List of Abbreviations
anti-HLA – antibodies to human leukocyte antigen major histocompatibility complex
aPTT – activated partial thromboplastin time
HIV – human immunodeficiency virus
DNA – deoxyribonucleic acid
CNI – calcineurin inhibitors
BMI – body mass index
CT – computed tomography
DGF – delayed graft function
P – pancreas
РКИ – randomized controlled trial
DM – diabetes mellitus
GFR – glomerular filtration rate
KT – kidney transplantation
PT – pancreas transplantation
US – ultrasound examination
CKD – chronic kidney disease
CVP – central venous pressure
ECG – Electrocardiography recording, transcription, description, and interpretation of electrocardiographic data
HLA – human leukocyte antigen, human major histocompatibility complex
Terms and Definitions
Pancreas transplantation – a surgical procedure and replacement therapy method consisting of transplanting a pancreas obtained from another human.
Pancreas recipient – a patient who has undergone pancreas transplantation.
Pancreas graft rejection – a pathological process in which the recipient's immune system recognizes the pancreatic graft as a foreign object, activating antibody-mediated (humoral) and/or cellular inflammatory response systems, which can lead to marked organ dysfunction.
Diabetes mellitus – a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both, accompanied by damage, dysfunction, or failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
Type 1 diabetes mellitus – a carbohydrate metabolism disorder caused by the destruction of pancreatic β-cells.
Chronic kidney disease – kidney damage or decreased function lasting for 3 months or more. The disease is classified into 5 stages, which differ in patient management tactics and the risk of developing end-stage renal failure and cardiovascular complications.
1. Brief information on the disease or condition
These guidelines describe medical care technologies involving examinations aimed at selecting management tactics for patients with type 1 diabetes mellitus with various complications, including end-stage chronic kidney disease, determining indications for pancreas transplantation, queue prioritization for inclusion in the waiting list, and stabilizing the clinical condition and assessing the feasibility of patient recovery/rehabilitation after pancreas transplantation surgery.
1.1 Definition of the disease or condition
Pancreas transplantation – a type of replacement therapy in patients suffering from type 1 diabetes mellitus with target organ complications, consisting of the transplantation of an allogeneic pancreas or part of it.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
To date, the number of patients with DM worldwide has reached over 415 million. According to International Diabetes Federation projections, by 2040 more than 640 million people will suffer from DM. In the Russian Federation, as in all countries worldwide, there is a marked increase in detected DM cases. According to the federal DM register, at the end of 2016, 4.35 million people (3.0% of the population) were under dispensary observation in the RF, of whom: 92% (4 million) had type 2 DM, 6% (255 thousand) had type 1 DM, and 2% (75 thousand) had other types of DM. Various complications of diabetes mellitus pose the greatest danger, especially its systemic vascular complications—nephropathy, retinopathy, lesions of major heart and brain vessels, and peripheral vessels of the lower extremities. These very complications are the leading cause of disability and mortality in DM patients. The presence of chronic kidney disease as a complication of type 1 diabetes mellitus allows this category of patients to be considered as potential kidney and pancreas recipients. Simultaneous kidney and pancreas transplantation aims to improve the quality of life of patients with type 1 diabetes mellitus and prevent the development of diabetic nephropathy in the renal graft.
1.3 Epidemiology of the Disease or Condition
By October 1990, 1021 pancreas transplantations in various modifications had already been registered worldwide. According to the International Pancreas Transplant Registry, by 1998 there were already more than 12,000 cases of PT. By 2016, according to the WHO Global Observatory on Donation and Transplantation, at least 2,342 pancreas transplantations are performed annually, and a steady growth of this type of care by 1.9% annually is also noted. The vast majority of pancreas transplantations are performed from deceased donors (pancreaticoduodenal complex) combined with kidney transplantation, although transplantes of a pancreatic fragment from living related donors have also been registered. The latter type of transplantation is of interest in light of the problem of deceased donor organ shortages, but selecting potential donors for hemipancreatectomy requires extremely thorough screening to rule out the risk of metabolic alterations associated with impaired endocrine function post-surgery.
1.4 Features of Coding the Disease or Condition
Z94.8 – Presence of other transplanted organs and tissues.
T86.8 – Failure and rejection of other transplanted organs and tissues.
1.5 Classification of the disease or condition
Classification according to the source of the donor organ | Pancreas transplantation from a deceased donor | Living-related donor pancreas transplantation |
|---|---|---|
Classification according to the number of previous transplants | Primary pancreas transplantation | Repeat pancreas transplantation |
Classification according to the number of organs transplanted simultaneously | Isolated pancreas transplantation | Simultaneous pancreas transplantation (with other organs: kidney/liver) |
Classification according to organ integrity | Whole pancreas transplantation (or pancreatoduodenal complex) | Segmental (distal) pancreas transplantation |
Classification according to prior kidney transplantation | Simultaneous pancreas-kidney transplantation | Pancreas transplantation after kidney transplantation |
1.6 Clinical presentation of the disease or condition
Patients with type 1 diabetes mellitus and stage 5 chronic kidney disease are considered candidates for simultaneous pancreas-kidney transplantation [1-6, 199].
Patients with type 1 diabetes mellitus who have a functioning kidney graft are candidates for pancreas transplantation after kidney transplantation [1-6, 199-207].
Patients with severe, poorly controlled hyperglycemia are candidates for isolated pancreas transplantation if they have preserved renal function (GFR > 40 mL/min/1.73 m2) [1-6].
Contraindications to pancreas transplantation are similar to those for other organ transplantes. They are divided into absolute and relative contraindications. The former include all preexisting pathological conditions and social circumstances in which surgery may pose an immediate threat to the patient's life or worsen its prognosis.
Pancreas transplantation is not indicated in irreversible obstructive pulmonary disease, decompensated respiratory failure, severe refractory heart failure, progressive degenerative CNS diseases, refractory systemic and local infections (AIDS, hepatitis virus replication, active tuberculosis, etc.), septic conditions, malignant neoplasms, and drug and/or alcohol addiction.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for establishing the diagnosis/condition: based on anamnesis data pathognomonic for diabetes mellitus and chronic kidney disease, physical examination of the patient, and laboratory and instrumental studies confirming the presence of diabetes mellitus, chronic kidney disease, and graft dysfunction.
2.1 Complaints and Anamnesis
It is recommended to carefully collect complaints and medical history from all potential candidates for pancreas transplantation to identify factors that may influence the choice of treatment strategy [7, 8, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: an appointment (examination, consultation) with a general practitioner detailing the full medical history, objective status, and medications taken helps identify any condition that may affect recipient safety during surgery or in the long term, as well as latent or ongoing infection in the recipient that may worsen after transplantation.
It is recommended to refer potential candidates for simultaneous pancreas-kidney transplantation for evaluation before the expected start of dialysis with the aim of pre-emptive simultaneous transplantation [208, 210, 211, 237, 239].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: pre-emptive transplantation is associated with a significantly higher recipient survival rate compared to the non-pre-emptive group [208, 210, 211]. Dialysis during simultaneous pancreas-kidney transplantation worsened patient survival (HR 1.66), especially if the duration of dialysis was 12 months or more [208].
All candidates for pancreas transplantation are recommended to quit smoking before and after transplantation to reduce the risk of graft thrombosis, increase patient and graft survival, and reduce the incidence of cardiovascular complications and malignancies [10-14].
GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
It is not recommended to exclude candidates for simultaneous pancreas-kidney transplantation due to obesity (as defined by BMI). It is recommended to implement weight loss measures in obese candidates prior to transplantation [15-17, 237].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
2.2 Physical Examination
It is recommended to assess the psycho-emotional status of a candidate for pancreas transplantation or simultaneous pancreas-kidney transplantation to identify potential non-compliance [21-23].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: the psychosocial assessment of potential candidates for pancreas transplantation and simultaneous pancreas-kidney transplantation is usually carried out in an interdisciplinary context. This makes it possible to evaluate the patient's psychological and behavioral health, as well as their family and social environment, which can facilitate or hinder adaptation to the complexities and challenges of chronic illness, transplantation, and lifestyle modification.
It is recommended for candidates for pancreas transplantation or simultaneous pancreas-kidney transplantation to have an appointment (examination, consultation) with a surgeon to rule out significant surgical pathology. It is recommended to screen pancreas transplant candidates for conditions that impair wound healing, including obesity, malnutrition, tobacco use, and previous abdominal surgeries, in order to identify risks for wound healing and hernia formation [10, 24-27, 226].
GRC CLOE 2Grade of Recommendation C (Level of Evidence – 2).
Comments: all pancreas transplantation procedures are associated with the risk of wound complications, including infection and hernia formation, which is partly due to the effects of immunosuppressants on wound healing. Diabetes mellitus significantly increases this risk. The incidence of postoperative hernia is about 7% at 10 years and doubles in patients who lead an active lifestyle or are smokers. Wound healing is also affected by the development of superficial and deep tissue infections [24-27].
It is recommended for candidates for pancreas transplantation or simultaneous pancreas-kidney transplantation to have an appointment (examination, consultation) with a dentist to identify indications for oral cavity sanitation prior to transplantation [227-229, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: a dental examination is essential to identify oral infections and sanitize infection foci before transplantation and the initiation of immunosuppressive therapy. Diabetics have an increased risk of periodontal disease [28-31]. According to international protocols of transplant centers, all active dental diseases should be actively treated prior to transplantation, since postoperative immunosuppression reduces the patient's ability to resist systemic infection [227-229, 237].
It is recommended for candidates for pancreas transplantation or simultaneous pancreas-kidney transplantation to have an appointment (examination, consultation) with a urologist to rule out urinary tract pathology, renal, bladder, and prostate cancer [32-34, 176, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended for women over 40 years old to have an appointment (examination, consultation) with an oncologist to rule out breast neoplasm [35, 36, 177, 237].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended that patients with signs or symptoms of active heart disease (e.g., angina pectoris, arrhythmia, heart failure, valvular heart disease – following instrumental and functional diagnostic examinations) be evaluated by a cardiologist and treated in accordance with current clinical guidelines prior to further consideration for pancreas transplantation [3, 7, 8, 37, 178, 237, 239].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended for candidates for pancreas transplantation or simultaneous pancreas-kidney transplantation to have an appointment (examination, consultation) with a neurologist to rule out nervous system pathology, identify and correct diabetic neuropathy, assess residual neurological deficit, determine the timing for safe transplantation, and stratify perioperative risk [2, 38, 179, 254].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: it is suggested to refrain from placing patients on the waiting list earlier than 6 months after a stroke and earlier than 3 months after a TIA. Patients should undergo carotid duplex ultrasound [39-42].
It is recommended that candidates for pancreas transplantation or simultaneous pancreas-kidney transplantation undergo an appointment (examination, consultation) with an endocrinologist to achieve glycemic control, assess and correct diabetes complications prior to transplantation, and rule out other endocrine disorders (such as hyperparathyroidism, etc.) [4, 43, 44, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
2.3 Laboratory Diagnostics
It is recommended to determine the main ABO blood groups and the D antigen of the Rhesus system (Rh factor) in a potential recipient prior to pancreas or pancreas-kidney transplantation to determine donor-recipient blood group compatibility or incompatibility [45-51, 180].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to determine class I and II HLA antigens (genes), perform a crossmatch test based on the recipient's immune antibodies and the donor's major histocompatibility complex antigens, and measure the levels of antibodies against major histocompatibility complex antigens in the recipient's serum to determine donor-recipient compatibility or incompatibility [45-51, 180].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: there must be ABO blood group compatibility and human leukocyte antigen (HLA) matching between the potential donor and recipient, which creates optimal conditions for a successful transplantation. The importance of donor-recipient HLA matching in kidney transplantation has been confirmed by numerous studies. However, the impact of HLA matching on graft survival in pancreas or simultaneous transplantation compared to other factors is less significant. HLA matching should not be the primary factor in selecting a donor-recipient pair.
It is recommended to perform a complete blood count (including erythrocyte count, platelet count, leukocyte count, and total hemoglobin level), differential leukocyte count (leukocyte formula), and blood glycated hemoglobin level in potential pancreas or pancreas-kidney recipients to detect/rule out anemia, systemic inflammatory response syndrome, and monitor glycemic control [7, 230, 237, 239].
GSI CLEL 5 Grade of Recommendation C (Level of Evidence – 5).
It is recommended to test blood sodium levels, blood potassium levels, blood chloride levels, and acid-base balance and blood gases in potential pancreas or pancreas-kidney recipients to identify metabolic disorders and correct them prior to the surgical transplantation procedure [7, 52, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: electrolyte and acid-base imbalances are frequently observed in patients with diabetes mellitus and chronic renal failure.
It is recommended to perform a general biochemical blood panel (including total protein, albumin, creatinine, urea, aspartate aminotransferase activity, and alanine aminotransferase activity) in potential pancreas or pancreas-kidney recipients to assess the function of individual organs and systems [75, 167, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform molecular genetic blood testing for Epstein-Barr virus (Epstein-Barr virus) in potential pancreas or pancreas-kidney recipients prior to transplantation to rule out viremia [53, 55, 241].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform annual blood tests for M and G class antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) and M and G class antibodies (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in potential pancreas or pancreas-kidney recipients to rule out HIV infection prior to transplantation [54, 55, 56, 241].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform annual qualitative blood tests for hepatitis B surface antigen (HBsAg) (Hepatitis B virus), hepatitis B core IgM antibodies (anti-HBc IgM) (Hepatitis B virus), and antibodies to hepatitis B surface antigen (anti-HBs) (Hepatitis B virus) in potential pancreas or pancreas-kidney recipients to rule out infection and prescribe antiviral therapy prior to transplantation [55, 56, 241].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform annual blood tests for hepatitis C virus (Hepatitis C virus) antibodies in potential pancreas or pancreas-kidney recipients receiving renal replacement therapy to monitor hepatitis C infection and its treatment prior to transplantation [55, 56, 57, 241].
Strong Recommendation Grade CLevel of Evidence 5 Level of Recommendation Confidence C (Level of Evidence – 5).
It is recommended to perform molecular genetic blood testing for cytomegalovirus (Cytomegalovirus) in potential pancreas or pancreas-kidney recipients to timely detect viremia and prevent the development of CMV disease [55, 56, 58, 242].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to evaluate the coagulogram (screening hemostasis test) (including blood fibrinogen level, antithrombin III activity, blood plasminogen level, prothrombin time in blood or plasma, and activated partial thromboplastin time (APTT) using activators [kaolin/cephalin]) in potential pancreas or pancreas-kidney recipients to rule out thrombophilia/hemophilia, which can lead to graft vessel thrombosis or bleeding during the intraoperative or early postoperative period [60, 74, 168].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
2.4 Instrumental Diagnostics
It is recommended to perform an abdominal ultrasound (comprehensive) in potential pancreas or pancreas-kidney recipients to rule out abdominal pathology [232, 233].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform duplex scanning of brachiocephalic arteries (carotid and vertebral) with color Doppler blood flow mapping, ultrasound Doppler study of lower extremity vessels (arteries and veins), and duplex scanning of pelvic vessels in potential pancreas and kidney recipients to detect peripheral artery occlusive disease and/or varicose veins and their potential thrombotic complications [7, 233, 237, 239, 255, 256, 257].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: potential recipients with clinically manifest PAD should undergo visualization and treatment of their PAD following a consultation with a cardiovascular surgeon prior to transplantation. Potential recipients with clinically manifest PAD should undergo non-contrast computed tomography of the abdomen and pelvis for abdominal/pelvic visualization to assess arterial calcification and clarify the clinical picture for surgical planning [61-64].
