the pancreas can be drained by it. A segment of the donor duodenum already joined to the pancreatic head is used for this purpose. All of this is done through either 1 incision in the abdomen or 2 along either groin.[12]

Retrieval of the pancreas from a donor is generally part of the removal of multiple intra-abdominal organs. A combined liver and pancreas graft is removed using a unique technique. After the liver is removed, the pancreas is removed en bloc, along with the duodenum and spleen, and the vascular stumps of the superior mesenteric and splenic arteries are preserved, and that of the portal vein. The pancreatic and vascular grafts are then immersed in 1L of Belzer solution. The pancreatoduodenal graft is prepared by removing the spleen. The duodenal segment is shortened, with invagination of the duodenal borders, mobilization of the portal vein is done, and vascular Y graft reconstruction is done, which involves using iliac arteries from the donor with the pancreatic graft superior mesenteric artery and splenic artery. The preferential access route is midline laparotomy. The pancreas transplant is preferentially done in the right iliac fossa of the recipient, as the right iliac vessels are more accessible. The pancreas can be drained by systemic or portal venous blood. Drainage of exocrine secretion of the graft can be enteric in the form of side-to-side duodenojejunal anastomosis or involving the bladder in the form of side-to-side duodenovesicular anastomosis.[6]

The surgical techniques of pancreas transplantation have changed over the years. Most of the transplant units around the world now transplant the solid pancreas together with a segment of the duodenum. The superior mesenteric and splenic arteries are attached to a Y graft from the bifurcation of the donor common iliac artery as arterial inflow. Venous drainage is to the common iliac vein or inferior vena cava. Some units also drain venous fluids into the portal venous system. Drainage of the pancreatic exocrine secretion has always been the main problem in pancreas transplantation. Various technical modifications have been developed. The body and tail of the pancreas with pancreatic duct occluded can be transplanted into the bladder, jejunum, or stomach. Another way is to transplant the whole organ with a segment of the duodenum into the urinary bladder, jejunum, or duodenum.[7]

Monitoring pancreatic graft is challenging as there is no simple marker of early graft injury with no equivalent to GFR in kidney transplantation. Hyperglycemia is a late event and means significant and irreversible graft injury. Basal and stimulated C-peptide levels measure graft function. An increase in serum amylase and lipase levels relevant to graft rejection is unknown. In SPK, kidney graft function is used as a surrogate for pancreatic graft, assuming the changes also occur in the pancreas, although discordant graft rejection is also known. In the bladder drainage technique, amylase production can be used to measure graft function, and a biopsy of donor duodenum can also be taken by cystoscopy. Alteration in urinary amylase levels is associated with impairment in pancreatic graft function, but it should be balanced against the urological and biochemical complications of bladder drainage. In empirically drained pancreatic grafts, a percutaneous radiologically guided biopsy is now increasingly advocated and appears safe; however, monitoring the graft remains a problem.[7]

In the classic technique, the venous outflow from the pancreas allograft is directed to the recipient's iliac vein. This endocrine drainage into the systemic circulation causes hyperinsulinemia, which may lead to accelerated atherosclerosis. Another technique is using portal venous drainage through the superior mesenteric vein. It not only provides venous outflow similar to that of a native pancreas but also has the theoretical advantage of delivering allograft antigens to the liver. The delivery of antigens to the liver by the portal vein induces immunotolerance in the recipient. According to initial reports, rejection rates are lower in pancreases drained through the portal vein than in those drained into the systemic circulation.[19] Whole-pancreaticoduodenal grafts have been standard in pancreas transplants since the mid-1980s. The duodenal segment is an important component of the pancreatic graft because it permits safe drainage of exocrine secretions.[16]

The immunosuppression in pancreas transplantation is similar to any other solid organ transplantation. Most units start induction with thymoglobulin, alemtuzumab, or basiliximab, followed by tacrolimus and mycophenolate. Steroids are also used in some units. Up till now, there is no conclusive evidence regarding optimal induction therapy.[7] Higher levels of immunosuppression are thought to be required in those receiving pancreas transplantation, possibly due to the increased immunogenicity of the pancreas and/or autoimmune status of the recipient.[14]

 Patients received modern induction therapy, either interleukin (IL)-II receptor antagonist or anti-thymocyte globulin, from March 1999. Now, induction therapy consists of an anti-CD52 monoclonal antibody (alemtuzumab), which was first started in December 2007. Before 1999, patients received either anti-CD3 antibody (OKT3) or no induction therapy. Recipients are given a combination therapy of tacrolimus and mycophenolate mofetil as maintenance therapy. Recipients received cyclosporine, azathioprine, and prednisone until 1996. The routine administration of prednisone was stopped in 2008. Patients are given a low dose of low molecular weight heparin twice daily, and it was started in 2008 as prophylaxis to prevent graft thrombosis. Before that, regular antithrombotic therapy was given at the same dose once daily. Patients are given vitamin K antagonists for at least 3 months due to partial graft thrombosis. Computed tomography imaging is done between the fourth and seventh days after transplantation, depending on renal (graft) function.[13]

