The Influence of Recipient Age on Outcomes Following Pancreas-Kidney Transplantation

Abstract

The influence of recipient age on outcomes following simultaneous pancreas-kidney transplantation (SPKT) in the modern era is uncertain. We retrospectively studied 255 patients undergoing SPKT at our center from 11/01 to 8/20. Recipients were stratified according to age group: age <30 years (n=16); age 30-39 years (n=91); age 40-49 years (n=86), and age ≥ 50 years (n=62 [24.3%], including 9 patients ≥60 years of age). Three-month and one-year outcomes were comparable. The eight-year patient survival rate was lowest in the oldest age group (47.6% versus 78% in the 3 younger groups combined, p<0.001). However, eight-year kidney and pancreas graft survival rates were comparable in the youngest and oldest age groups combined (36.5% and 32.7%, respectively), but inferior to those in the middle 2 groups combined (62% and 50%, respectively, both p<0.05). Death-censored kidney and pancreas graft survival rates increased from youngest to oldest recipient age category because of a higher incidence of death with functioning grafts (22.6% in oldest age group compared to 8.3% in the 3 younger groups combined, p=0.005). Recipient age does not appear to significantly influence early outcomes following SPKT. Late outcomes are similar in younger and older recipients, but inferior to the middle 2 age groups.

Introduction

Vascularized pancreas transplantation was originally developed as a therapeutic modality to re-establish endogenous insulin secretion responsive to normal feedback control and represents a method of complete β-cell replacement that frees the patient with diabetes mellitus (DM) from the need to monitor serum glucose and from dependence on exogenous insulin administration.¹ In return for these potential benefits, however, pancreas transplant recipients under major surgery and require long-term immunosuppression. Consequently, despite the high likelihood of rendering patients ex-diabetic, pancreas transplantation is considered a treatment for DM rather than a cure. For these reasons, pancreas transplantation is frequently reserved for those patients with insulin-requiring DM that will already be committed to chronic immunosuppression for another reason, most commonly a kidney transplant for end stage diabetic nephropathy.^2-4 In the previous century, pancreas transplantation was performed predominantly in young to middle-aged adults with type 1 diabetes mellitus (T1DM), usually as a simultaneous pancreas-kidney transplant (SPKT) in patients with end stage renal disease (ESRD).⁵ However, steadily improving outcomes in the new millennium have occurred secondary to better donor and recipient selection and management, advances in organ preservation and immunosuppression, refinements in surgical techniques, and improved medical care of these patients in parallel with better understanding of the pathophysiology of DM.^2-4 Consequently, recipient selection for SPKT has expanded to include patients with a type 2 diabetes mellitus (T2DM) phenotype (that disproportionately affects minorities, the elderly, and obese patients).^2,6,7 Concurrently, improvements in diabetes management, education and awareness, better insulin analogues and glucose sensors, sophisticated and more patient-friendly insulin pumps, and the promise of the artificial or bionic pancreas have potentially reduced the number of younger patients with diabetes developing ESRD. As a result, an aging of the DM population being referred for transplant evaluation has occurred.⁸

There has been a growing body of literature evaluating outcomes of SPKT in elderly patients.9-19 Whereas “elderly” following kidney transplantation alone usually refers to patients in the age range of 65-70 years and older^20-22, the definition of “elderly” following SPKT is much younger (age range of 45-50 years and older). Although many transplant centers apply age limits of 45-50 years or less for SPKT consideration, there is currently no consensus on a strict chronological age cut-off for candidacy. Recipient age is an important variable that influences patient and graft survival outcomes, with some data suggesting that SPKT is most beneficial for recipients <40-45 years of age compared to those >45-50 years of age.^23-26

Most patients <45 years of age are considered to be acceptable candidates for SPKT until proven otherwise, provided that they are not obese and do not have significant coronary or peripheral vascular disease. Patients with DM older than 55 years of age are not considered candidates for SPKT at many transplant centers and this barrier to access is further compounded by the fact that many kidney transplant centers do not perform pancreas transplants.^2-4,9-19 The majority of literature has focused on assessing transplant outcomes in elderly compared to younger SPKT recipients. The purpose of this study was to retrospectively analyze our single center experience in 255 SPKT recipients in the modern era and determine the effects, if any, that age has on short and long- term outcomes.