It is recommended to perform targeted chest X-ray in potential pancreas or pancreas-kidney recipients to rule out pulmonary pathology. In the presence of any chest pathology or as clinically indicated, it is recommended to perform contrast-enhanced computed tomography of the chest with multiplanar and three-dimensional reconstruction [233, 234].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform an ECG in potential pancreas or pancreas-kidney recipients to identify existing foci of ischemia or cardiomyopathy [65-68, 177, 237, 239].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).
It is recommended to perform echocardiography, Holter ECG monitoring, and an exercise stress test using an ergometer in potential pancreas or pancreas-kidney recipients to determine cardiac functional reserve. In case of ambiguous test results or signs of myocardial ischemia, coronary angiography is recommended to assess the coronary bed [68, 69, 75, 169, 237, 239].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: Potential recipients who have been on dialysis for at least two years or have risk factors for pulmonary hypertension (e.g., portal hypertension, connective tissue disease, congenital heart disease, chronic obstructive pulmonary disease) should undergo echocardiography. There is evidence that abnormal echocardiographic findings and positive results of non-invasive stress tests are significant prognostic factors for coronary artery disease, cardiac events, and patient death. There is no evidence that angiography is required in asymptomatic patients with a negative non-invasive stress test.
It is recommended to perform contrast-enhanced computed tomography (CT) of the abdominal organs with intravenous bolus injection, multiplanar, and three-dimensional reconstruction in potential pancreas or simultaneous pancreas-kidney transplant recipients to determine vascular anatomy, diagnose neoplasms, and assess the patency of the inferior vena cava [233, 235, 236, 258, 259].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended that potential pancreas and kidney transplant recipients be screened to rule out erosive and ulcerative lesions of the upper gastrointestinal tract [179].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: Gastrointestinal bleeding is one of the most frequent complications of pancreas transplantation. Preoperative exclusion of gastric and duodenal ulcers reduces the likelihood of this complication in the early postoperative period, although the risk of bleeding from the duodenal anastomosis site persists. Esophagogastroduodenoscopy is the standard method for ruling out erosive and ulcerative lesions of the upper gastrointestinal tract prior to elective abdominal surgery in patients at high risk of bleeding and receiving immunosuppression (e.g., in accordance with clinical guidelines for preoperative preparation) [70].
It is recommended to perform cystoscopy in pancreas or simultaneous pancreas-kidney transplant candidates with an increased risk for bladder cancer screening [71-73, 194, 195].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: Cystoscopy for bladder cancer screening is necessary for pancreas transplant candidates in high-risk groups: heavy smokers (≥ 30 pack-years) and individuals with prior exposure to antineoplastic agents (e.g., cyclophosphamide**) [71].
It is recommended to perform a chest CT scan for current or former heavy smokers (≥ 30 pack-years) for lung cancer screening [225].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
2.5 Other Procedures
No.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
It is recommended to administer hemodialysis to patients with insulin-dependent diabetes mellitus and renal impairment prior to transplantation to correct fluid and electrolyte imbalances [5, 181, 182].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: Routine use of hemodialysis immediately prior to kidney transplantation is not indicated. Hyperkalemia is the most common indication for pre-operative hemodialysis. The risks of hemodialysis versus medical therapy must be weighed against the risks of intraoperative fluid overload, electrolyte, and acid-base disturbances, particularly in cases where a deceased-donor kidney is transplanted with a significant risk of delayed graft function (DGF). Preoperative hemodialysis may induce a pro-inflammatory state, delay surgery, increase cold ischemia time, and elevate the risk of DGF.
It is recommended to prescribe antithrombotic agents to patients with chronic kidney disease awaiting pancreas-kidney transplantation to reduce the risk of vascular and thrombotic complications [18-20, 174, 175].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: Since there is no standardized thromboprophylaxis protocol for patients awaiting pancreas-kidney transplantation, preoperative management must be discussed at a multidisciplinary team meeting (cardiologist, hematologist, etc.) [74]. Many patients on the active transplant waiting list have vascular disease and/or prothrombotic conditions that must be evaluated prior to transplantation. Dual antiplatelet therapy is generally prescribed to patients with coronary artery stents for six to twelve months; perioperative management plans for these patients should be discussed with a cardiologist to completely rule out the risk of discontinuation. The possibility of withholding anticoagulant therapy and postoperative anticoagulation should be discussed with a hematologist before placing patients on the waiting list.
Some patients will remain active on the transplant waiting list while continuing antiplatelet and/or anticoagulant therapy. Indications for use must be clearly documented for each individual. The potential increased risk of perioperative bleeding must be weighed against the potential harm of arterial or venous thrombosis. Antithrombotic agents are prescribed to many patients following pancreas transplantation, but drug selection depends on individual risk (thrombophilia, bleeding risk). This necessitates the involvement of a hematologist to identify thrombophilias and a cardiologist/nephrologist to assess the risk-benefit balance [76]. If necessary, the effects of antiplatelet therapy can be mitigated by intraoperative platelet infusions.
It is recommended to provide perioperative prophylaxis with systemic antibacterial and systemic antifungal drugs in pancreas or pancreas-kidney transplant recipients [77, 78, 212, 213, 243].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: Fungal, primarily candidal, infection is a frequent complication following pancreas transplantation, causing both systemic candidiasis and locally spreading infectious processes (wound infection or local peritonitis). The increased incidence of candidal infection is due to prolonged post-transplant antibiotic therapy and the high probability of fungal transmission with the donor pancreatoduodenal complex.
It is recommended to use restrictive intraoperative recipient hydration with electrolytes (B05BB solutions affecting water-electrolyte balance) to prevent pancreatic edema [79, 183].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comments: Careful adherence to peri- and postoperative fluid balance is necessary to prevent pancreatic edema and ensure optimal function of the kidney graft (if a simultaneous procedure is performed). Balanced solutions may be an optimal and safer choice for intraoperative intravenous fluid therapy.
3.2 Surgical Treatment
It is recommended to evaluate and prepare the deceased-donor pancreas graft on a back table before the recipient's surgery begins [81-84].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: Back-table preparation of the graft is an essential step in the transplantation process.
It is necessary to assess the quantity, quality, and integrity of the vessels of the pancreatoduodenal complex, the pancreatic parenchyma, and the duodenum. Next, connective (adipose) tissue along the superior and inferior borders of the pancreas is ligated and divided. The following graft preparation steps must then be performed: splenectomy is carried out by separate ligation and division of the corresponding 2nd- and 3rd-order arteries and veins. The proximal stump of the splenic artery is marked with a ligature. The inferior mesenteric vein is ligated at the lower border of the pancreas.
