Version May 2024
INTRODUCTION — Simultaneous pancreas-kidney (SPK) transplantation is an established, definitive treatment for selected patients with diabetes and end-stage kidney disease (ESKD) [1]. Nearly 90 percent of pancreas transplants in the United States are performed as SPK transplants, with the remainder performed as sequential pancreas after kidney (PAK) transplants or pancreas transplants alone (PTA) [2].
This topic reviews patient selection and the pretransplant evaluation for SPK and PAK transplantation in patients with insulin-requiring diabetes mellitus and ESKD. Patient and graft outcomes, other benefits and complications (other than those induced by immunosuppression) associated with these procedures, surgical considerations and immunosuppression, and the diagnosis and treatment of rejection are discussed elsewhere:
●(See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)
●(See "Pancreas allograft rejection".)
The roles of PTA and islet transplantation in patients with diabetes without kidney failure are discussed separately:
●(See "Pancreas and islet transplantation in diabetes mellitus".)
EPIDEMIOLOGY — According to the International Pancreas Transplant Registry (IPTR), more than 61,000 pancreas transplants were performed worldwide between 1966 and 2020 including >34,000 in the United States. In the United States during 2020, 939 pancreas transplants were performed; 822 were done as simultaneous pancreas-kidney (SPK) transplants, 69 pancreas transplantation alone (PTA), and 48 sequential pancreas after kidney (PAK) transplants [2-4].
While SPK transplants most often involve grafts procured from a single deceased donor following brain death, a few are simultaneous living-donor kidney and deceased-donor pancreas transplants, and some SPK transplants (3 percent) are performed from a deceased donor after cardiac death [5]. Simultaneous living-donor kidney and segmental pancreas transplantation is rarely performed at present.
PAK typically involves transplantation of a deceased-donor pancreas graft into a recipient following either a functioning living- (most common, 80 percent) or deceased-donor kidney allograft. Some patients with diabetes without advanced kidney disease may be candidates for PTA.
The vast majority of SPK and PAK transplants are performed in patients with type 1 diabetes, although an increasing number are performed in patients with a type 2 diabetes phenotype [6]. According to the IPTR, approximately 21 percent of SPK and 14 percent of PAK transplants are performed in patients with a type 2 diabetes phenotype [7]. Among patients with type 2 diabetes who received a kidney transplant between 2000 and 2016, only 2 percent received an SPK transplant, and the remaining received kidney transplant alone (KTA) [8].
INDICATIONS FOR SPK OR PAK TRANSPLANT — Pancreas and kidney transplantation is a therapeutic option for patients with insulin-requiring diabetes and advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). The majority of these patients receive a simultaneous pancreas-kidney (SPK) transplant, although some will receive a sequential pancreas after kidney (PAK) transplant. Patients with insulin-requiring diabetes with normal or near-normal kidney function may be considered for pancreas transplant alone (PTA) if they have hypoglycemic unawareness or brittle diabetes with wild variations in blood glucose levels, and/or if their quality of life is unacceptable because of diabetes-related sequelae. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Indications for transplantation'.)
In general, SPK and PAK transplants are primarily indicated for patients with type 1 diabetes. However, SPK and PAK transplants may be performed for some patients with insulin-requiring diabetes who meet certain selection criteria and exhibit a type 2 diabetes phenotype. A type 2 diabetes phenotype may be characterized by the presence of detectable C-peptide levels, older age of onset of diabetes (and older age at transplant), history of non-insulin-requiring diabetes preceding the need for insulin therapy, shorter duration of insulin dependence, and history of obesity. Whether these patients truly have type 2 diabetes is subject to debate, but clearly they do not meet the classic presentation of type 1 diabetes. In addition to exhibiting the above phenotypic characteristics, potential SPK and PAK transplant candidates with non-type 1 diabetes usually meet the following selection criteria [9-11] (see 'Patient selection' below):
●Age <60 years
●Body mass index (BMI) <30 kg/m2
●Insulin requiring for a minimum of three years with a total daily insulin requirement <1 unit/kg/day
●Fasting C-peptide level <10 ng/mL
●Presence of complicated or hyperlabile diabetes
It is important to note that data on how either C-peptide levels or total daily insulin requirements relate to outcomes following pancreas transplantation are sparse and incompletely understood. The above guidelines are based upon the assumption that patients with extreme insulin resistance may not be appropriate candidates for pancreas transplantation. In addition, selection criteria for SPK and PAK transplant are variable and center specific as some centers will exclude any patient with detectable C-peptide levels. However, International Pancreas Transplant Registry (IPTR) data as well as a number of single-center reports suggest that measuring C-peptide levels is largely irrelevant in terms of either patient selection or predicting outcomes. Moreover, individual centers may have other cut-offs for SPK or PAK candidate exclusion, such as age above 50 years or BMI >28 kg/m2. Alternatively, other centers may transplant patients up to 65 years of age and with a BMI of 30 to 35 kg/m2.