Materials and Methods

Study Design
We retrospectively reviewed 255 SPKTs performed at Wake Forest Baptist Health between 11/14/01 – 8/12/20 (minimum 4 month follow-up) and identified 62 recipients age 50 years and older (24.3%) including 9 patients age 60 years and older. The oldest SPKT recipient in this study (age 64 years) was actually #13 in our overall experience, dating back to 10/8/02. The youngest recipient (age 16 years) was a highly sensitized teenager with a previously failed living donor kidney transplant. All patients received similar immunosuppression and perioperative management strategies.^27-31

Recipient Selection
General indications for SPKT were insulin-requiring diabetes with complications and the predicted ability to tolerate the operative procedure, manage the requisite immunosuppression, and deal with the need for close follow- up post-SPKT irrespective of chronologic age or C-peptide production.^27-31 Specific indications for SPKT included stage 4/5 chronic kidney disease or ESRD and the absence of any contraindications. An extensive cardiovascular and peripheral vascular evaluation is an important part of the pretransplant evaluation in patients with DM.^26,32-35 Contraindications at our center included age >65 years; insufficient cardiovascular reserve; current substance abuse; active infection or recent malignancy; major ongoing psychiatric illness, recent noncompliance or lack of adequate social support; significant obesity (body mass index [BMI] >32 kg/m2); severe vascular disease; or inability to either understand or commit to the more intense follow-up associated with SPKT compared to kidney transplantation alone.^27-31 Selection criteria for SPKT in T2DM included patients <65 years of age, insulin- requiring for a minimum of 3 years with a total daily insulin requirement <1 u/kg/day, a fasting C-peptide level <12 ng/ ml, absence of severe vascular disease or tobacco abuse, adequate cardiac function, and presence of "complicated" or hyperlabile diabetes.^27-31 For purposes of this study, T2DM was defined as having a pretransplant C-peptide level ≥2.0 ng/ml (n=50).

Technical Aspects
All patients were blood type ABO compatible and T- and B-cell negative by flow cytometry crossmatch. Nearly all SPKTs were initially approached as intent-to-treat with portal-enteric (P-E drainage, n=216) using an anterior approach to the superior mesenteric vein (pancreas positioned above the small bowel mesentery) and enteric exocrine drainage to the proximal ileum in the recipient (side-to-side duodeno-enterostomy without a diverting Roux limb).³⁶ Arterial inflow was based on the recipient's right common iliac artery after the pancreas dual artery blood supply was reconstructed with a donor common iliac bifurcation "Y" graft.37 In patients with unsuitable anatomy for P-E drainage, systemic-enteric (S-E) drainage (n=39) was performed with the pancreas positioned below the mesentery with vascular anastomoses to the right common iliac artery and vein.38 Of the first 121 SPKTs (from 11/01 – 8/10), all but two were performed by transplanting the kidney to the left iliac vessels and the pancreas to the right common or external iliac artery through a midline intraperitoneal approach. However, since 8/10, most SPKTs were performed with ipsilateral placement of the kidney and pancreas to the right iliac vessels in order to reduce operating time and to preserve the left iliac vessels for future transplantation.

Anti-coagulation
In selected SPKT recipients, 2000-3000 units of intravenous heparin (30-50 u/kg) was administered as a single dose during surgery prior to implantation of the pancreas and a heparin infusion was continued post-transplant (continuous infusion of 300 units/hour for 24 hours, then 400 units/hour for 24 hours, and then 500 units/hour until post-operative day 5) in the absence of bleeding.³⁹ Indications for intravenous heparin included preemptive SPKT, history of thrombophilia or clotting disorder in the recipient, small or diseased donor or recipient vessels, prolonged pancreas cold ischemia (>16 hours), extended donor criteria, or history of prior pancreas graft thrombosis. Oral aspirin (81 mg/day) was administered to all patients.