On the posterior surface of the head of the pancreas, the orifice of the common bile duct is suture-ligated securely. The portal vein stump is mobilized from the surrounding tissues for ease of its subsequent anastomosis. The superior mesenteric artery is mobilized with ligation and transection of the ganglion tissue of the celiac plexus. The proximal duodenal stump of the graft is transected distal to the pylorus (at the level of the upper lateral margin of the pancreatic head), closed with a mechanical suture, and additionally invaginated with a purse-string suture. The distal duodenal stump of the graft is also transected and closed with a mechanical suture at the transition of the vertical part into the lower horizontal part of the duodenum and additionally invaginated with a purse-string suture. The root of the mesentery of the transverse colon and small intestine, including its branches of the superior mesenteric artery and vein, is also closed with a mechanical suture with double-row locking continuous suturing using sterile, non-absorbable 4/0 polypropylene surgical suture material. The proximal stumps of the superior mesenteric artery and the corresponding vein are suture-ligated securely at the lower margin of the pancreas. The orifice of the superior mesenteric artery and the orifice of the splenic artery are connected by a Y-graft (the bifurcation zone of the donor's common iliac artery into the external and internal iliac arteries). Anastomoses are performed with a continuous suture using sterile, absorbable PDS surgical suture material or sterile, non-absorbable 5-6/0 polypropylene surgical suture material [80-84].
It is recommended to use an extraperitoneal approach to the right iliac fossa as the surgical approach for isolated pancreas transplantation [82-86].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to use a midline laparotomy, placing the pancreas graft in the right paracolic gutter and the kidney graft in the left iliac fossa as the surgical approach for simultaneous pancreas-kidney transplantation [81, 86].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: in some cases, placement of both grafts on the right side is possible, with the pancreas graft implanted caudad to the kidney graft. A retroperitoneal approach is advisable in terms of isolating peripancreatic secretions from the abdominal cavity organs in the postoperative period, while a midline laparotomy provides good maneuverability when performing additional procedures: simultaneous kidney transplantation, removal of the peritoneal catheter.
It is recommended to use the recipient's external or common iliac arteries for an end-to-side arterial anastomosis with the pancreas graft artery to reconstruct the blood supply to the pancreas graft [80-82, 86].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: the choice of the common right iliac artery for the anastomosis is considered optimal, as its use allows the pancreas graft to be positioned in any orientation (head up or head down).
It is recommended to perform an anastomosis between the graft portal vein and the recipient's inferior vena cava or common iliac vein to restore venous outflow from the pancreas graft. The recipient's superior mesenteric vein may also be used [87-89].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: implantation of the pancreas begins with the reconstruction of the graft's venous outflow. There are two main methods of venous reconstruction: portal and systemic. Portal venous reconstruction is considered more physiological as it mitigates potential hyperinsulinemia caused by blood passing through the liver. Systemic venous outflow can lead to peripheral hyperinsulinemia with subsequent development of insulin resistance and lipid metabolism disorders. Currently, systemic venous drainage is most commonly used, but the choice depends on the individual recipient.
It is recommended to restore the exocrine outflow of the pancreas via enteric drainage in pancreas or simultaneous pancreas-kidney transplant recipients to minimize metabolic complications [89-91].
GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).
Comments: to date, over 40 methods of pancreas transplantation have been described depending on the type of graft and the technique of exocrine drainage formation. Duodenocystostomy is considered the simplest, allowing monitoring of urinary amylase levels as one of the markers of graft function and rejection in the postoperative period.
Creation of a duodenojejunostomy is considered more preferable, as unlike duodenocystostomy, it does not lead to the development of enzymatic and/or hemorrhagic cystitis and metabolic disorders in the post-transplant period.
The most modern technique is duodenoduodenostomy. This method is more physiological and allows endoscopic monitoring of the donor duodenum status and graft biopsy when necessary.
3.2.1 Surgical complications
It is recommended to prevent venous thrombosis of the pancreas with a continuous intravenous infusion of heparin sodium** using a syringe infusion pump for 2-4 days post-transplantation. The target APTT should not exceed 50 seconds. Subsequent anticoagulant therapy can be carried out using heparin-group drugs [92, 93, 164].
GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).
Comments: pancreas thrombosis currently remains the most frequent complication of the early postoperative period, which in the vast majority of cases leads to graft loss, repeat abdominal interventions, and pancreas graft pancreatectomy. Currently, the incidence of early thrombosis in simultaneous transplantation is 4.1-5.5%, with a downward trend. The main clinical manifestation of thrombosis is a sudden increase in glycemia levels, the appearance of dark hemorrhagic discharge in abdominal drains, and the disappearance of amylase in the drains and urine in cases of bladder drainage of exocrine secretions. A confirmed diagnosis of acute thrombosis requires immediate pancreas graft pancreatectomy, except for cases of late thrombosis not accompanied by signs of intoxication.
It is recommended in the event of mural thrombosis of the splenic vein of the pancreas graft to administer systemic anticoagulant therapy with heparin sodium** without surgical intervention [94, 184, 185].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: such a measure makes it possible in some cases to avoid the progression of thrombosis and preserve the graft.
It is recommended to perform endovascular intervention (endovascular catheter thrombectomy, endovascular balloon angioplasty, or endovascular vessel stenting) for both arterial and venous partial thrombosis of the pancreas graft vessels [95-97].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: the efficacy of these interventions does not exceed 50 %.
It is recommended to use intravenous infusion of octreotide** for the prevention of pancreatitis in the early postoperative period in pancreas transplant recipients [93, 98-102].
GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
Comments: graft pancreatitis is the second most frequent complication following simultaneous kidney-pancreas transplantation. The so-called physiological acute pancreatitis occurs as a normal reaction to ischemia-reperfusion. This form of acute pancreatitis develops in almost 100% of cases, is asymptomatic, manifests only as elevated amylase and lipase levels in the fluid drained from the abdominal cavity and an elevated C-reactive protein level in the recipient's blood, and gradually subsides due to its natural course and the routine use of prednisolone** (methylprednisolone**) during the induction phase of immunosuppressive therapy. Prevention consists of adequate conditioning and selection of the potential pancreas donor.
Acute destructive pancreatitis (pancreonecrosis) is most often caused by nuances of the surgical technique of pancreatic transplantation at various stages. Among the main factors are vascular thrombosis, which can be triggered by technical issues or acute/hyperacute humoral rejection. The primary surgical errors include damage to the inferior pancreaticoduodenal or dorsal pancreatic arteries and incorrect creation of the venous anastomosis, leading to delayed blood outflow from the pancreas. Treatment should aim to eliminate the causes of pancreatitis and includes antibiotic therapy, anticoagulant therapy, endovascular surgical techniques to correct vascular problems, and timely pancreatic necrosectomy. However, despite the use of these therapeutic and surgical methods, the onset of early acute pancreatitis in the vast majority of cases leads to rapid loss of the pancreatic graft.
It is recommended to restore the continuity of the gastrointestinal tract using surgical methods while preserving the transplanted pancreas in cases of timely diagnosed duodenal anastomosis leakage [103, 104].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: the danger of leakage with enteric drainage lies in the rapid development of peritonitis and sepsis. If duodenal anastomosis leakage is diagnosed late and widespread peritonitis has developed, it is more advisable to perform a pancreatectomy of the graft.
It is recommended to perform endoscopic hemostasis for gastrointestinal bleeding in pancreas transplant recipients (including simultaneous kidney-pancreas transplantation) with enteral drainage. The use of octreotide** infusion is not recommended to stop gastrointestinal bleeding [70, 97, 103, 104, 105, 106].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
3.3 Immunosuppressive therapy
Organ transplantation stimulates the development of an immune response, which can lead to graft dysfunction and loss. Immunosuppressive therapy is aimed at suppressing the recipient's immune system response and prevents rejection. Off-label medicinal products may only be used with the ICD-10 code T86.8 (in accordance with Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022, "On Approval of the List of Diseases or Conditions (Groups of Diseases or Conditions) for Which the Use of a Medicinal Product is Permitted in Accordance with Characteristics of the Medicinal Product Not Indicated in its Instructions for Use").
List of main medications currently received by patients:
calcineurin inhibitors (CNIs) (primarily #tacrolimus**, less commonly cyclosporine**);
#mycophenolate mofetil**/#mycophenolic acid**;
prednisolone** or methylprednisolone**;
induction therapy (for patients with low risks, #basiliximab** is predominantly used, while antithymocyte globulin** is used for high-risk patients).