Patients qualifying for an SPK or PAK transplant are usually referred to the transplant center by a nephrologist because of stage 4/5 CKD. Approximately 16 percent of SPK transplants are performed in patients prior to the initiation of dialysis therapy [12]. Most of these patients will have advanced diabetic nephropathy, but some may have kidney disease from a condition other than diabetes. Thus, ESKD does not have to be secondary to advanced diabetic nephropathy to qualify for either SPK or PAK transplantation if the patient has insulin-requiring diabetes. This unique situation offers the opportunity to treat both the kidney disease and insulin-requiring diabetes successfully regardless of cause.
SELECTION OF OPTIMAL PROCEDURE — The selection of the optimal procedure for individual patients depends upon patient-specific factors and organ availability. For younger patients (ie, <45 years old) with type 1 diabetes who have no other cardiac risk factors and few other comorbidities, in the absence of a living-kidney donor, simultaneous pancreas-kidney (SPK) transplant provides the best survival compared with either dialysis or deceased-donor kidney transplantation alone (KTA). The achievement of normoglycemia and insulin independence may increase longevity and also improve quality of life [13-18]. Whether a successful pancreas transplant can improve or induce regression of the long-term clinical complications of diabetes remains unclear [19-22]. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Other potential benefits'.)
Compared with living-donor KTA, SPK and pancreas after kidney (PAK) transplantation may also provide superior long-term survival if there is neither kidney nor pancreas graft loss in the first year following transplantation [17,23-25]. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Patient survival'.)
Another potential advantage of SPK transplantation is that median waiting times are shorter (two to three years) compared with deceased-donor KTA (four to six years). However, because the one- and four-year mortality for waitlisted SPK transplant candidates has been reported to be 6.6 and 41.3 percent, respectively [26], performing a living-donor KTA may be preferred if an individual is facing a long waiting time for SPK transplantation, is not doing well on dialysis, or has "stable" diabetes. In addition, from a societal perspective, a living-donor KTA "adds" a kidney to the list, which means that someone else can benefit from the deceased-donor kidney that is targeted for SPK transplant. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Patient survival'.)
Following KTA, in the absence of sensitization, the waiting time for a PAK transplant is usually one to two years [27]. Thus, patients with a similar clinical profile who have the option to receive a living-donor kidney allograft may do well to choose PAK transplant provided they are willing to undergo two separate transplant procedures. If the candidate, on the other hand, is not yet on dialysis or has an anticipated short waiting time for SPK transplant (based upon blood type, degree of sensitization, and geographic region), then waiting for an SPK transplant is a reasonable option.
In an analysis of the United Network for Organ Sharing (UNOS) registry from 1995 to 2010 of all adults registered for an SPK or PAK, the following observations were reported [28]:
●Five-year patient survival was comparable between SPK and PAK (86 versus 83 percent, respectively), but 10-year patient survival was higher with SPK compared with PAK (70 versus 63 percent, respectively). Patient survival for all transplanted patients was superior to that of patients remaining on the waitlist for an SPK.
●Ten-year kidney allograft survival rates were similar (61 percent) for recipients of either an SPK or a living-donor KTA. Patients who received a PAK after either living- or deceased-donor KTA had superior 10-year kidney allograft survival compared with those who did not. Kidney allograft survival rates were highest (70 percent) for recipients of a living-donor KTA followed by a sequential PAK.
●Ten-year pancreas allograft survival rates were 59 percent for SPK, 44 percent for PAK following living-donor KTA, and 42 percent for PAK following deceased-donor KTA.
