Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications

INTRODUCTION — Simultaneous pancreas-kidney (SPK) transplantation is an established treatment for selected patients with insulin-requiring diabetes with either advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). In the United States, nearly 90 percent of pancreas transplants are performed as SPK transplants, with the remainder performed as sequential pancreas after kidney (PAK) transplants or pancreas transplants alone (PTA) [1,2]. The vast majority of SPK, PAK, and PTA transplants are performed in patients with type 1 diabetes, although some programs offer such transplants to insulin-using patients with type 2 diabetes.

While SPK transplantation usually employs grafts procured from a single deceased donor, PAK typically involves transplantation of a deceased-donor pancreas graft into a recipient with either a functioning living- (most common) or deceased-donor kidney allograft. Selected patients without substantial kidney disease may be candidates for PTA.

The benefits and nonimmunologic complications associated with either SPK or PAK transplantation in patients with diabetes mellitus are presented here. Patient selection for and the clinical approach to these procedures are discussed separately:

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

●(See "Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression".)

BENEFITS — The major benefits of simultaneous pancreas-kidney (SPK) transplantation are decreased mortality and improved quality of life. The decreased mortality is due in large part to the well-established survival benefit conferred by kidney transplantation alone (KTA; even without pancreas transplantation) compared with dialysis [3]. However, adding a pancreas to a kidney transplant, either simultaneously or sequentially, may be associated with an incremental survival benefit beyond KTA compared with dialysis [4-15]. This finding remains true even in the setting of early pancreas graft loss [16,17]. (See "Kidney transplantation in adults: Patient survival after kidney transplantation", section on 'Survival compared with dialysis'.)

The improved quality of life is due to freedom from frequent blood sugar monitoring, insulin therapy, glucose variability, and dialysis [7,18-30]. Although both SPK and KTA are associated with an increased energy level and better overall functional status, SPK transplant recipients experience additional improvements in sense of well-being, autonomy, and independence. By rendering an individual "ex-diabetic," a functioning pancreas transplant removes the stigma of diabetes by eliminating fear of hypoglycemia, promoting fewer dietary restrictions, and providing opportunities for improved lifestyle change and incremental gains in quality-adjusted life years [7,22-28,31-34].

Our understanding of the relative benefits of SPK compared with KTA is hampered by the absence of any randomized trials. All of the claims regarding the benefits of pancreas transplantation are based upon limited and generally poorly controlled studies. SPK transplantation, by achieving euglycemia, should theoretically decrease the long-term retinal, kidney, neurologic, and macrovascular complications of diabetes. However, no randomized trials have been performed, and studies of secondary complications of diabetes must be interpreted in light of the fact that most patients undergoing pancreas transplantation have had diabetes for well over two decades and often have advanced-stage complications that may be irreversible. The majority of studies examining the effects of pancreas transplantation on the secondary complications of diabetes are older, inadequately powered, and/or lack appropriate control groups [35-43].

The majority of patients who undergo SPK transplantation have type 1 diabetes. However, the procedure may also confer benefits for selected patients with type 2 diabetes [44-49].

Survival rates after SPK transplantation are comparable between patients with types 1 and 2 diabetes when adjusted for other risk factors [39,40,44,45,47,49-52]. An analysis of data obtained from the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) showed no difference between patients with types 1 and 2 diabetes in the rate of death or kidney or pancreas failure once adjustments for age, race, body weight, dialysis time, and cardiovascular comorbidities were made. Numerous other single-center studies have corroborated these findings. A Scientific Registry of Transplant Recipients (SRTR) study demonstrated that, in patients with type 2 diabetes undergoing SPK transplantation, having a functioning pancreas allograft at three months (94 percent of patients) conferred a survival advantage for SPK transplantation compared with either living-donor or deceased-donor KTA [53].

Patient survival — Survival for SPK transplant recipients is much better than that of waitlisted patients who continue to receive dialysis [4-13,54,55]. In a retrospective review of 351 patients on dialysis with type 1 diabetes, at seven years, survival rates were higher among 130 who underwent SPK transplantation compared with 190 who remained on the waiting list (77 versus 40 percent, respectively) [55]. Cardiovascular risk factors, hypertension, and other clinical characteristics were similar between groups. However, it is well established that patients who undergo KTA have improved survival compared with those who are eligible for transplantation but remain on the waiting list. In addition, a number of studies have reported that the contribution of the pancreas transplant adds to the mortality benefit of KTA for patients with diabetes. (See "Kidney transplantation in adults: Patient survival after kidney transplantation", section on 'Survival compared with dialysis'.)