Immunosuppression and Post-Transplant Management Patients received depleting antibody induction with either single dose alemtuzumab or multi-dose alternate day rabbit anti-thymocyte globulin (RATG, 1.5 mg/kg/dose, total 3-5 doses) in combination with tacrolimus, mycophenolate mofetil or mycophenolic acid, and tapered steroids or early steroid withdrawal.^31-35 RATG was the primary induction agent from 2001-2004. From 2005 through 2008, 46 SPKT patients were prospectively randomized to receive either alemtuzumab or RATG induction therapy.^28,29 Since 2009, alemtuzumab has been the primary induction agent. The majority of SPKT recipients (n=191) received single dose alemtuzumab induction (30 mg intravenous administered intra-operatively) in combination with tacrolimus (target 12 hour trough levels 8-10 ng/ml), full dose mycophenolate (720 mg bid), and either early steroid elimination or rapid prednisone taper (dose reduction to 5 mg/day by 1 month following SPKT).28,29 The remaining 64 patients received RATG induction with triple maintenance immunosuppression ± early steroid withdrawal. All patients received anti-infective prophylaxis with peri-operative cefazolin for surgical site prophylaxis, fluconazole for one month, valganciclovir for 3-6 months (6 months in patients for primary cytomegalovirus [CMV] exposure, 3 months for all other patients), and trimethoprim-sulfamethoxazole long-term.^27-31 Most patients were discharged from the hospital after placement of a tunneled central venous catheter and received intravenous fluid and electrolyte supplementation as an outpatient for a variable period. Treatment of hypertension, hyperlipidemia, anemia, and other medical conditions was initiated as indicated, aiming to maintain the blood pressure <140/90 mm Hg, fasting serum cholesterol <200 mg/dl, and hemoglobin >7-8 gm/dl.

Statistical Analysis
Data were compiled from both prospective and retrospective databases, with confirmation by medical record review in accordance with local Institutional Review Board approval. We examined relationships between recipient characteristics (age, gender, race, weight, BMI, dialysis history, waiting time, surgical technique, induction therapy) and donor characteristics (kidney and pancreas cold ischemia time, immunocompatibility, CMV status, Kidney Donor Profile Index) with outcomes classified into early (up to 1 year) and late (>1 year) time periods. Early outcomes included hospital length of stay, re-laparotomy in the first 3 months, and one year kidney and pancreas graft survival rates as well as patient survival. Late outcomes included long term kidney and pancreas graft survival rates and patient survival. For categorical variables, the chi-square test and Fisher's exact test were utilized when appropriate. Categorical data were summarized as proportions and percentages and continuous data were summarized as means and standard deviations. Renal allograft loss was defined as death with a functioning graft (DWFG), transplant nephrectomy, return to dialysis, kidney retransplantation, or a return to the pretransplant serum creatinine level in a preemptively transplanted patient. Pancreas graft loss was defined as DWFG, allograft pancreatectomy, pancreas retransplantation, or resumption of daily exogenous insulin therapy for >1 month. Actuarial survival rates were determined by Kaplan-Meier analysis. A two-tailed p-value of <0.05 was considered significant.

Results

From 11/14/01 – 8/12/20, we performed 255 SPKTs at our center with a minimum 4 month follow-up through December 2020. A total of 4 recipient age groups were stratified: age <30 years (n=16); age 30-39 years (n=91); age 40-49 years (n=86), and age ≥50 years (n=62 [24.3%], including 9 patients ≥60 years of age). Mean follow-up ranged from 86 to 105 months in the 4 groups (187 patients [73.3%] had at least 5-year follow- up and 160 patients [62.7%] had at least 8-year follow-up). The 4 groups were similar for many donor, preservation, and immunologic characteristics (Table 1). However, the youngest age group had proportionately fewer male donors (44% vs 68%, p=0.056, Table 1) and more African American recipients (56% vs. 24%, p=0.02, Table 2) compared to the 3 older age groups combined. Other recipient characteristics did vary by age group (Table 2). The oldest age group had fewer male recipients (42% vs 61%, p=0.012) compared to the 3 younger age groups combined. Increasing recipient weight (p=0.03) and BMI (p=0.007) were noted with each older age group. The two older age groups combined also had proportionately slightly more patients with an elevated (≥2.0 ng/ml) pretransplant C-peptide level (23%) compared to the 2 younger groups combined (15%, p=0.15). Duration of pretransplant DM increased with each older recipient category (p<0.001). Differences in these latter variables suggested that a T2DM phenotype was more prevalent in the older age groups.