These findings suggest that both patient and kidney allograft longevity are maximized by achieving an insulin- and dialysis-free state, whether this is accomplished by either an SPK or a PAK, preferably following a living-donor KTA. Adding a pancreas to a kidney transplant (either simultaneously or sequentially) provides a survival advantage beyond KTA compared with all treatments available to the patient with diabetes and uremia. Since the inception of UNOS in 1987, 79,187 lives (4.6 life-years per recipient) have been "saved" by SPK transplantation and 14,903 lives (2.4 life-years per recipient) by solitary pancreas transplantation in the United States [29]. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Patient survival'.)
In our opinion, for patients who have an available living-kidney donor, the decision to be placed on the deceased-donor waitlist in order to receive an SPK transplant depends upon their dialysis duration and tolerability, their predicted waiting time on the list for SPK, and the severity and progression of diabetic complications. However, in general, the availability of a human leukocyte antigen (HLA)-identical (or zero HLA mismatch) living donor takes precedence over an SPK transplant because of the projected longer lifespan of the kidney in this setting.
For suitable candidates who are not on dialysis (or just starting dialysis and doing well) and for whom a relatively short waiting time for SPK transplant is anticipated (ie, <2 years), we suggest proceeding with an SPK transplant rather than living-donor KTA as per patient preference.
However, we recommend that suitable candidates who have already been on dialysis for at least one year, are not doing well on dialysis, or are anticipating a waiting time for SPK transplant of two years or more proceed with living-donor KTA if available. Because patients with insulin-requiring diabetes and end-stage kidney disease (ESKD) have a high annual mortality rate on dialysis (5 to 10 percent), the shorter waiting time associated with a living-donor KTA becomes an important consideration. In addition, not all patients with insulin-requiring diabetes and ESKD qualify for SPK transplant or are even interested in receiving a pancreas transplant, particularly if they believe that their diabetes is well controlled and are not experiencing extreme glucose hyperlability, hypoglycemia unawareness, or life-threatening, sight-threatening, limb-threatening, progressive, or accelerated complications of diabetes. Finally, when analyzing the relative value of receiving either a kidney or pancreas transplant or both, it is apparent that a functioning kidney transplant (in the absence of a functioning pancreas transplant) is a better predictor of long-term patient survival compared with a functioning pancreas transplant (in the absence of a functioning kidney transplant). Although patients with both kidney and pancreas grafts functioning have the best longevity, a functioning living-donor KTA represents an excellent option from a life expectancy perspective.
In general, if a patient believes that diabetes is controlling their life more than they are controlling their diabetes, or if the presence of diabetes (independent of kidney failure) is self-perceived to be causing a significant impairment in their overall quality of life, then either SPK or PAK transplantation should be considered as a treatment option. In our experience, the above queries are critical to understanding the relationship between the patient and their diabetic condition. Although qualitative and not rigorously scientific, most patients can tell the clinician when they lost control of their diabetes management. In this setting, pancreas transplantation to improve quality of life is not only an endpoint but also a turning point in their overall health and well-being.
For patients who have a well-functioning transplanted kidney, the decision to undergo PAK transplantation depends upon their quality of life and overall satisfaction with KTA, their willingness to undergo another surgical procedure, and/or the presence of progressive or accelerated diabetic complications.
PATIENT SELECTION — The primary determinants for recipient selection are the presence of glucose hyperlability reflecting underlying insulin deficiency, the degree of difficulty in achieving adequate glucose control, progressive diabetic complications (including chronic kidney disease [CKD]), degree of nephropathy (which determines type of transplant), cardiovascular risk and iliac vascular disease, other comorbidities (eg, substance abuse, lung or liver disease, obesity), emotional and psychosocial stability, and overall functional and performance status. In other words, the need for insulin therapy alone is not sufficient to qualify for any type of pancreas transplantation.
Age — Appropriate candidates for simultaneous pancreas-kidney (SPK) transplantation are generally younger than kidney transplantation alone (KTA) candidates with diabetes, reflecting several factors. Patients with type 1 diabetes mellitus tend to develop end-stage kidney disease (ESKD) at an earlier age than patients with type 2 diabetes mellitus. In addition, longstanding diabetes contributes to a higher incidence of other complications, such as cardiovascular disease, which affects transplant candidacy.