Among patients with type 1 diabetes, SPK transplantation appears to confer better survival than KTA, at least when compared with deceased-donor KTA [55-65]. As examples:

●A small, 10-year study evaluated outcomes after SPK transplantation in 14 patients with type 1 diabetes and end-stage diabetic nephropathy versus 15 diabetics subjected to deceased-donor KTA [62]. Ten-year mortality was significantly lower among those who underwent SPK transplantation (20 versus 80 percent).

●A retrospective study of 18,549 patients with type 1 diabetes reported that the eight-year survival rate was similar for SPK (72 percent) and living-donor kidney recipients (72 percent) but higher than that observed for deceased-donor kidney recipients (55 percent) [60].

●Patient survival was evaluated among 130, 379, and 296 recipients of living-related-donor kidneys, SPKs, and deceased-donor kidneys, respectively [63]. Patient survival was significantly lower for the deceased-donor KTA group versus that observed with recipients of SPK and living-related-donor KTAs.

●In a nationwide cohort of kidney replacement therapy in patients with type 1 diabetes with 30-year follow-up from the Netherlands, SPK transplant recipients with a functioning graft at one year (91 percent) had the longest survival (median 17.4 years) compared with either deceased-donor or living-donor KTA recipients [4]. The 10- and 20-year mortality hazard ratios (HR) favoring SPK over KTA were 0.56 and 0.69, respectively.

It is less clear whether SPK transplantation has any benefit over KTA from a living donor. In some, but not all, studies, SPK transplantation is associated with better survival compared with KTA from a living donor. The potentially superior benefit gained by SPK versus living-donor KTA generally depends upon the early function of the pancreas allograft. SPK recipients who have good pancreas function early on tend to do better than living-donor KTA recipients. This was shown in an analysis of OPTN/UNOS registry data [66]. At 72 months, patient survival was similar between SPK and living-donor KTA (84 versus 80 percent at 72 months, respectively). After adjusting for multiple variables, compared with SPK recipients, living-donor KTA recipients had a lower risk of graft failure (HR 0.71, 95% CI 0.61-0.83) and patient death (HR 0.78, 95% CI 0.65-0.94).

However, in a more detailed analysis of the same data in which SPK recipients were stratified based upon a functioning pancreas allograft at one year, patient survival at 84 months posttransplant was highest in SPK recipients with a functioning pancreas graft 12 months posttransplant, followed by living-donor KTA, SPK recipients with a nonfunctioning pancreas, and then deceased-donor KTA (89, 80, 74, and 65 percent, respectively) [67]. Kidney allograft survival was also highest in SPK recipients with a functioning pancreas.

Some patients receive a living-donor KTA as the first option and then subsequently receive a pancreas after kidney (PAK) transplant. With the PAK transplant, there is an initial increase in mortality (which is true for any type of transplant procedure; there is a finite, albeit low, perioperative mortality risk). In a retrospective study of over 11,000 patients with diabetes on the waitlist from 1995 to 2000, mortality within four years of transplantation was evaluated among those who underwent PAK, SPK, and pancreas transplant alone (PTA) versus patients waiting for the same procedure [3]. Overall relative risk (RR) of all-cause mortality at four years was significantly higher for those who underwent PAK transplant versus those on the waitlist for PAK transplant (RR 1.42, 95% CI 1.03-1.94). The higher mortality risk in this study was primarily due to deaths occurring in the first three months posttransplant. However, in a follow-up study using the same database and controlling for confounding variables such as duplicate counts, a multivariate analysis demonstrated similar mortality among patients with diabetes who underwent PAK transplantation compared with those on the waiting list for PAK transplant [13].

Another study based on the UNOS database between 1997 and 2007 compared living-donor KTA with a functioning allograft at one year (n = 2989) versus pancreas after living-donor kidney transplant that had occurred within the first year post-kidney transplantation (n = 484) [68]. Compared with living-donor KTA and after adjusting for multiple donor- and recipient-related factors, despite the initial increase in mortality, PAK recipients had a nonsignificant trend toward better survival at eight-year follow-up (adjusted HR 0.78, 95% CI 0.57-1.07).