Early outcomes
One-year patient and kidney graft survival rates were comparable across age groups (95-98% for the 3 older groups and 93% for the youngest group, Table 3). One-year pancreas graft survival rates were 92% in the 2 older groups compared to 86% in the 2 younger groups (p=NS). The rates of graft loss secondary to pancreas thrombosis ranged from 3.5% to 6.6% whereas early (≤3 months) technical pancreas graft failure rates ranged from 4.8% to 8.8% but recipient age was not a significant factor. Hospital length of stay was observed to be one day longer for patients age 40 and older but this was not statistically significant. The rate of early (≤3 months) relaparotomy was highest in the youngest group (50%) compared to 31.4% (p=NS) in the other 3 age groups combined. Overall, recipient age did not appear to significantly influence early outcomes following SPKT.

Late outcomes
Patient survival was slightly higher in the 2 middle groups (80.2% combined) compared to the youngest and oldest groups combined (66.7%, p=0.06, Table 3). Kidney graft survival rates (68.4% combined for 2 middle groups versus 55.1% for youngest and oldest groups combined, p=0.048) were significantly higher whereas pancreas graft survival rates (61.6% combined for 2 middle groups versus 51.3% for youngest and oldest groups combined, p=0.13) were slightly but not significantly higher in the 2 middle groups. Actuarial patient, kidney, and pancreas graft survival rates (uncensored) according to recipient age category are shown in Figures 1-3, respectively. Patient survival in the oldest age group was inferior to the other age groups (particularly beyond 6 years follow-up) whereas kidney graft survival was highest in the age 40-49 year group and lowest in the age <30 year group (both p<0.05). In contrast, pancreas graft survival was comparable across age groups. For patients with at least 8-year follow-up, the 8-year patient survival rate was significantly lower in the oldest age group (47.6% versus 78% in the 3 younger groups combined, p=0.0004). However, 8-year kidney graft survival rates were comparable in the youngest and oldest age groups (36.5% combined), but inferior to those in the middle 2 groups (62% combined, p=.0038). Similarly, 8-year pancreas graft survival rates were comparable in the youngest and oldest age groups (32.7% combined), but inferior to those in the middle 2 groups (50% combined, p=.043). Actuarial death-censored kidney and pancreas graft survival rates are shown in Figures 4 and 5.

Death-censored kidney and pancreas graft survival rates increased from youngest to oldest recipient age category because of a higher incidence of DWFGs (22.6% in oldest age group compared to 8.3% in the 3 younger groups combined, p=0.002, Table 3). There was a trend toward lower death-censored kidney graft survival in the youngest age group whereas death-censored pancreas graft survival was comparable across age groups. Each of the actuarial graft survival curves was notable for a decrease in in both kidney and pancreas graft survival occurring at 3 years follow-up in the youngest age group.

Mortality and graft loss
In the 9 patients ≥60 years of age, patient, kidney, and pancreas graft survival rates were 44.4% with a mean follow-up of 78 months. Three of the five deaths occurred >8 years following SPKT. Four patients experienced DWFGs (2 secondary to infection, one cancer, one cardiovascular cause) and the remaining patient developed ESRD at 19 months and refused to return to dialysis treatment (she died with a functioning pancreas graft). In all 4 groups combined, of the 61 deaths, 28 (46%) occurred >8 years post-SPKT.