Upper recipient age limits for pancreas transplantation vary by center within the United States and usually range between 45 and 65 years old. It is important to note, however, that of the 280 kidney transplant centers in the United States, fewer than one-half actually perform SPK transplants (and the majority of these centers actually perform <5 SPK transplants per year), so access to SPK transplantation is highly variable [17,24-26,30].
We believe that highly selected patients between the ages of 50 to 65 years may benefit from SPK or pancreas after kidney (PAK) transplantation if they do not have significant comorbidities such as advanced cardiovascular, cerebrovascular, or peripheral vascular disease. At the other end of the recipient age spectrum, very few pancreas transplants are performed in the pediatric population (18 years or younger), particularly with advances in the early diagnosis of diabetes and kidney disease, insulin delivery systems, and glucose monitoring.
Single-center studies have reported similar patient, kidney, and pancreas allograft survival rates in patients older than 50 years compared with younger recipients [31-34]. However, both reporting and selection bias may influence data from smaller studies. An analysis of the United Network for Organ Sharing (UNOS) database including 20,854 pancreas transplant recipients between 1996 and 2012 demonstrated that graft survival was superior in recipients 40 to 49 years of age, with reduced patient survival in those 50 to 59 years of age and poor graft and patient survival in those >60 years of age [35]. However, according to International Pancreas Transplant Registry (IPTR) data, some patients age 60 years and older may benefit from SPK transplantation.
Glomerular filtration rate (GFR) — The national pancreas allocation system requires SPK transplant candidates to meet criteria for kidney transplant listing (GFR ≤20 mL/min or dialysis dependence) in order to receive credit for waiting time.
Insulin requirement — Daily insulin requirements and serum C-peptide levels are assessed in order to determine whether the patient will likely benefit from pancreas transplantation. Since pancreas transplantation restores endogenous insulin production, patients who are insulinopenic or who have undetectable or very low C-peptide levels are most likely to benefit from the procedure.
The previous national pancreas allocation system [36], which required patients with a C-peptide >2 ng/mL to have a body mass index (BMI) ≤30 kg/m2, was removed in 2019. This allowed transplant centers to list selected mildly obese patients with type 2 diabetes [37] to receive pancreas transplant.
In general, patients with insulin requirements exceeding 1 unit/kg/day may not always achieve euglycemia after pancreas transplant. In our practice, a very high daily insulin requirement suggests that the patient may have insulin resistance or anti-insulin/islet cell antibodies; such patients may be less likely to benefit from pancreas transplantation and be rendered insulin free, although no randomized trials have examined this issue.
However, patients who are on peritoneal dialysis may have large insulin requirements due to the use of dextrose-containing dialysate. Consequently, this factor must be taken into consideration when such patients are assessed for pancreas transplantation because their daily insulin requirements will likely decrease when peritoneal dialysis is discontinued following kidney transplantation.
Complications of insulin therapy, including the presence of hypoglycemic unawareness and frequency/severity of either hypoglycemic or hyperglycemic episodes, may increase the urgency for pancreas transplantation.
Body mass index (BMI) — The maximum allowable BMI for SPK or PAK transplantation varies between centers but is often lower than that for KTA [38,39]. This is because, unlike kidney transplantation, pancreas transplantation requires intra-abdominal surgery, and posttransplantation wound healing and surgical complications are affected to a greater extent by an elevated BMI. Most centers use a BMI threshold of 30 kg/m2. Some centers may consider performing SPK transplants in selected patients with a BMI in the 30 to 35 kg/m2 range, whereas very few pancreas transplants are ever performed in patients with a BMI >35 kg/m2 (see 'Contraindications' below). By comparison, BMI thresholds for KTA typically range from 36 to 40 kg/m2, although some centers will consider selected patients with a BMI >40 kg/m2 depending on body habitus and other associated factors. In some studies, increasing recipient BMI is an independent risk factor for pancreas graft loss and death in the short term, whereas obesity is a risk factor for pancreas graft loss in the long term [40,41].