Kidney allograft survival — Overall, kidney allograft survival rates among type 1 diabetic recipients of SPK transplants are generally comparable with those seen with living-donor KTAs and superior to those observed after deceased-donor KTAs [69]. The reason for the improved kidney allograft survival among SPK recipients compared with recipients of deceased-donor KTAs likely reflects the effects of prolonged euglycemia in recipients with functional pancreas allografts, demographic and clinical differences in the patients with type 1 diabetes who are selected for SPK versus KTA, and deceased-donor organ quality (younger donors and shorter waiting times for SPK recipients). Overall, SPK candidates are younger, have a lower body mass index (BMI), and are more often preemptively transplanted compared with diabetic, deceased-donor KTA recipients. In addition, SPK recipients experience shorter cold ischemia times (CITs), experience less delayed graft function, and more often receive depleting antibody induction agents.

The beneficial effects of the pancreas allograft on kidney allograft survival in SPK recipients are evident when outcomes are stratified by time from transplantation. One study demonstrated that, after 10 years of transplantation, kidney allografts in SPK recipients were less likely to have allograft failure compared with deceased-donor KTA (adjusted HR 0.58, CI 0.40-0.84) and living-donor KTA (adjusted HR 0.63, CI 0.40-1) [70].

These benefits were also reported in short-term follow-up based on the function of the pancreas at one year. Kidney allografts in SPK recipients who had a functioning pancreas allograft at one year had significantly better survival compared with kidney allografts in deceased-donor KTAs and living-donor KTAs, whereas recipients with a failed pancreas at one year (13 percent) had a higher probability of kidney failure and higher mortality compared with living-donor but not deceased-donor KTA [67].

Retrospective data suggest that SPK transplants performed prior to the need for dialysis (eg, preemptive transplantation) may be associated with improved kidney allograft survival compared with SPK transplants performed after the initiation of dialysis [71]. Preemptive SPK transplantation may also be associated with improved long-term patient survival and a greater likelihood of patients returning to gainful employment [72]. In a single-center retrospective study, preemptive SPK transplantation was associated with a kidney (but not pancreas) death-censored survival benefit when adjusting for confounding factors [73]. However, in this study, patients on dialysis undergoing SPK transplantation with a longer duration of pretransplant dialysis did not experience inferior survival outcomes. Similar observations have been made for preemptive transplantation of kidney allografts alone. (See "Kidney transplantation in adults: Timing of transplantation and issues related to dialysis", section on 'Preemptive transplantation'.)

Although pancreas transplantation is associated with a finite risk (5 percent) of early graft failure (usually secondary to thrombosis) in all three recipient categories, the mean graft longevity in the absence of early graft loss (conditional graft survival) is 14 years for both the kidney and pancreas grafts following SPK transplantation [74]. Moreover, pancreas graft survival of 25 years and longer was reported in a single-center cohort of SPK transplant recipients [75].

Other potential benefits — In addition to potentially improved survival, pancreas transplantation may decrease morbidity. Studies have examined the effect of pancreas transplantation on multiple sequelae of diabetes including the following:

●Glucose metabolism

●Lipid metabolism and atherosclerosis

●Nephropathy

●Retinopathy

●Circulation

●Fertility

●Fracture risk

We discuss the effect of pancreas transplantation on each of these areas below. We focus on studies among kidney transplant recipients. The effects of PTA (ie, in non-end-stage kidney disease [ESKD] patients) are discussed elsewhere. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Metabolic effects' and "Pancreas and islet transplantation in diabetes mellitus", section on 'Effects on the chronic complications of diabetes'.)

●Glucose metabolism – Successful pancreas transplantation is defined as restoration of normoglycemia without the need for exogenous insulin. However, basal and stimulated peripheral serum insulin concentrations are two to three times higher than normal in recipients of pancreas grafts with systemic venous drainage. This hyperinsulinemia is due to the delivery of insulin into the systemic circulation [76,77] so that first-pass hepatic uptake and degradation, which removes 50 to 90 percent of the insulin reaching the liver via the portal vein, are bypassed. Although systemic hyperinsulinemia has been associated with the metabolic syndrome and other complications in the nontransplant setting, there is no evidence to date to suggest that this contrived hyperinsulinemia associated with systemic venous drainage of a pancreas transplant is related to any unique morbidity.

Glucose counterregulation also improves after pancreas transplantation because the transplanted pancreas produces not only insulin but also glucagon [20,78,79]. Most recipients have had diabetes for many years and therefore have abnormal counterregulation of hypoglycemia due to decreased glucagon and epinephrine responses (see "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus"). Glucagon responses are normalized and epinephrine responses are improved after successful pancreas transplantation. Importantly, symptom recognition of hypoglycemia is restored and occurs at higher blood glucose concentrations [20]. Hypoglycemia may be a complication of pancreas transplantation but has only been reported sporadically [21] and is usually mild.