In the 3 older age groups, major causes of death were cardiac, malignancy, infection, stroke, and respiratory failure, whereas in the youngest group the causes of death were primarily cardiac or infection. Death as a cause of kidney graft loss increased from 14% to 61% (p=0.02, Table 3), whereas death as a cause of pancreas graft loss increased from 25% to 60% (p=0.007) from youngest to oldest recipient age category. The rate of death-censored dual graft loss (excluding early graft losses), which were usually secondary to acute or chronic rejection in both organs, was highest in the youngest age group (31.25%) and progressively decreased in each successive recipient age category such that it only accounted for 7.9% of graft losses in the 3 oldest age groups combined (p=0.007).

Discussion

Diabetes and kidney disease remain among the top ten causes of death in the United States (US). A functioning pancreas transplant mitigates glycemic variability and achieves endogenous glucose homeostasis while eliminating the daily stigma and burden of diabetes in exchange for the administration of and side effects associated with chronic immunosuppression. Moreover, a functioning SPKT treats not only DM but kidney failure, resulting in improvements in quality of life and life expectancy compared to other renal replacement options. According to the International Pancreas Transplant Registry (IPTR), as of 2020, >34,000 pancreas transplants have been performed in the US in the past 50+ years including >80% in the SPKT category.^2-4 At present, approximately 1000 pancreas transplants are performed annually in the US including >800 SPKTs in patients with diabetes and advanced kidney disease or kidney failure.^2-4

Success rates for SPKT have progressively improved secondary to refinements in diagnostic and therapeutic technologies and surgical techniques, advancements in immunosuppression and anti-infective prophylaxes, new and effective techniques in organ retrieval and preservation technology, and increased experience in the selection of donors and recipients.^2-4 In evaluating trends, the proportion of patients age 50–64 years listed for pancreas transplantation doubled from 1998 to 2010¹⁷, but remained relatively stable at 20% of all waitlist additions for SPKT from 2015-2019.^2-4 Patients age 50-64 years currently represent 2.3% of all pancreas transplants performed annually, including 2.1% of SPKTs.³ In patients age 65 years or older, waitlist additions likewise remained stable at a mean of 1.0% of all waitlist additions and 0.3- 0.7% of SPKT waitlist additions in the past 5 years. The proportion of pancreas transplants performed in patients >65 years of age was also relatively stable (mean 0.5% of all pancreas transplants and 1.2% of SPKTs) from 2015-2019.^2-4,40 In the past two decades, education and management of DM, including advanced insulin delivery and glucose monitoring technologies, have improved dramatically, resulting in delayed progression to chronic kidney disease and ESRD in patients with DM.^8,41 As a result, there is an increasing population of patients with DM being referred for transplantation at older ages, underscoring the need to better understand criteria for candidacy (other than chronological age alone) based on an acceptable risk-benefit balance and ethical considerations for both the patient and the transplant waitlist.^{2-4,8,17,18,40,41}

An important consideration in evaluating transplant outcomes is understanding the interaction between donor and recipient factors and their effect on early technical failure. Finger, et al., retrospectively reviewed all pancreas transplants (n=1115) at a single institution over a 13-year period and developed a composite risk model to predict early technical failure in pancreas transplantation. They demonstrated that while donor age (>50 years) played a predictive role for technical graft failure, recipient age did not.⁴² Another concern is the growing disparity between pancreas and kidney donor availability and demand, thus warranting careful examination of expansion of the candidate pool, specifically older individuals who presumably have shorter life expectancies. Salvalaggio, et al., analyzed the implications of SPKT from older donors on recipient survival and graft longevity and determined that utilization of a graft from an older donor is superior to waiting longer, even for younger recipients.43 These data suggest that perhaps age matching is a potential strategy for increasing both the donor and recipient pools. Kayler, et al., examined age matching utilizing data from the Scientific Registry of Transplant Recipients (SRTR) to analyze all waitlisted candidates for SPKT over a 15-year period.⁴⁴ Transplantation of older donor organs (>40 years) into either old or young recipients was inferior as compared to transplantation of young donor organs (<40 years). However, there was a clear survival benefit for older patients undergoing SPKT compared to not receiving a transplant. In general, most studies support the contention that SPKT is feasible in older recipients, and that recipient age alone is not a primary risk factor for patient mortality or graft failure. However, careful selection of donor organs and recipients is important to optimize outcomes.