At the other end of the BMI spectrum, patients with a very low BMI may have a higher mortality following SPK transplantation possibly because of associated conditions such as deconditioning, frailty, malnutrition, and sarcopenia [17,24-26,30,42]. Furthermore, an elevated BMI is often associated with insulin resistance [43] and, in a single-center, retrospective series, was associated with posttransplant diabetes [38]. It is important to note, however, that in the absence of early graft loss or surgical complications, SPK transplantation in obese recipients is associated with excellent long-term outcomes. Limited data are available with SPK transplant in patients who have previously undergone bariatric surgery. However, in those patients who remain insulin dependent following successful bariatric surgery with significant weight loss, SPK transplantation remains a viable option [44]. In addition, many patients with obesity may benefit from structured weight loss programs and "prehab" in an attempt to improve their transplant candidacy and subsequent outcomes.
Other criteria — In addition to age, duration of diabetes and insulin use, C-peptide levels (as a marker of endogenous insulin secretion), daily insulin requirements, and BMI, potential recipients should be screened for tobacco and other substance use, functional capacity, presence and severity of diabetic-related complications, and additional comorbidities. The evaluation for comorbidities is discussed below. (See 'Pretransplant evaluation' below.)
CONTRAINDICATIONS — Although contraindications may vary by transplant center, absolute contraindications that are adopted by most centers include:
●Age >65 years (see 'Age' above)
●Non-insulin-requiring diabetes (see 'Insulin requirement' above)
●Body mass index (BMI) >35 kg/m2 (see 'Body mass index (BMI)' above)
●Advanced cardiopulmonary disease (ejection fraction below 30 percent, pulmonary artery systolic pressure >50 mmHg, or positive cardiac stress test with uncorrectable coronary artery disease) (see 'Cardiovascular evaluation' below)
●Heavy smoking (>1 pack per day or patients with moderate-to-severe smoking-related morbidities [coronary heart disease, symptomatic or documented cerebrovascular or peripheral vascular disease, chronic obstructive lung disease, history of noncutaneous malignancy]) (see 'Cardiovascular evaluation' below)
●Severe peripheral vascular (aorto-iliac) disease (see 'Evaluation of peripheral vascular disease' below)
●Moderate to severe dysfunction in other (non-kidney) organ systems (lung, liver, central nervous system [CNS]) including cirrhosis, portal hypertension, advanced chronic obstructive pulmonary disease, dementia, or severe neurologic deficits
●Active malignancy with the exception of nonmelanoma skin cancer or low-grade prostate cancer (see 'Cancer screening' below)
●Severe local or systemic infection (see 'Infectious disease evaluation' below)
●Inadequate psychosocial support and financial resources (see 'Psychosocial evaluation' below)
●Active substance addiction or abuse (see 'Psychosocial evaluation' below)
●Major psychiatric illness that cannot be managed sufficiently to enable posttransplant care and safety (see 'Psychosocial evaluation' below)
●Poor overall functional and performance status (severe deconditioning or malnutrition, frailty, dementia, wheelchair user, need for chronic oxygen therapy) (see 'Functional assessment' below)
●Chronic nonhealing wounds
●Projected life expectancy <5 years
Relative contraindications to simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplantation may also vary depending upon the transplant center. A list of commonly accepted relative contraindications is provided in the table (table 1).
PRETRANSPLANT EVALUATION — Patient selection is aided by a comprehensive medical evaluation before transplantation performed by a multidisciplinary team that confirms the diagnosis of insulin-requiring diabetes, determines the patient's ability to withstand the operative procedure and requisite chronic immunosuppression, establishes the absence of any exclusion criteria, and documents end-organ complications for future tracking following transplantation. Potential recipients are carefully screened for coronary heart disease, congestive heart failure, peripheral vascular disease, active infections, and chronic nonhealing wounds. All candidates for pancreas allografts should undergo an extensive pretransplant evaluation for cardiovascular disease. In general, however, the pretransplant medical evaluation for a patient with diabetes is similar regardless of whether they are being considered for either a simultaneous pancreas-kidney (SPK) transplant, pancreas after kidney (PAK) transplant, or kidney transplant alone (KTA) with the exception that thrombophilia screening is performed prior to consideration for pancreas transplantation. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
Cardiovascular evaluation — Probably the single most important clinical aspect of recipient selection is the overall assessment of cardiovascular risk, burden, and reserve. Cardiovascular disease remains the most common cause of death following pancreas transplantation among patients with diabetes [30,45]. Coronary heart disease, defined by prior myocardial infarction, coronary bypass, or percutaneous coronary angioplasty in the past was associated (independent of age) with a 20 percent one-year mortality in SPK and PAK transplant recipients, four times greater than in diabetic recipients without a history of myocardial infarction and/or revascularization [30]. Among such patients, traditional cardiovascular risk factors include a long duration of diabetes, hypertension, dyslipidemia, tobacco use, older age, and male sex. Nontraditional risk factors include long dialysis duration, proteinuria, and hyperparathyroidism. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus" and "Risk factors and epidemiology of coronary heart disease in end-stage kidney disease (dialysis)".)