More physiologic control of levels of insulin, glucagon, and glucose, in particular, and carbohydrate metabolism, in general, have been maintained for up to 20 years or longer after successful pancreas transplantation [80-86]. The immediate glucometabolic effects of a functioning pancreas transplant are dramatic and truly render these patients "ex-diabetic." Pancreas transplant recipients have few if any dietary restrictions, and the majority no longer even check their blood glucose levels. A functioning pancreas transplant mitigates glycemic variability, optimizes time in range, eliminates the daily stigma and burden of diabetes, and is the single most effective way of achieving normoglycemia long term for a diabetic patient. Depending on the type of pancreas transplant, the expectation is that 85 to 90 percent of recipients will be rendered completely insulin free at one year posttransplant. The mean pancreas graft life expectancy, which maintains this euglycemic state, is a decade or longer.

●Lipid metabolism and atherosclerosis – Serum triglyceride and low-density lipoprotein cholesterol (LDL-C) concentrations tend to fall and serum high-density lipoprotein cholesterol (HDL-C) concentrations tend to rise in recipients of pancreas transplants [87,88]. Several studies have suggested that SPK transplantation may reduce predicted cardiovascular risk as well as the progression of macrovascular disease [8,15,37,41-43,70,89,90]. A longitudinal, single-center retrospective study comparing 101 SPK and 26 KTA recipients with insulin-dependent diabetes mellitus suggested that peripheral vascular complications and progression of peripheral vascular disease were both decreased in SPK recipients, which was attributed to a superior metabolic vascular risk profile [91].

●Diabetic kidney disease – Recurrent and de novo diabetic nephropathy is prevented by successful pancreas transplantation [35,92-94]. PTA may reverse established diabetic lesions in patients with early diabetic kidney disease (DKD). In one series, functional and structural analyses of the native kidneys were performed after successful PTA in 13 patients with type 1 diabetes [93]. These patients began with a normal creatinine clearance; nine had moderately increased albuminuria (formerly called "microalbuminuria"), and four had overt proteinuria. When compared at five years with a control group treated with conventional insulin therapy, those with PTA had a lower glomerular filtration rate (GFR) due presumably to the nephrotoxic effect of cyclosporine. However, histologic changes of DKD (increased mesangial and glomerular volume) were stable versus an increase in the control group. Subsequent follow-up of eight of these patients at 10 years suggested that successful pancreas transplantation could eventually reverse established lesions of DKD [35]. Significant reductions were observed in the thickness of the glomerular basement membranes (GBM; 404 versus 594 nm at baseline) and the mesangial fractional volume (0.27 versus 0.33) (figure 1). All of these patients had pancreas graft survival exceeding 10 years.

Ultrastructural benefits of euglycemia have also been shown in kidney allografts. A study of patients with type 1 diabetes mellitus examined kidney allograft structure in living-donor KTA (n = 17) and in SPK recipients (n = 25). Compared with SPK, kidneys of patients who had KTA had wider GBMs (369 versus 281 nm) and increased mesangial fractional volume (0.23 versus 0.16) at a median follow-up of 10 years. This study excluded recipients with either failed kidney or pancreas allografts [95].

Data on the effects of pancreas transplantation on native kidney function are limited. One study suggested that PTA might decrease proteinuria. In this study, 32 patients with a functioning PTA had a decrease in protein excretion one year after pancreas transplantation compared with 30 matched patients with type 1 diabetes who did not have a pancreas transplant [96]. However, the use of calcineurin inhibitors independent of the achievement of euglycemia may reduce proteinuria. For patients who undergo PTA, it is estimated that up to 15 percent may eventually develop end-stage kidney disease (ESKD). Nevertheless, the requisite use of calcineurin inhibitors in this population does not appear to accelerate chronic kidney disease (CKD), and it is widely believed that the majority of patients with a functioning pancreas transplant experience a stabilization of nephropathy. In a landmark study of 66 consecutive PTA recipients with 10-year follow-up, only six patients (9 percent) developed stage 4 or 5 chronic kidney disease [94]. In those patients with normoglycemia at 10 years and in the absence of pretransplant macroalbuminuria, 74 percent maintained stable kidney function.