Complications

Pancreas transplantation is related to high procedure-specific morbidity and mortality, with many complications requiring reoperations, including hemorrhage, sepsis, pancreatitis, and thrombosis. Venous thrombosis was once a major cause of morbidity, but now monitoring the coagulation has overcome it. The ischemia-reperfusion injury also occurs in the form of reperfusion pancreatitis, leading to sepsis and exocrine leakage in some cases. Mycotic aneurysm formation due to infection of the vascular anastomosis also occurs, and greater risk in pancreas transplantation is possibly due to the contamination by enteric organisms at the time of organ retrieval or at the time of enteric anastomosis.[7] The pancreas transplant community suggests that anticoagulation is essential during the perioperative periods in non-uremic recipients.

During the surgery, as in any other operation, there is a risk of bleeding, which can occur in approximately 5% of patients. Thrombosis is the most common cause of non-immunogenic graft failure, with an incidence of 10 to 35% in the literature, but the appropriate use of anticoagulants such as heparin, citrate, or epoprostenol can reduce it. Other complications include enteric anastomotic leak, graft pancreatitis, pancreatic-enteric fistula, and intra-abdominal sepsis. Cardiac morbidity and postoperative infections are some other complications. Rejection rates are in the range of 5 to 25%. It depends on the type of immunosuppression regimen being used. Acute rejection is a risk factor for chronic rejection (10% for pancreas transplant alone and 4% for the simultaneous pancreas-kidney transplant).[12]

Risk factors for rejection include nonprimary SPK transplants, race mismatch, increasing donor age, and primary pancreas transplant alone (PTA). Surveillance biopsies in such cases may be indicated. Biopsy of the graft allows the surgeon to identify rejection accurately, and therefore, it should be used for pancreas transplant monitoring. Clinical parameters that include hyperglycemia, C-peptide level, hemoglobin A1C, serum amylase, lipase, and urinary amylase in case of bladder drainage can not be used alone, and these are not very helpful because they are either too late or nonspecific. The biopsies from the renal graft alone in SPK patients don't determine the pathologic condition of the pancreatic graft. After SPK transplantation, the similarities between pancreas graft biopsies and kidney grafts are not 100%, and grafts can show different types and degrees of rejection.  Results of a biopsy taken from a duodenal cuff and pancreas parenchymal biopsy can also differ. The most commonly performed biopsy technique for the pancreas transplant is a percutaneous ultrasound-guided biopsy. This can be done safely and effectively in bladder-drained and enterically drained transplants.[14]

Imaging plays a major role in assessing and evaluating thrombosis in the pancreatic graft. Commonly used imaging is Doppler ultrasound, contrast-enhanced ultrasound, CT angiography, MRI, and MR angiography. Thrombosis may affect arteries or veins and can be classified as complete or partial. Complete thrombosis results in graft loss until the thrombectomy is done urgently, while partial loss can be treated with anticoagulants. Outcomes after the complete thrombosis of the portal vein are worse than the partial thrombosis of the splenic or superior mesenteric vein.[20] The pancreas transplant procedure is complex, and it is associated with significant mortality and morbidity. Postoperative complications of pancreatic transplantation are still common despite many improvements in surgical techniques. These complications include graft rejection, pancreatitis, peripancreatic fluid collections, exocrine leaks, vascular thrombosis, and hemorrhage.[21]

Duodenal graft complications (DGC) can also occur in some 20% of pancreatic transplant recipients.[16] The primary complication, which can result in pancreatic graft loss, is a technical failure followed by acute or chronic rejection. Technical failure is recognized as the loss of the graft in the first 3 months of a transplant, which may be due to vascular thrombosis (50%), pancreatitis (20%), infection (18%), fistulas (6.5%), and hemorrhage (2.4%). Rejection is the main complication that results in graft loss in PAK and PTA recipients. Other complications include infection and dehiscence of the abdominal wall. 10 to 20% of surgical complications after pancreas transplant require a review laparotomy. The risk factors for surgical complications are prolonged time in peritoneal dialysis,  donor or recipient having a body mass index >28kg/m² for a donor or recipient age over 45 years, prolonged preservation time (>20 hours), cerebrovascular disease as a cause of donor death, retransplantation, and prior abdominal surgery. Pancreatic transplants with vesical drainage can result in severe urological and metabolic complications.

Approximately 10 to 25% of patients having pancreatic transplants with bladder drainage are converted to intestinal drainage of the graft. The main metabolic complications that occur in bladder drainage is metabolic acidosis and dehydration due to loss of water and sodium bicarbonate in the urine. Adequate fluid and bicarbonate replacement in the follow-up of pancreatic transplants with bladder drainage is required. One of the main complications in pancreatic transplants with intestinal drainage is an intestinal leak because it poses risks to the patient's survival. It mostly occurs during the immediate postoperative period, and the incidence of the intestinal leak is 5 to 8%. The early leak is due to technical problems, which include impaired blood irrigation and ischemia. The risk factors for an early intestinal leak are prolonged cold ischemia time, duodenal trauma, postreperfusion pancreatitis, and intra-abdominal infection. Its treatment generally results in the removal of the pancreatic graft. 