We screen all pancreas transplant candidates for coronary heart disease to identify modifiable cardiac conditions and potentially reduce morbidity and/or mortality on the waiting list and following transplantation. Additionally, the evaluation may identify patients who have limited expected survival due to severe cardiac disease; such patients should not undergo transplantation. (See 'Contraindications' above.)
The optimal approach to screening the potential pancreas transplant recipient is not clear, and there are no reliable comparative studies in this cohort to guide the evaluation. Most centers screen with either noninvasive tests or cardiac catheterization or both [45]. Our approach depends upon cardiovascular risk factors, including dialysis duration, duration of diabetes, and smoking history.
●In all candidates who are already on dialysis and who have had diabetes >25 years, any smoking history, or other cardiovascular risk factors or disease (age >55 years, hypertension, history of myocardial infarction, congestive heart failure, low ejection fraction, valvular heart disease, arrhythmias, pulmonary hypertension, cerebrovascular disease, or previous major amputation) [46-48], we refer for formal cardiology evaluation and potential cardiac catheterization. Such patients are considered to be at especially high risk for coronary heart disease. The decision to proceed with cardiac catheterization is made in conjunction with the patient's cardiologist and nephrologist, recognizing the risk of contrast nephropathy. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Cardiovascular disease' and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Coronary artery disease'.)
●In all candidates who are not on dialysis, have had diabetes for ≤25 years, are nonsmokers, and have no other cardiovascular risk factors, we perform noninvasive testing and reserve cardiac catheterization for those patients who have a positive noninvasive stress test. For patients who are able to exercise and achieve 85 percent maximum heart rate, we use an exercise stress test.
The requirement for catheterization in higher-risk patients is that a significant number of false-negative noninvasive stress results are observed among patients with end-stage kidney disease (ESKD) [49].
Among patients who are not yet on dialysis, or who are on dialysis but have significant residual kidney function, it is important to weigh the need for cardiac catheterization against the risk of contrast-induced nephropathy. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography".)
Given the significant mortality of waitlisted patients with diabetes who are on dialysis [26], decisions regarding pretransplant catheterization and revascularization must be carefully considered, with the input of a cardiologist, if necessary. Significant coronary heart disease that is not amenable to revascularization may exclude candidates from pancreas transplant consideration. It is important to note, however, that most patients with diabetes and ESKD have identifiable cardiac and/or peripheral vascular disease. It is not the presence but rather the severity of the cardiovascular disease (and if it is correctable) that determines whether the patient is an appropriate candidate for pancreas transplantation.
In patients with smoking-related morbidities (coronary artery disease, symptomatic or documented cerebrovascular or peripheral vascular disease, chronic obstructive lung disease, history of noncutaneous malignancy), complete smoking cessation is required and should be validated by urine nicotine tests prior to transplant. (See 'Contraindications' above.)
A newer contraindication is chronic severe hypotension related to severe diabetic autonomic neuropathy or chronic dialysis, either of which may result in significant and irreversible cardiac dysfunction. Many of these patients require the use of oral vasopressors (such as midodrine) or other agents (such as fludrocortisone) to maintain an adequate systolic pressure. Although some patients may manifest orthostatic hypotension (which by itself is not a contraindication), the inability to consistently maintain a systolic pressure above 100 mmHg places the transplanted pancreas at high risk for vascular thrombosis and the transplanted kidney at risk for ongoing ischemic damage with poor recovery of kidney function [50].