As another example of the benefits of sustained euglycemia on nephropathy, in the studies cited above comparing SPK with living- and deceased-donor KTA, patients with a functioning pancreas transplant appear to have the best long-term kidney graft survival rate. In addition, successful PAK transplantation is associated with improved long-term kidney graft function and survival outcomes compared with KTA [12].

●Diabetic neuropathy – There is stabilization and, in some cases, improvement in peripheral and autonomic diabetic neuropathy after pancreas transplantation [36,97-101]. In one study, stabilization of neuropathy was documented by physical examination, sensory nerve conduction, motor nerve conduction, and cardiorespiratory reflex among 115 patients 10 years after transplantation [36].

Morphologic changes among transplant recipients may be seen much earlier. Using corneal confocal microscopy (CCM), which is a highly sensitive technique to examine early nerve damage in patients with diabetes, a significant improvement was demonstrated in nerve morphology (nerve fiber density, branch density, and length) among 15 patients with diabetes 12 months after pancreas transplantation compared with baseline [102,103].

●Diabetic retinopathy – Diabetic retinopathy is a common microvascular complication of diabetes [104,105]. (See "Diabetic retinopathy: Classification and clinical features", section on 'Prevalence and natural history'.)

Approximately 80 percent of pancreas transplant candidates have diabetic retinopathy at the time of transplant [106]. The effect of pancreas transplant on diabetic retinopathy is not clear. Some studies have found no benefit in terms of halting or reversing the progression of advanced retinopathy after pancreas transplantation [107-109].

Other reports, however, have noted stabilization or occasional regression of retinal lesions following successful pancreas transplantation [110,111]. The difference between studies might be related to the use of different methods of classifying diabetic retinopathy. One study found that recipients of SPK transplants had less retinal damage (ascertained by funduscopy and the need for laser treatment) three years after transplant compared with a group receiving KTA [38].

Another study showed that 79 percent of SPK recipients experienced stabilization in diabetic retinopathy, 10 percent progressed, and 10 percent improved at a median follow-up of 17 months, whereas 49 percent of the matched control group of patients with diabetes (with no transplant) progressed (figure 2) [112]. None with advanced-grade or laser-treated diabetic retinopathy were improved in either group. The concern that early worsening of diabetic retinopathy due to sudden glucose normalization and perioperative morbidity following pancreas transplantation has been largely refuted [113,114].

●Fracture risk – The risk of fracture may be lower following SPK transplant compared with that after KTA. This was suggested by a retrospective analysis of 11,145 diabetic transplant recipients (4933 SPK and 6212 KTA recipients) who were identified from the United States Renal Data System (USRDS) [115]. After adjusting for multiple covariates, SPK transplantation was associated with a lower fracture risk (HR 0.79, 95% CI 0.66-0.96). The protective effect of SPK transplant on fracture was particularly evident among men. The reasons underlying the apparent protective effect of SPK transplantation on fractures cannot be determined from this retrospective study [116].

●Reproductive health – The International Pancreas Transplant Registry (IPTR) has reported 47 pregnancies among 34 pancreas-kidney recipients, which resulted in 38 live, healthy infants. Excellent metabolic control was observed in all pregnancies. Adverse results included the loss of a pancreas and a kidney allograft in two patients and the acceleration of retinopathy in another. Several other studies have documented the safety of planned pregnancy in SPK recipients with stable kidney and pancreas allograft function [117-120]. (See "Sexual and reproductive health after kidney transplantation".)

●Quality of life – SPK transplantation has been shown to improve quality of life compared with KTA [7,22-28,31-34]. Pancreas transplantation offers the benefits of independence from finger sticks for glucose monitoring and from insulin injections, avoidance of hypoglycemic episodes, and reduced risk of developing diabetic retinopathy and neuropathy [65,121]. In one study of patients with type 1 diabetes and ESKD, SPK transplantation was more cost effective over five years than KTA or dialysis after adjusting for quality of life [122,123].

COMPLICATIONS

General complications — Complications are generally more severe and common in the first year posttransplant in simultaneous pancreas-kidney (SPK) transplant compared with kidney transplantation alone (KTA) recipients and are generally related either to the more complex surgery or to immunosuppression that is required.