The criteria for diagnosing pancreatic graft rejection include high serum creatinine levels (SPK), decreased urinary amylase in bladder-drained grafts, and high serum lipase levels. Pancreatic biopsy done ultrasound-guided is the gold standard used for diagnosis of rejection. Infectious complications are the primary causes of morbidity and mortality in pancreas transplantation. The most frequent is a bacterial infection, and the abdominal wall and urinary tract are most commonly affected. Patients with pancreas transplants have a high risk of developing an infection by cytomegalovirus due to antilymphocyte serum in immunosuppression therapy. The mean incidence is 25%. Early diagnosis of the type of infection, especially fungal infection, is important for treatment success. Antibiotics, antifungal, and antiviral agents are recommended for use in such cases. In the late phase, chronic rejection and infections are major complications.[6]

Clinical Significance

Patient survival is more than 96% at 1 year after transplant and more than 83% at 5 years after transplant. The longest surviving graft was recorded as SPK transplant 26 years, 24 years pancreas after a kidney, and 23 years for pancreas transplant alone. According to the Diabetes Control and Complications Trial, pancreas transplantation restores glycemic control by lowering HbA to within normal limits even after 10 years, with mean HbA at 6 years being 42 mmol/L as compared to 55 mmol/L of patients being treated by intensified insulin regimes, with several studies showing improvement in lipid metabolism.[12]

The only available treatment that can restore long-term normoglycemia without the risks of hypoglycemia is pancreas transplantation. Diabetic glomerular lesions dramatically improve at 10 years post pancreas transplantation.[22] Patients with diabetes and end-stage renal disease have excessive morbidity and mortality, and SPK transplant has shown significant improvement in the quality of life and life expectancy of such patients.[14] Improvements in neurological function in diabetic patients after 24 months of stable transplant have been found. Pancreas transplantation improves cardiac outcomes and reduces diabetic lesions in kidney transplants in type 1 diabetic patients. It also improves the quality of life, neuropathy, retinopathy, and healing of certain skin lesions.[23]

Enhancing Healthcare Team Outcomes

Pancreas transplantation offers a cure for type 1 diabetes mellitus and not only helps patients maintain glycemic control but also prevents secondary diabetic complications. It is a procedure associated with high morbidity and mortality, although, in the past decade, graft survival rates have increased due to advancements in surgical techniques and better regimens of immunosuppression. Although surgeons play a pivotal role in pancreas transplantation, multiple disciplinary approaches are needed in caring for such patients, including endocrinologists, nephrologists, specialized nurses, and other supporting staff.

 Several studies have been done on long-term results after pancreas transplantation. Sutherland et al (2001) described it first with the help of a large series. Twenty-two years of follow-up of 1000 pancreas transplantations in Wisconsin was reported by Sollinger et al, followed by more recent reports describing risk factors and long-term experiences. The largest European series came from Innsbruck, Austria, which reported 509 consecutive pancreas transplantations with long-term follow-up results. After comparing results from different transplant centers, it is found that no standard definition of pancreas graft survival is being used, making comparison difficult. The Pancreas Transplant Committee of the Organ Procurement Transplantation Network in 2008 emphasized having a unified definition of pancreas graft function and failure for global use. Mandal showed in 2004 that low-volume pancreas transplantation centers (<10 transplantation/year), as compared to medium (10 to 20 transplantations/year) or high (>21 transplantations/year) volume centers, have a poorer outcome in graft survival.[13]

Pancreas transplantation rates have dropped despite increased survival over the past decade.[14] This can be increased if the organ donation campaign is improved and the donor pool is expanded using less-than-ideal donors such as deceased donors, living donors, and pediatric donors.[24] Being better informed and trained about the benefits and risks of pancreas transplantation makes doctors advise, inform, and refer patients for transplants. They can also better manage the challenges that patients have during treatment.[12]

Nursing, Allied Health, and Interprofessional Team Interventions

Regular examination and blood workups are essential to managing transplant patients after they get discharged from the hospital in the outpatient setting. Careful follow-up and effective communication between the transplant center and the primary care settings help in the diagnosis of complications such as sepsis and rejection. Patients' blood sugar and amylase levels should be monitored because sharp rises in these markers are signs of potential complications that should not be ignored. Other preventive measures include relevant vaccinations during travel, treatment for infection on the appearance of first signs and symptoms, and immediate assessment of patients are essential to avoid prolonged hospital stays. In the management of such patients, doctors and nurses need awareness regarding drug interactions, especially in the context of immunosuppressants and poly-pharmacy.[12]