Shah et al., in a retrospective single institution analysis, examined the effect of recipient age on posttransplant outcome in all pancreas transplants (n=405) over an 8-year period.¹³ A total of 64% of pancreas transplants occurred in patients older than 40 years of age, and 25% in patients older than 50 years. Analysis of outcomes stratified according to recipient age by decade (<30, 30-39, 40-49, 50-59, >60 years) demonstrated similar short-term (7 and 90 day) pancreas graft survival and equivalent one-year patient, kidney, and pancreas graft survival rates. Regression analysis demonstrated a trend towards worse five-year patient survival with increasing recipient age, although survival was still excellent in the oldest groups (84%). Interestingly, in this study, the youngest recipient age group (<30 years) actually had the lowest pancreas graft survival rate while all other age groups had equivalent pancreas graft survival rates. However, the causes of graft loss varied significantly by recipient age. For example, younger patients were more likely to lose grafts to acute or chronic rejection whereas older patients were more likely to lose functioning grafts to death. This finding of lower pancreas graft survival in the younger age groups is also borne out by IPTR data.^2-4,17,25

In another single center retrospective study from 1996– 2010, Afaneh, et al., reported on 136 consecutive pancreas transplants, 17 of which were in patients age 50 years or older.12 The two groups studied had comparable major and minor surgical complication rates and the incidence of non- surgical infections and overall patient and graft survival rates were similar in younger and older recipients. Scalea, et al., reported a single center retrospective analysis of SPKT and solitary pancreas transplants in recipients ≥55 years of age transplanted from 1999-2012.16 Of the 740 patients studied, only 28 (3.8%) were ≥ age 55 years. Patient and graft survival outcomes were comparable for younger and older recipients, although cardiovascular events were more frequent in patients >45 years of age. In 2020, Mittal, et al., reported a single center retrospective analysis comparing patients age 23–54 years (n=444) to those age 55–67 years (n=83, 15.7%) receiving pancreas transplants between 2002 and 2016.¹⁹ While there were no differences in death-censored pancreas or kidney graft survival rates between groups, the authors concluded that mortality was higher in older patients and strongly associated with pancreas and kidney graft failure.

Larger database studies include a retrospective SRTR analysis of all adult solitary pancreas transplant and SPKTs between 1996 and 2012.14 Of the 20,854 pancreas transplants included in the analysis reported by Siskind, et al., 3440 (16.7%) of the recipients were 50 years of age or older. For older patients, long- term graft survival (10-15 years) was diminished compared to younger recipients and as age increased, survival decreased. The authors also demonstrated inferior uncensored patient and graft survival rates in the older group and recommended taking this data into consideration when making candidacy decisions rather than using it as exclusion criteria. Similarly, Gruessner, et al., analyzed outcomes and risk factors for patients ≥60 years of age.45 Using SRTR and IPTR data between 2000-2017, 358 deceased donor pancreas transplants (327 SPKTs) were reported in patients age 60 years or older (the oldest recipient was age 73 years). Approximately 25% of these patients were identified as having T2DM. Wait-list mortality for elderly patients with diabetes was 50% at 5 years but mean waiting time for pancreas transplantation was <1 year. The most common cause of graft loss in this group was DWFG and the most common causes of death were cardiovascular, infection, and malignancy. In the SPKT category, the death-censored pancreas graft survival rate was >90% at 5 years follow-up. The authors concluded that SPKT in elderly patients with labile diabetes can be successfully performed with careful patient selection and using young donors with short cold ischemia times.