Due to perioperative complications, greater morbidity and early mortality is associated with SPK compared with KTA. This difference is reflected by longer initial hospital stay, more frequent rehospitalization during the first 30 days (55 percent after SPK versus 30 percent after KTA) and first year posttransplant, greater severity of illness requiring rehospitalization, and increased risk of perioperative mortality [13,124-127]. Surgical complications (including graft thrombosis) can also occur after pancreas after kidney (PAK) and pancreas transplantation alone (PTA), resulting in part in inferior pancreas graft survival rates in solitary pancreas (PAK or PTA) compared with SPK transplants [45,128-131]. Approximately 5 to 8 percent of all pancreas transplants in the United States are lost secondary to early technical failure (depending upon transplant category) with reoperative rates ranging from 12 to 43 percent [74,132-141]. Graft thrombosis (primarily venous in origin) continues to be the leading cause of technical failure, accounting for 80 percent of early technical pancreas graft losses [132-135,137-144]. Other reasons for early technical failure include anastomotic leaks, pancreatitis, bleeding, infection, and primary nonfunction. In addition, metabolic derangements and gastrointestinal, urologic, and wound complications may contribute to poor early outcomes and morbidity. However, early relaparotomy rates have continued to decrease over time with better donor selection, minimization of cold ischemia time, and improved techniques of enteric drainage of the exocrine secretions [132-146].

Pancreas failure — Until recently, a uniform definition of pancreas graft failure was lacking. Pancreas graft failure has been defined by resumption of diabetes medications, which may include any chronic medication, insulin only, or medications near or exceeding those required pretransplant [147]. Pancreas graft failure has also been defined by absence of measurable C-peptide or by elevated glycated hemoglobin (HbA1c) levels. Considering this important limitation, the one- and five-year unadjusted pancreas graft survival rates in SPK recipients are approximately 89 and 75 percent, respectively [148]. Five-year graft survival rates for PTA and PAK transplants are inferior to SPK transplants, at 57 and 65 percent, respectively. The inferior graft survival rates among solitary pancreas transplant recipients have been attributed to higher rates of early thrombosis and acute rejection in the absence of a simultaneously transplanted kidney. (See "Pancreas allograft rejection".)

In 2018, the United Network for Organ Sharing (UNOS) Pancreas Transplantation Committee implemented a new standardized definition for pancreas graft failure that is to be used for program-specific reporting to the International Pancreas Transplant Registry (IPTR) and the Scientific Registry of Transplant Recipients (SRTR). The new definition of pancreas graft failure includes any of the following criteria:

●A recipient's transplanted pancreas is removed

●A recipient re-registers for a pancreas

●A recipient registers for an islet transplant after receiving a pancreas transplant

●A recipient's insulin use is ≥0.5 units/kg/day for 90 consecutive days

●A recipient dies

However, this definition is not perfect, because some patients may have been managed pretransplant with total daily insulin requirements of <0.5 units/kg/day whereas others may have a (partially) functioning graft but develop insulin resistance from either posttransplant weight gain or medication. Attempts to incorporate either C-peptide or glycated hemoglobin levels into the definition have proven to be difficult and unreliable.

The early (first three months) technical failure rate for pancreas recipients in the United States is approximately 5 percent for SPK, 5.5 percent for PAK, and 7 percent for PTA recipients, with graft thrombosis accounting for the majority of these early graft losses [74]. Graft thrombosis occurs primarily in the first week following transplant and is associated with graft pancreatitis, hypotension, reperfusion injury, and prolonged cold ischemia times (CITs), as well as hypercoagulable states. Other causes of early technical failure (in descending order of frequency) include infection, pancreatitis, anastomotic leak, bleeding, and primary nonfunction in the absence of thrombosis. Early technical failure rates may be greater with higher donor or recipient body mass index (BMI). Early technical failures account for over one-half of graft losses in the first posttransplant year and usually necessitate graft pancreatectomy [124,149,150]. Between 2015 and 2019, however, early technical failure rates have decreased to 5 to 7 percent in all three categories of pancreas transplants (SPK, PAK, and PTA). From 3 to 12 months posttransplant, the primary causes of graft failure include acute or chronic rejection, death with a functioning graft, and infection. One-year rates of immunologic pancreas graft loss are 1.4 percent in SPK and 3 to 5 percent in solitary pancreas transplant recipients.

Donor factors — Donor factors influence surgical complications, technical failures, and long-term pancreas allograft survival [151-153].

In a single-center study, technical failure (defined as graft loss within the first 90 days following transplantation) was 10.2 percent. Thrombosis and pancreatitis were the leading etiologies. Donor risk factors for technical failure were age >50 years, BMI ≥30 kg/m², serum creatinine ≥2.5 mg/dL, and preservation time >20 hours [150].