Multicomponent therapy is the standard treatment method for the majority of recipients worldwide and can be adjusted depending on specific conditions and immunological risk. Due to the development of new immunosuppressive protocols and novel immunosuppressants, standard therapy is likely to change. In addition, any starting immunosuppression protocol must be tailored to the individual patient's needs depending on side effect profiles, efficacy, or protocol requirements.
3.3.1 Calcineurin inhibitors
As a first-line CNI, it is recommended to use #tacrolimus** at a dose of 0.2 mg/kg/day per os in pancreas or simultaneous kidney-pancreas transplant recipients, aiming for an initial trough concentration of 10–15 ng/mL, 8–12 ng/mL after 3–6 weeks, and up to 6–10 ng/mL after 6 weeks due to higher efficacy [6, 107-109, 186, 217, 220, 221, 237, 239, 261].
GRC CLOE 2Grade of Recommendation C (Level of Evidence – 2).
Comments: considering that pancreas transplantation is in the vast majority of cases performed simultaneously with kidney transplantation and carries a high risk of acute and chronic rejection of both grafts along with certain difficulties in the timely diagnosis of pancreatic rejection, it is recommended to use more effective immunosuppressive therapy regimens.
It is recommended to regularly monitor whole blood #tacrolimus** concentrations in all post-transplant patients for optimal dosage adjustment [112, 188, 189, 237, 239].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: #tacrolimus** has significant side effects that are potentially dangerous for both the graft and the recipient: the drug is nephrotoxic, and its long-term use causes chronic graft dysfunction, which can lead to the loss of a kidney graft or severe chronic kidney disease in recipients without a transplanted kidney. Both CNIs belong to drugs with a narrow therapeutic window, falling outside of which can lead to severe intoxication or lack of sufficient effect. Due to the narrow therapeutic window and the high likelihood of drug-drug interactions, monitoring CNI levels is necessary to objectively assess the drug content in the blood. A specific feature of tacrolimus** pharmacokinetics in type 1 diabetes mellitus recipients is that its bioavailability is 26–30% lower than in patients whose chronic kidney disease was caused by other pathologies. The low bioavailability of #tacrolimus** is due to manifestations of autonomic gastrointestinal diabetic neuropathy and may require higher doses of the drug. The use of extended-release formulations is preferred in diabetic patients [111].
It is recommended to switch pancreas and kidney-pancreas transplant recipients experiencing #tacrolimus** intolerance to cyclosporine** (initial dose 50 mg orally twice daily) while maintaining trough concentrations (100–125 ng/mL) as part of a combined immunosuppressive therapy regimen combined with antithymocyte globulin** induction therapy to manage side effects and prevent rejection [269, 270, 271].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended that pancreas and kidney-pancreas transplant recipients undergoing #basiliximab** induction therapy receive cyclosporine** at an initial dose of 5 mg/kg with subsequent adjustment to maintain a blood trough concentration in the range of 200 to 250 ng/mL during the first two weeks post-transplant, 150 to 200 ng/mL during the third and fourth weeks, and 125 to 175 ng/mL thereafter for the prevention of rejection [265].
AG CLEL 2Recommendation Grade C (Level of Evidence – 2).
Comments: it should be taken into account that high cyclosporine** concentrations > 150 ng/mL were associated with pancreatic graft thrombosis and renal allograft dysfunction (in kidney-pancreas recipients) [271].
3.3.2 #Mycophenolic acid**/#mycophenolate mofetil**
It is recommended to include #mycophenolic acid** at a dose of 720 mg twice daily or #mycophenolate mofetil** at an equivalent dose of 1000 mg twice daily in the initial combined immunosuppressive therapy regimen for pancreas-kidney transplant recipients without contraindications, in combination with prednisolone** and calcineurin inhibitors for the prevention of rejection [114-116, 192, 219-221, 217, 237, 239, 261].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to use valganciclovir** for the prevention of cytomegalovirus infection or to employ a preemptive strategy with regular monitoring of CMV viremia in patients taking #mycophenolic acid**/#mycophenolate mofetil**, due to the high incidence of CMV infection [59, 154, 222-224].
GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: the co-administration of #mycophenolic acid**, prednisolone**, and CNIs provides a sustained reduction in biopsy-proven rejection rates. #Mycophenolic acid** is not nephrotoxic; however, it suppresses bone marrow function and can cause CMV infection as well as gastrointestinal disturbances, particularly diarrhea. The use of #mycophenolate mofetil** increases the risk of polyomavirus nephropathy, especially in combination with #tacrolimus** [119].
#Mycophenolic acid** is not officially approved for use in combination with #tacrolimus**, although this is the most common drug combination worldwide, recommended by guidelines; however, the dosage in this combination lacks scientific validation [122, 237, 239]. #Tacrolimus** has no effect on the accumulation of #mycophenolic acid**; nevertheless, the accumulation (bioavailability) of #mycophenolic acid** is 30% higher compared to #cyclosporine**. Due to the high incidence of side effects, some centers routinely practice reducing the dose of mycophenolic acid** in patients receiving tacrolimus** .
3.3.3 Azathioprine**
#Azathioprine** may be recommended for use at a dose of 100 mg daily per os in low immunological risk patients as an immunosuppressant, particularly in patients with intolerance to #mycophenolic acid**/#mycophenolate mofetil** [117-118, 121, 191, 196].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: instead of #azathioprine**, #mycophenolic acid**/#mycophenolate mofetil** is used as standard therapy in most transplant centers worldwide. According to prospective randomized trials, #mycophenolic acid** significantly reduces the incidence of rejection compared to #azathioprine** [118]. Although data from a large prospective study show that #azathioprine** can yield acceptable outcomes in patients with low immunological risk, #azathioprine** is more commonly used by patients with intolerance to #mycophenolic acid** [119].
3.3.4 Prednisolone**, methylprednisolone**
It is recommended to include #prednisolone** (#methylprednisolone**) in the initial immunosuppressive therapy regimen for pancreas or simultaneous pancreas-kidney transplant recipients during the perioperative and early postoperative periods in combination with a calcineurin inhibitor and #mycophenolate mofetil** / #mycophenolic acid** to prevent acute graft rejection [92, 197, 198, 237, 239].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: #prednisolone** or #methylprednisolone** has numerous side effects, particularly with long-term use. Most practicing specialists still consider #prednisolone** or #methylprednisolone** a core component of immunosuppressive therapy, even in light of subsequent successful withdrawal reported in many prospective randomized trials. These studies suggest that the risks associated with withdrawing #prednisolone** or #methylprednisolone** depend on concomitant immunosuppressants, immunological risk, recipient race, and the time elapsed since transplantation. Although the risk of rejection decreases over time, the potential benefit of withdrawal after a prolonged course of #prednisolone** or #methylprednisolone** may not be significant. Currently, it has become clear that rapid withdrawal of #prednisolone** or #methylprednisolone** has neither a positive nor a negative effect on pancreas graft survival, though it slightly increases the risk of renal graft function loss [92, 123].
3.3.5 Immunosuppressants: #Everolimus**
It is recommended to prescribe #everolimus** at a dose of 0.75–1.5 mg twice daily to achieve a target trough concentration of 3–8 ng/mL as an alternative immunosuppressive component in selected pancreas or simultaneous pancreas-kidney transplant recipients who have an intolerance to standard immunosuppressive therapy or require a reduction in calcineurin inhibitor dosage [190, 266, 267].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to significantly reduce the CNI dosage to prevent nephrotoxicity when used in combination with #everolimus** in pancreas recipients [125-126].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
3.3.6 Induction immunosuppressive therapy
#Antithymocyte globulin** is recommended as induction immunosuppressive therapy in high immunological risk patients, which includes recipients of simultaneous pancreas-kidney transplantation [127-132].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: in many countries, particularly the USA, anti-T-lymphocyte "induction" therapy is used for prophylaxis. Additionally, this potent agent is used to treat episodes of severe steroid-resistant rejection [92, 132-138].