Patients with diabetes and ESKD who are determined not to be appropriate candidates for pancreas transplantation may still be appropriate candidates for KTA versus dialysis therapy, which is another reason to consider a living-donor KTA as the initial option.
Evaluation of peripheral vascular disease — Peripheral vascular disease is common among patients with diabetes and ESKD and may prevent successful transplantation of either the kidney or pancreas because of technical and hemodynamic considerations.
Careful examination of iliac and peripheral pulses should be done in all patients. To identify patients with iliac calcifications, we screen all patients with diabetes older than 45 years of age, those with longstanding hypertension, or those with poor femoral pulses or evidence of vascular disease elsewhere (eg, coronary heart disease or cerebrovascular disease), with a noncontrast abdominopelvic computed tomography (CT) scan. Many centers screen all diabetic pancreas transplant candidates with a noncontrast CT scan. In addition, many centers will perform carotid and iliac artery duplex ultrasonographic imaging as part of the standard evaluation for transplantation in this patient population.
The diagnosis of peripheral vascular disease is difficult to establish in such patients because of the presence of medial artery calcifications that render vessels noncompressible for a standard ankle brachial index and/or toe brachial index.
Patients with symptoms of peripheral vascular disease (eg, claudication), diminished pulses on exam, or abnormal imaging are referred to a vascular specialist for further assessment and testing.
Hypercoagulability evaluation — In contrast to KTA, the risk of pancreas thrombosis is relatively high because it is a low microcirculatory flow organ with its blood supply based on collateral circulation. Consequently, patients with a history of thrombophilia (hypercoagulability) or those on anticoagulation represent a unique risk factor for early pancreas graft loss. In addition, diabetes may be associated with a prothrombotic state [51]. For these reasons, we recommend thrombophilia screening on all potential pancreas transplant recipients with the selective use of perioperative anticoagulation to reduce the risk of early thrombosis. (See "Screening for inherited thrombophilia in asymptomatic adults".)
Cancer screening — Malignancy in the past two years, with the exception of cutaneous squamous, basal cell tumors, and early prostate cancer with low Gleason score, is another contraindication (see 'Contraindications' above). In cases of localized and treated cancer, the cancer-free interval will depend upon the stage and type of cancer. Consultation and "clearance" may need to be obtained from an oncology specialist, but ultimately a determination will need to be made if the patient's mortality in the absence of transplantation is predicted to be higher than their risk of recurrence. Standard cancer screening for SPK or PAK transplantation is similar to KTA and may include chest radiography, mammography, gynecologic examination, dermatology assessment (particularly with any history of skin cancer), colonoscopy, and prostate-specific antigen testing depending upon age and sex. In general, however, patients being considered for pancreas transplantation are younger than those being evaluated for KTA. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Laboratory and imaging tests' and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Malignancy'.)
Infectious disease evaluation — Incurable or incompletely treated or unresolved active or chronic infections represent another contraindication and may include chronic active hepatitis B, hepatitis C, and uncontrolled HIV. However, in the absence of cirrhosis, adequately treated hepatitis B (hepatitis B surface antigen [HbsAg] negative) or hepatitis C virus are no longer considered contraindications to transplantation. In the case of hepatitis C viral infection without cirrhosis, transplantation may precede treatment for hepatitis C to take advantage of organs from hepatitis C-positive donors and provided that the patient has been accepted as a good candidate for anti-hepatitis C virus treatment. In addition, HIV-infected patients with adequately controlled HIV infection, characterized by a CD4 count >200, undetectable HIV RNA levels, a stable antiretroviral regimen for a minimum of three months, and absence of opportunistic infections in the past 12 months, may be considered acceptable for pancreas transplantation. However, patients with chronic nonhealing wounds or osteomyelitis are not considered appropriate for transplantation. Similar to KTA, patients who have traveled out of the country or who have immigrated to the United States may require specialized testing and "clearance" by an infectious disease specialist depending upon previous exposures and the endemicity of the region. (See "Kidney transplantation in adults: Kidney transplantation in patients with HIV" and "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Infections'.)