In a separate analysis using data from the SRTR, donor risk factors for pancreas allograft failure including sex, age, race, BMI, height, cause of death, preservation time, donation after cardiac death (DCD), and creatinine were used to create a pancreas donor risk index (PDRI) to estimate the risk of early pancreas failure. Increased PDRI was significantly associated with graft loss within the first posttransplant year for all types of pancreas transplants. Donors with PDRI less than 1.16 (SPK) or less than 0.86 (PTA) had the best survival probability at one year [154].

Mild donor obesity was examined in a different study that found that pancreata from donors with BMI 30 to 35 kg/m² did not carry a higher risk of pancreas graft failure at short- and long-term follow-up compared with pancreata from lean donors (BMI 20 to 25 kg/m²) [155].

Although these models in theory can be used to improve the utilization of donors perceived to be at higher risk, in practice they are not used prospectively in donor evaluation or clinical decision-making pursuant to a given pancreas offer.

Recipient factors — Recipients over age 45 years carry a twofold greater risk of graft loss, most often due to technical failure, and a threefold greater risk of dying than younger patients [151,156,157]. However, some highly selected older individuals may do as well as younger individuals. The selection of individuals for SPK transplantation is discussed elsewhere. (See "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Patient selection'.)

In the IPTR data report, for example, there was little difference in pancreas allograft survival rates between SPK recipients 30 to 40 years of age and those older than 40 years of age [158].

An analysis of the 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 [159].

Age cut-off for pancreas transplant varies by center within the United States between 45 and 65 years old. We believe that highly selected patients between the ages 50 to 60 years may benefit from SPK transplantation if they do not have significant comorbidities such as advanced cardiovascular, cerebrovascular, or peripheral vascular disease [160-162].

In addition, inferior pancreas outcomes are more common among patients with obesity (defined as BMI >30 kg/m²) [163,164] and among Black patients [165-169].

Infection — The immunosuppressive strategies used in SPK and PAK transplantation expose the patient to an increased risk of bacterial, fungal, and viral infections. As with other immunosuppressed transplant recipients, cytomegalovirus (CMV) infection is among the most common viruses causing clinically significant infection in SPK recipients. In the EuroSPK 001 study, for example, the rate of CMV infection following SPK transplantation, was 11, 40, 37, and 52 percent, for donor-minus (D-)/recipient-minus (R-), D-/R+, D+/R+, and D+/R- pairs, respectively [170-173]. Up to 63 percent of patients with diabetes who undergo pancreas transplantation are CMV seronegative. This circumstance may further increase the risk of CMV infection, particularly in the setting of depleting antibody induction (which is administered in 85 percent of pancreas transplant recipients).

As in kidney transplant recipients, BK virus may be a significant cause of kidney graft loss in SPK recipients [174]. The major diseases caused by BK virus are tubulointerstitial nephritis and ureteral stenosis. (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)

Metabolic disturbances — The traditional method of exocrine pancreas drainage was to the bladder because it revolutionized the safety of the transplant procedure in the late 1980s to early 1990s. However, metabolic disorders (acidosis, dehydration) associated with bladder drainage prompted a shift to pancreas transplantation using enteric drainage in the late 1990s and thereafter. SPK with bladder drainage is associated with numerous metabolic and hemodynamic disturbances including normal anion gap metabolic acidosis, hyponatremia, dehydration, and orthostasis.

●Metabolic acidosis – SPK transplantation with bladder exocrine drainage is often associated with the loss of large quantities of bicarbonate-rich pancreatic secretions into the urine, leading to a normal anion gap metabolic acidosis, hyponatremia, and volume depletion. The hyponatremia is presumably due to the combination of hypovolemia-induced stimulation of the release of antidiuretic hormone and the replacement of solute-rich pancreatic secretions with free water. As a result, many SPK recipients with bladder drainage require chronic sodium bicarbonate supplementation; the dose is often as high as 100 to 150 mEq/day.

Problems with acidosis and volume depletion are greatly reduced with enteric exocrine drainage of the pancreas graft [125,126,145]. In a single-center report of 30 and 23 patients with bladder and enteric drainage, respectively, the incidence of metabolic acidosis was significantly lower in those with enteric drainage (0 versus 83 percent) [126]. In the new millennium, approximately 90 percent of pancreas transplants are performed with enteric drainage in all three categories. Surgical considerations including pancreatic drainage are discussed elsewhere. (See "Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression", section on 'Surgical considerations' and "Pancreas-kidney transplantation in diabetes mellitus: Surgical considerations and immunosuppression", section on 'Bladder versus enteric exocrine drainage'.)