Against the background of induction therapy, the incidence of pancreas and kidney graft rejection is initially lower, but its impact on long-term graft survival outcomes is less definitive.
3.3.7 Interleukin inhibitor induction – #basiliximab**
#Basiliximab** (administered intravenously as a bolus or infusion over 20–30 minutes, 20 mg two hours before transplantation and four days after) is recommended as induction immunosuppressive therapy to reduce the incidence of acute rejection in simultaneous pancreas-kidney transplant recipients [218, 237, 239, 261, 262].
GCR CLEL 3Grade of Recommendation C (Level of Evidence – 3).
Comments: in the context of simultaneous pancreas-kidney transplantation, #basiliximab** yields similar long-term survival outcomes for both grafts compared to T-cell-depleting therapy. However, a higher incidence of acute rejection in the early postoperative period has been noted, requiring closer monitoring of the transplanted pancreas function and the use of early diagnostic markers for pancreas rejection, which remains a very challenging task [131, 139, 141].
4. Medical Rehabilitation and Sanatorium-Resort Treatment
It is recommended to implement an individualized medical rehabilitation program for pancreas or simultaneous pancreas-kidney transplant recipients after stabilization of their condition in the early postoperative period to restore physical activity, prevent thromboembolic complications, sarcopenia, and functional deconditioning, and to improve exercise tolerance, quality of life, and social adaptation [239, 244, 253-255].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: medical rehabilitation should be conducted by a multidisciplinary team taking into account graft function, the condition of the surgical wound, the risk of infectious and cardiovascular complications, the severity of diabetic neuropathy, retinopathy, peripheral artery disease, and comorbid CKD. In the early postoperative period, breathing exercises, early mobilization, graded walking, and thrombosis prevention are indicated. Following surgical wound healing, there should be a gradual progression of aerobic and resistance exercise under clinical monitoring [244-247]. For pancreas transplant recipients, NHS Blood and Transplant recommends walking in the first weeks to prevent thrombosis, and upon favorable recovery, increasing physical activity after 6–8 weeks; Mayo Clinic also indicates that post-transplant physical activity should be regular, gradually increased, and tailored individually [248, 249].
An active lifestyle should be maintained; however, following kidney and pancreas transplantation, patients should avoid contact sports or activities that carry a risk of direct impacts or other injuries to the transplanted organ (e.g., kickboxing) [143-146].
Alcohol or substance abuse may increase the risk of adverse events [147, 148].
5. Prevention and Dispensary Observation
It is recommended to schedule routine outpatient follow-up visits (examinations, consultations) with an endocrinologist involving a nephrologist, clinical dietitian, cardiologist, urologist, and other specialist physicians as clinically indicated for pancreas or simultaneous pancreas-kidney transplant recipients, aimed at the early detection of graft dysfunction, transplantation complications, adverse effects of immunosuppressive therapy, and the progression of diabetes complications [239, 248, 249].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: by the time of pancreas transplantation, patients present with a wide range of diabetes-related complications, many of which continue to progress for some time after pancreas transplantation, necessitating ongoing patient monitoring by various specialists [11, 15, 16]. Therefore, outpatient follow-up must be multidisciplinary and include monitoring of graft function, immunosuppressive therapy complications, cardiovascular risk, infectious complications, and oncological screening [239, 248, 249].
In the case of an uncomplicated postoperative course, it is recommended to conduct scheduled follow-up outpatient visits (examinations, consultations) at the transplant center to monitor pancreas and renal graft function, adjust immunosuppressive therapy, and ensure early detection of infectious, surgical, metabolic, cardiovascular, and oncological complications: at least once a month during the first year post-transplantation, and at least once every 3 months thereafter; in patients with stable graft function and no complications, the follow-up interval may be individually extended to 3–6 months [250, 251, 253].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: the frequency of follow-up visits depends on the specific features of the postoperative period and the time elapsed since the intervention, the presence or absence of complications directly related to pancreas transplantation or the progression of diabetes mellitus complications. Regular monitoring by experienced surgeons (transplant surgeons) is essential for the early detection of complications or graft dysfunction and for monitoring strict adherence to the prescribed immunosuppressive regimen.
It is necessary to perform (approximately every 4–8 weeks in the first 6 months after pancreas transplantation) a C-peptide level test and a blood insulin level test, blood pancreatic amylase and blood lipase levels, a blood creatinine test with glomerular filtration rate calculation, a urine protein test, blood concentration levels of immunosuppressive therapy drugs, a glycated hemoglobin blood test, and an ultrasound examination of the pancreas graft with color Doppler mapping to rule out parietal thrombosis of the pancreas vessels. These tests are aimed at the early detection of potential complications at the subclinical stage.
Annual screening should include a dermatological examination, cardiovascular system examination, tumor screening (including lymph node examination, fecal occult blood test, targeted chest X-ray, gynecological and urological examination), and a comprehensive abdominal ultrasound, including ultrasound of native and transplanted kidneys, and esophagogastroduodenoscopy. If necessary, further diagnostic tests should be performed to treat or slow the progression of any identified complication.
Complications of immunosuppressive therapy occur frequently, including specific complications of various drugs, as well as consequences of excessive immunosuppressive therapy (namely, opportunistic infections and malignancies). The risk of developing certain localized malignancies and cardiovascular diseases is several times higher in transplant recipients than in the general population. Malignancies account for significant morbidity and mortality in the transplant population. Cardiovascular diseases and infections are the most frequent cause of death in pancreas recipients. Other important long-term issues include non-adherence to the prescribed therapy regimen, the development of anti-HLA antibodies, and the recurrence of diabetes mellitus [9-10, 12, 13, 9, 17, 18, 61].
6. Organization of Medical Care
6.1 Indications for planned hospitalization
Preparation for pancreas transplantation.
Preparation for simultaneous kidney transplantation (sanation of infection focus, nephrectomy).
Pancreas graft dysfunction.
Kidney graft dysfunction (in simultaneous kidney and pancreas transplantation).
Instability of calcineurin inhibitor concentrations.
Performance of a puncture biopsy of the pancreas and/or kidney graft (in simultaneous transplantation).
6.2 Indications for emergency hospitalization
Availability of a compatible donor pancreas from a deceased donor.
Availability of a compatible donor pancreas and kidney for simultaneous transplantation.
Pancreas and/or kidney graft dysfunction in life-threatening conditions.
Acute graft pancreatitis.
Surgical/urological complications post-transplantation.
Acute conditions or exacerbations of chronic diseases in the early post-transplantation period.
6.3 Indications for hospital discharge
Satisfactory function of the pancreas graft (and kidney graft in simultaneous transplantation).
Absence of indications for inpatient stay.
7. Additional Information
7.1 Transplantation in pregnancy
7.1.1 Pregnancy planning
It is recommended to plan pregnancy for female pancreas or pancreas-kidney recipients only under conditions of good general health, stable graft function, and ongoing immunosuppressive therapy, as well as in the absence of signs of pancreas graft dysfunction (and kidney graft dysfunction, in cases of simultaneous transplantation), arterial hypertension, proteinuria, hydronephrosis, or chronic infection. The ideal time for pregnancy is the second year after the performed transplantation [151-154, 236].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: diabetes mellitus is often accompanied by sexual and reproductive dysfunctions. After kidney transplantation, sexual life and reproductive function are restored [151, 236]. Women with diabetes mellitus and end-stage renal disease must be well-informed regarding pregnancy issues. Pregnancy should proceed with good general health and pancreas graft status, usually no earlier than 1–2 years after transplantation [150].