Independent of recipient age, recent studies have focused on the impact of sarcopenia and functional status on outcomes following SPKT.46-48 DM is believed to contribute directly to the pathophysiology of frailty by increasing the risk of sarcopenia. Patients with T1DM in particular are at greater risk for sarcopenia secondary to the catabolic effect of insulin deficiency and excess accumulation of intramyocellular lipids and advanced glycation end products. Consequently, the distribution of impaired functional status in the SPKT candidate population is fairly equal across age groupings. Similar to data in other solid organ transplant recipients, the presence of frailty and reduced functional status are important predictors of patient survival in SPKT candidates and recipients irrespective of age.

In our series ranging from November 2001 to August 2020, we report a large single center retrospective experience with SPKT in 255 patients, including 62 (24.3%) ≥ age 50 and 9 ≥ age 60 years. All patients received depleting antibody induction (75% with single dose alemtuzumab) in combination with tacrolimus/mycophenolate ± steroid maintenance immunosuppressive therapy and 85% underwent pancreas transplantation with P-E drainage. A total of 66 patients (26%) were African American and 20% overall had a T2DM phenotype. Similar to most previous studies, we found that recipient age did not influence 3-month and one-year outcomes following SPKT. However, we corroborated an “age effect” on late outcomes characterized by more dual immunologic graft losses in younger patients and more DWFGs in older patients. The net effect of these findings was that kidney and pancreas graft survival rates were comparable at the extremes of age but inferior to those achieved in the middle 2 age groups. In all 4 groups combined, DWFG accounted for 39% of both kidney and pancreas graft losses and was the single most common cause of graft loss. Additionally, of the 61 deaths, 28 (46%) occurred >8 years post-SPKT. It is important to note that the 5-year survival rate in this patient group in the absence of transplantation is <50%. Moreover, the ultimate goal of transplantation is for the allograft to “outlive” the patient, so DWFG is actually a desirable outcome provided that death was neither premature nor directly related to the transplant or chronic immunosuppression. Not surprisingly, the major causes of death were cardiovascular, infectious, and malignancy (particularly in the older recipient group). Death-censored graft survival rates progressively improved from youngest to oldest recipient age category, which mirrors outcomes with kidney alone transplantation in elderly recipient groups.^20-22

This study has the typical limitations of an observational study from a single center including the retrospective design. In addition, the number of patients in each group, particularly the youngest age cohort, are relatively small, which could bias the statistical analysis. The age group designations may seem arbitrary but reflect previous studies pursuant to this topic and are of clinical relevance because many centers apply age limitations in recipient selection. Potential strengths of the study are the standardization of management protocols and granularity of data collection during the period of study. Unique aspects of this experience include the long duration and completeness of follow-up in all 4 age groups, the administration of depleting antibody induction (primarily alemtuzumab), use of the portal-enteric drainage technique, the relatively large number of elderly recipients as well as African American recipients, differentiation of the T2DM phenotype, and presentation of both early and late outcomes.

As SPKT outcomes have improved in the past two decades, long-established contraindications for populations that were generally excluded due to concerns of excessive risk with uncertain benefit, including elderly patients, are now being challenged.18,43-45 Similar data exists amongst deceased donor kidney transplant recipients where the oldest recipients have the worst overall survival but death-censored graft survival rates improve with older recipient age20-22, suggesting perhaps a benefit of immunosenescence, the presence of more aggressive disease in younger patients, or reflective of more stringent patient selection with older age.49 Additionally, age-related differences in compliance may likewise account for the equivalence in death-censored graft survival rates when comparing younger and older recipient populations.

In summary, improvement in SPKT outcomes likely reflects adjustments in both candidate and donor selection. The transplant community has continued to pursue serving the DM population with ESRD in an environment of improved diabetes management, resulting in candidate evaluation and transplantation at ages that were once considered exclusions. As a result, there has been an increase in SPKT in elderly patients that has appeared to have leveled off in the past five years. While outcomes in this population are mixed^9-19,43-45, SPKT is generally supported when disease severity, comorbidity, and likely benefit is considered, rather than age alone. Limitations in the current data include the small number of patients represented in single center retrospective analyses and the lack of granular information in registry data. However, analogous to kidney transplantation alone, SPKT may provide both a survival and quality of life benefit to all appropriately selected candidates regardless of age.^25,50-54