●Hyperglycemia – Hyperglycemia can result from pancreatic dysfunction due to rejection or technical problems, to calcineurin inhibitor toxicity, or to recurrent diabetes. Cyclosporine and tacrolimus both adversely affect beta cell function [175,176]. These effects include decreased insulin gene expression, decreased stability of insulin messenger RNA (mRNA), decreased insulin synthesis, and decreased insulin secretion in vivo [177]. In addition, glucocorticoids can cause insulin resistance and weight gain, which in some cases can lead to the development of type 2 diabetes posttransplant. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)

Recurrent autoimmunity may also cause hyperglycemia [127,178-180].

Posttransplant erythrocytosis (PTE) — PTE is defined as persistently elevated hemoglobin and hematocrit levels that occur following kidney transplantation and persist for more than six months in the absence of thrombocytosis, leukocytosis, or another potential cause of erythrocytosis. One single-center, retrospective analysis has suggested that PTE may be more common among recipients of SPK compared with KTA [181] (see "Kidney transplantation in adults: Posttransplant erythrocytosis", section on 'Risk factors'). However, with the advent of enteric exocrine drainage, the incidence of PTE has decreased dramatically and is no longer a common problem, potentially owing to less dehydration than with bladder drainage and contemporaneous changes in immunosuppressant agents.

Other complications — Other common nonimmunologic complications include wound problems, gross hematuria, recurrent urinary tract infections (UTIs), and vascular thrombosis [13,124-126,132-146].

In a retrospective review that compared 276 SPK with 1833 KTA recipients, following SPK transplant, there was an increase in the risk of deep venous thrombosis (DVT; 18 versus 6 percent) and pulmonary thromboembolism (4.7 versus 1.7 percent) [182]. DVT tended to occur more often on the side of the pancreas than the kidney (57 versus 43 percent), and the risk of DVT was greatest in the first posttransplant month.

Patients with bladder-drained pancreata are more likely to have hematuria, urethritis, urethral stricture, UTIs, and urine leak than enteric-drained pancreata [125,126]. Exocrine drainage into the bladder is not physiologic and results in a unique set of urologic, metabolic, infectious, and other issues that can be difficult to manage and can become chronically debilitating for patients. In this setting, patients with intractable, recurrent, or refractory complications were then treated with open conversion from bladder to enteric drainage (enteric conversion). Enteric conversion is in essence a surgical complication of bladder drainage [145,183-185]. Paradoxically, the success of enteric conversion paved the way for the resurgence of interest in primary enteric drainage. Rates of enteric conversion range from 10 to 40 percent in some series, but several studies have reported excellent long-term pancreas (and kidney) graft function with significant resolution of symptoms, even if the enteric conversion is performed several years following SPK transplantation.

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 insulin-requiring diabetes with either advanced chronic kidney disease (CKD) or end-stage kidney disease (ESKD). In the United States, nearly 90 percent of pancreas transplants are performed as SPK transplants, with the remainder performed as sequential pancreas after kidney (PAK) transplant or pancreas transplant alone (PTA). While SPK usually employs grafts procured from a single deceased donor, PAK typically involves transplantation of a cadaveric pancreas graft into a recipient with either a functioning living- or deceased-donor kidney allograft. (See 'Introduction' above.)

●Benefits – The major benefits of SPK transplantation are decreased mortality and improved quality of life. The decreased mortality is due in part to the well-established survival benefit conferred by kidney transplantation (ie, even without pancreas transplantation) compared with dialysis. Our understanding of the relative benefits of SPK compared with kidney transplantation alone (KTA) is hampered by the absence of any randomized trials. All of the claims regarding the benefits of pancreas transplantation are based on limited and generally poorly controlled studies. Potential benefits of SPK transplantation include improved glucose and lipid metabolism, possibly a decrease in the risk of recurrent diabetic kidney disease, and stabilization and improvement in neuropathy and retinopathy. (See 'Benefits' above.)

●Complications – Nonimmunologic complications are the most severe in the first three months posttransplant and generally relate to the surgery or the immunosuppression required. Technical failures occur in approximately 5 to 8 percent of recipients depending on type of transplant, with graft thrombosis as the leading cause. Other complications may include graft pancreatitis, infections (intra-abdominal, urinary), wound issues, and systemic viral infections. (See 'General complications' 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.