Pancreas or pancreas-kidney recipients may be recommended to undergo Caesarean section for obstetric indications, although they have a higher risk of urinary bladder injury and other surgical complications during this intervention [148, 151, 236].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: with a stable functional state of the pancreas and/or kidney graft and ongoing immunosuppressive therapy, as well as in the absence of signs of graft rejection, arterial hypertension, proteinuria, hydronephrosis, or chronic infection, there is no significant difference in the outcomes of early, optimal, or late pregnancy [152, 153]. In hydronephrosis, there is a higher risk of pregnancy termination due to an increased likelihood of infection or urolithiasis, which may complicate the course of the third trimester of pregnancy. Pregnancy must be diagnosed as early as possible for the earliest possible initiation of dynamic monitoring and correction of immunosuppressive therapy. Pregnancy in women who have undergone organ transplantation is often not a problem, but these patients must in all cases be classified as high risk; pregnancy should proceed under the dynamic monitoring of an obstetriciangynaecologist, nephrologist, and urologist.
7.1.2 Pregnancy management tactics
All pregnant women with a history of pancreas transplantation are recommended to monitor risk factors in order to detect early signs of graft dysfunction and infection [151-154].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: in particular, urinalysis should be performed once a month (early diagnosis of urogenital system infections), and bacteriuria should be eliminated regardless of the presence of clinical manifestations. To avoid fetal and nephrotoxicity, beta-lactam antibacterial drugs, penicillins, must be prescribed [165]. Prevention and suppression of any viral infections are necessary to avoid intrauterine defects (e.g., mental retardation of the child after intrauterine CMV infection). Microbiological culture examination of amniotic fluid is used for the early diagnosis of intrauterine infections [154].
7.1.3 Immunosuppressive therapy during pregnancy
It is not recommended to use mycophenolic acid**/mycophenolic acid** and everolimus** for maintenance immunosuppressive therapy during pregnancy in female recipients after simultaneous pancreas and kidney transplantation [155-159].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: the drug #tacrolimus** [155, 156], used for immune system suppression after pancreas transplantation, is characterized by a fairly high safety profile. Only isolated studies indicate that mycophenolate mofetil** and #sirolimus possess teratogenicity, and therefore their use is contraindicated during pregnancy [157].
It is not recommended to breastfeed while using #mycophenolate mofetil** due to the high risk of immunosuppressants entering the newborn's body and the paucity of data on their safety regarding effects on the neonate [166].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1. | An appointment (examination, consultation) by an endocrinologist was performed for candidates for pancreas transplantation or simultaneous pancreas and kidney transplantation | Yes/no |
2. | An appointment (examination, consultation) by a surgeon was performed for candidates for pancreas transplantation or simultaneous pancreas and kidney transplantation | Yes/no |
3. | ABO blood group typing and Rhesus factor (D antigen) determination were performed for a potential recipient prior to pancreas or pancreas-kidney transplantation | Yes/no |
4. | Determination of class I and II HLA antigens (genes), a crossmatch test based on immune antibodies of the recipient and major histocompatibility complex antigens of the donor, and determination of antibodies to major histocompatibility complex antigens in the blood serum of the potential recipient were performed | Yes/no |
5. | Annual determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in the blood, and determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in the blood performed for potential recipients of a pancreas or a pancreas and kidney | Yes/no |
6. | Annual determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in the blood, determination of hepatitis B virus (Hepatitis B virus) immunoglobulin M antibodies to core antigen (anti-HBc IgM) in the blood, and determination of hepatitis B virus (Hepatitis B virus) antibodies to surface antigen (anti-HBs) in the blood, qualitative test performed for potential recipients of a pancreas or a pancreas and kidney | Yes/no |
7. | Annual determination of antibodies to hepatitis C virus (Hepatitis C virus) in the blood performed for potential recipients of a pancreas or a pancreas and kidney receiving renal replacement therapy | Yes/no |
8. | Coagulogram evaluation (exploratory hemostasis study) (determination of blood fibrinogen level, blood antithrombin III activity, blood plasminogen level, prothrombin time in blood or plasma, and activated partial thromboplastin time (APTT) using activators (kaolin/cephalin)) performed for potential recipients of a pancreas or a pancreas and kidney | Yes/no |
9. | Targeted chest X-ray performed for potential recipients of a pancreas or a pancreas and kidney | Yes/no |
10. | ECG performed for potential recipients of a pancreas or a pancreas and kidney | Yes/no |
11. | Esophagogastroduodenoscopy performed for potential recipients of a pancreas and kidney | Yes/no |
12. | Perioperative prophylaxis with systemic antifungals and systemic antibacterials performed in recipients of a pancreas or a pancreas and kidney transplant | Yes/no |
13. | Prevention of pancreatic venous thrombosis performed by continuous intravenous infusion of heparin sodium** using a syringe infusion pump for 2–4 days post-transplantation | Yes/no |
14. | Combined immunosuppressive therapy performed with a calcineurin inhibitor (preferably #tacrolimus** or cyclosporine**), #mycophenolate mofetil** / #mycophenolic acid**, prednisolone** (methylprednisolone**), and immunosuppressive induction therapy with #basiliximab** or antithymocyte globulin** | Yes/no |
15. | Therapy with #tacrolimus** performed as first-line therapy in recipients of a pancreas or a kidney and pancreas | Yes/no |
16. | Therapy with cyclosporine** performed in recipients of a pancreas or a kidney and pancreas in case of #tacrolimus** intolerance | |
17. | Regular monitoring of whole blood #tacrolimus** concentration performed in all post-transplant patients | Yes/no |
18. | CMV prophylaxis performed or preemptive strategy used with regular monitoring of CMV viremia in patients taking #mycophenolic acid** / #mycophenolate mofetil** | Yes/no |
19. | Follow-up outpatient appointment (examination, consultation) by an endocrinologist involving a nephrologist, clinical nutritionist, cardiologist, urologist, and other specialist physicians as indicated | Yes/no |
References
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Appendix A1. Working Group Composition
Arzumanov Sergey Viktorovich | Head of the Transplantation and Renal Replacement Therapy Group, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs - Branch of the National Medical Research Radiological Center of the Russian Ministry of Health (Obninsk), Doctor of Medical Sciences |
|---|---|
Belskikh Leonid Vladislavovich | Head of the Surgical Center for Organ Donation Coordination and Transplantation, Moscow Region Research Clinical Institute named after M.F. Vladimirsky (MONIKI), Surgeon (Moscow Region), Candidate of Medical Sciences |
Galeev Shamil Rinatovich | Deputy Director - Head of the Volzhsk Branch, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Doctor of Medical Sciences |
Gichkun Olga Evgenyevna | Leading Researcher, Department of Regulatory Mechanisms in Transplantology, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Candidate of Medical Sciences, Associate Professor |
Gauthier Sergey Vladimirovich | Director, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Academician of the Russian Academy of Sciences, Chief Transplantologist of the Russian Ministry of Health, Chairman of the Russian Transplant Society, Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences |
Zagainov Vladimir Evgenyevich | Chief Surgery Specialist, Privolzhsky District Medical Center of the FMBA of Russia, Head of the Department of Surgery, Nizhny Novgorod State Medical Academy of the Russian Ministry of Health, Chief Freelance Transplantologist of the Ministry of Health of the Nizhny Novgorod Region (Nizhny Novgorod), Doctor of Medical Sciences, Professor |
Zainutdinov Zainudin Musayevich | Head of the Clinic, Federal Research Center of Nutrition and Biotechnology (Moscow), Doctor of Medical Sciences |
Kurbangulov Ildar Raisovich | Surgeon, Surgical Department No. 1, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Candidate of Medical Sciences |
Malakhov Aleksey Gennadyevich | Surgeon, Surgical Department No. 1, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow) |
Minina Marina Gennadyevna | Deputy Chief Physician, Head of the Moscow Organ Donation Coordination Center, City Clinical Hospital named after S.P. Botkin of the Moscow Healthcare Department (Moscow), Doctor of Medical Sciences, Professor of the Russian Academy of Sciences |
Mozheyko Natalya Pavlovna | Head of the Department of Pathology, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Doctor of Medical Sciences |
Saydulaev Dzhabrail Azizovich | Head of Surgical Department No. 1, Surgeon, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Candidate of Medical Sciences |
Sibyakina Anna Anatolyevna | Endocrinologist, Consultative and Diagnostic Department, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow) |
Khomyakov Sergey Mikhailovich | Deputy Director - Head of the Center for Organizational and Methodological Guidance of Institutions Engaged in Activities Related to Human Organ and/or Tissue Transplantation, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Candidate of Medical Sciences |
Chebotareva Natalya Viktorovna | Head of the Center for Excellence in Nephrological Medical Care, Head of the Nephrology Department, Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs of the Russian Ministry of Health (Moscow), Doctor of Medical Sciences, Professor |
Conflict of interest.