Psychosocial evaluation — An adequate support system with requisite resources is needed to ensure the success of transplantation. Abstinence from all illicit drugs for a minimum of six months and documentation of compliance are necessary. Smoking cessation is strongly encouraged and at some centers is an absolute requirement. Social alcohol and medicinal marijuana use are considered acceptable, but overuse/dependency/abuse is a contraindication. The use of narcotics for chronic pain is a risk factor that must be carefully evaluated as it has been shown to be associated with inferior outcomes [52,53]. In cases of substance addiction, referral to a structured rehabilitation or cessation program may be indicated. Well-controlled psychiatric disorders are another risk factor that warrant further evaluation, if necessary, by a mental health specialist.
Functional assessment — Severe frailty, deconditioning, malnutrition, and sarcopenia are relative contraindications to transplant; some of these patients may benefit from structured "prehab" programs. The presence of untreatable advanced dysfunction of another major organ system or a projected life expectancy of <5 years because of other irreversible systemic illness or multiple comorbidities are additional contraindications to transplantation. (See 'Contraindications' above.)
We perform standard frailty or "fit" testing in all of our potential (SPK or KTA) candidates that includes grip strength, gait speed, timed repeated chair stands (get up and go test) and six-minute walk [54], balance test, assessment of level of physical activity, and activities and daily level scale. This frailty instrument generates a numerical score that categorizes patients as fit, intermediately fit, or frail. (See "Frailty", section on 'Instruments developed to identify frailty'.)
In an analysis of data from the Scientific Registry of Transplant (SRTR) between 2006 and 2019, the risk of mortality progressively increased for SPK transplant recipients capable of self-care (adjusted hazard ratio [aHR] 1.18, 95% CI 1.00-1.41), requiring assistance (aHR 1.31, 95% CI 1.06-1.60), and who are disabled (aHR 1.55, 95% CI 1.10-2.19), compared with that of patients with normal functioning [55].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●General principles – Simultaneous pancreas-kidney (SPK) transplantation is an established treatment for selected patients with diabetes and end-stage diabetic nephropathy. Pancreas transplants are performed as SPK transplants, sequential pancreas after kidney (PAK) transplants, or pancreas transplants alone (PTA). (See 'Introduction' above.)
●Selection of optimal procedure – Selection of the optimal procedure for individual patients depends on patient-specific factors and organ availability:
•For suitable candidates who are not on dialysis (or just started dialysis) and anticipate a short waiting time for SPK transplant (ie, <2 years), we prefer an SPK rather than living-donor kidney transplant.
•For suitable candidates who have already been on dialysis for a year or two and are anticipating a waiting time for SPK of two years or more, we prefer a living-donor kidney transplant alone (KTA) if one is available. Patients with diabetes and end-stage kidney disease (ESKD) on dialysis have high mortality on the waiting list.
•For patients who have a well-functioning transplanted kidney, the decision to undergo PAK transplantation depends upon patient quality of life and satisfaction with living-donor KTA, willingness to go through another procedure, and diabetes control and complications.
●Patient selection – Suitability of candidates for SPK transplantation depends upon patient-specific factors, including age, body size, comorbidities, functional status, social support, burden of vascular disease, and cardiovascular risk profile. In order to be placed on the waiting list, potential candidates must meet certain standards based on glomerular filtration rate (GFR), daily insulin requirements, C-peptide levels, and body mass index (BMI). Potential recipients are screened for tobacco and other substance use, functional capacity, presence and severity of diabetic-related complications, iliac and cardiac vascular disease, and additional comorbidities. (See 'Patient selection' above.)
●Pretransplant evaluation – Patient selection is aided by a comprehensive medical evaluation before transplantation performed by a multidisciplinary team that confirms the diagnosis of insulin-requiring diabetes, determines the patient's ability to withstand the operative procedure and requisite chronic immunosuppression, establishes the absence of any exclusion criteria, and documents end-organ complications for future tracking following transplantation. Potential recipients are carefully screened for coronary heart disease, congestive heart failure, peripheral vascular disease, active infections, and chronic nonhealing wounds. All candidates for pancreas allografts should undergo an extensive pretransplant evaluation for cardiovascular disease. In general, however, the pretransplant medical evaluation for a patient with diabetes is similar regardless of whether they are being considered for either an SPK/PAK or KTA. (See 'Pretransplant evaluation' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges R Paul Robertson, MD, and Christina L Klein, MD, who contributed to an earlier version of this topic review.
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