The working group declares no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
surgeons;
pediatric surgeons;
anesthesiologists-intensivists;
general practitioners (family doctors);
nephrologists;
urologists;
endocrinologists;
pediatric endocrinologists;
general practitioners (internal medicine);
pediatricians;
pathologists.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The update mechanism for clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Current instructions for medical product use are available on the official website of the Russian Ministry of Health at http://grls.rosminzdrav.ru/Default.aspx.
Federal Law No. 52-FZ dated March 30, 1999, "On the Sanitary and Epidemiological Welfare of the Population" (Collected Legislation of the Russian Federation, No. 14, Art. 1650; 2002, No. 1 (pt. I), Art. 2; 2003, No. 2, Art. 167; No. 27 (pt. I), Art. 2700; 2004, No. 35, Art. 3607; 2005, No. 19, Art. 1752; 2006, No. 1, Art. 10; 2007, No. 1 (pt. I), Art. 21, 29; No. 27, Art. 3213; No. 46, Art. 5554; No. 49, Art. 6070; 2008, No. 24, Art. 2801; No. 29 (pt. I), Art. 3418).
Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' Regarding Clinical Guidelines."
Federal Law No. 323-FZ dated November 21, 2011 (as amended on April 31, 2021) "The Fundamentals of Healthcare Protection in the Russian Federation", Article 47. Donation of Human Organs and Tissues and Their Transplantation (Grafting).
Decree of the Government of the Russian Federation No. 950 dated September 20, 2012, "On Approval of the Rules for Determining the Moment of Human Death, Including Criteria and Procedures for Establishing Human Death, the Rules for Discontinuing Resuscitation Measures, and the Form of the Protocol for Establishing Human Death."
Decree of the Government of the Russian Federation No. 852 dated June 1, 2021 (as amended on May 8, 2025) "On Licensing Medical Activities (Except for the Specified Activities Performed by Medical Organizations and Other Organizations Included in the Private Healthcare System on the Territory of the Skolkovo Innovation Center)."
Decree of the Government of the Russian Federation No. 33 dated January 23, 2016, "On the Procedure for Financial Support of Medical Activities Related to Human Organ Donation for Transplantation (Grafting) Purposes at the Expense of Federal Budget Appropriations."
Order of the Russian Ministry of Health No. 567n dated October 31, 2012, "On Approval of the Procedure for Providing Medical Care in the Profile 'Surgery (Human Organ and/or Tissue Transplantation)'."
Order of the Russian Ministry of Health No. 919n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Anesthesiology and Reanimatology'."
Order of the Russian Ministry of Health No. 928n dated November 15, 2012, "On Approval of Sanitized Procedure for Providing Medical Care to Patients with Acute Cerebrovascular Accidents."
Order of the Russian Ministry of Health No. 908n dated December 25, 2014, "On the Procedure for Establishing the Diagnosis of Brain Death in Humans."
Order of the Russian Ministry of Health No. 738n, Russian Academy of Sciences No. 3 dated November 10, 2022 (as amended on January 20, 2026) "On Approval of the List of Medical Organizations Engaged in Retrieval, Procurement, and Transplantation of Human Organs and/or Tissues."
Order of the Russian Ministry of Health No. 150n, Russian Academy of Sciences No. 1 dated March 25, 2025, "On Approval of the List of Transplant Objects."
Order of the Russian Ministry of Health No. 17n dated January 18, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Nephrology'."
Order of the Russian Ministry of Health No. 104n dated March 13, 2023, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Endocrinology'."
Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."
Order of the Ministry of Labor of Russia No. 374n dated July 26, 2024 "On Approval of Classifications and Criteria Used in the Implementation of Medical and Social Expertise of Citizens by Federal Medical and Social Expertise Institutions."
Order of the Ministry of Health of Russia No. 1094n dated November 24, 2021 "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Blank Forms for Medicinal Products, the Procedure for Issuing Said Blanks, Their Accounting and Storage, Prescription Blank Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting and Storage, as well as the Rules for Issuing Prescription Blanks, Including in the Form of Electronic Documents."
Order of the Ministry of Health of Russia No. 494 dated August 9, 2005 "On the Procedure for the Use of Medicinal Products in Patients for Vital Indications"
Information Letter of the Ministry of Health of Russia on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu).
WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation (WHA 63.22).
Istanbul Declaration on Organ Trafficking and Transplant Tourism, 2008.
Appendix B. Physician Action Algorithms
Figure 1 – Treatment algorithm for a patient with diabetes mellitus undergoing transplantation in type 1 diabetes mellitus and CKD via pancreatic transplantation
Figure 2 – Management algorithm for a potential pancreas recipient
Appendix C. Patient Information
Diabetes mellitus, due to its prevalence and inevitable complications, remains one of the most critical problems facing modern medicine. To date, pancreas transplantation is a recognized radical treatment method for complicated type 1 diabetes mellitus threatening the development of severe complications. Diabetes mellitus is commonly referred to as a "lifestyle," emphasizing that with high self-monitoring and compensation of carbohydrate metabolism using insulin therapy, patients with diabetes minimize the risk of late diabetic complications and maintain a high quality of life allowing patients to remain socially active. However, the situation is different for patients who have already developed chronic renal failure. In the case of irreversible diabetic nephropathy, the prognosis deteriorates significantly. Currently, there are several renal replacement therapy options for patients with diabetes and end-stage CKD. These primarily include dialysis replacement therapy or kidney transplantation combined with insulin therapy, or combined kidney-pancreas transplantation, which subsequently eliminates the need for insulin therapy. Islet of Langerhans transplantation can be used in patients during kidney transplantation or against the background of dialysis therapy, but it does not lead to insulin independence; currently, the efficacy of this method continues to be discussed. According to modern concepts, the following main groups of indications for pancreas transplantation are distinguished. Firstly, in the presence of indications for kidney transplantation in patients with diabetic nephropathy, it is advisable to establish an indication for simultaneous pancreas-kidney transplantation, since the latter option provides more long-term benefits, and the risk of surgery and complications of lifelong immunosuppressive therapy does not significantly differ from isolated kidney transplantation. In addition, the progression of diabetes complications in patients with a transplanted kidney for diabetic nephropathy is an indication for pancreas transplantation after kidney transplantation.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Information is not available.