Pancreas and Kidney Transplantation for Diabetic Nephropathy

The prevalence of diabetes mellitus (DM) in the US in 2015 according to the American Diabetes Association is estimated to be 30.3 million Americans, 9.4% of the population. Diabetes remains the seventh leading cause of death in the US in 2015, with 79,535 death certificates listing it as the underlying cause of death and a total of 252,806 death certificates listing diabetes as an underlying or contributing cause of death. Despite advances in genetically modified insulins and continuous glucose monitoring, many patients are unable to achieve consistent normoglycemia to a degree necessary to prevent glucose lability and end-organ damage. Invariably, patients are plagued by the development and progression of secondary complications of nephropathy, neuropathy, and retinopathy, as well as macrovascular and microvascular complications, which can appear years to decades after disease onset. Evidence from the Diabetes Control and Complication Trial (DCCT) demonstrating that intensive insulin therapy can mitigate secondary complications of diabetes gave added impetus to apply and hone pancreas transplantation for patients with insulin-dependent diabetes mellitus (IDDM). The majority of pancreas transplants are performed simultaneously in conjunction with a kidney transplant for patients with IDDM, primarily type 1 diabetes (T1D) and DM nephropathy. Sequential pancreas after kidney transplants also achieve the goals of correcting diabetes and eliminating the need for dialysis.

History of Pancreas Transplantation

Oskar Minkowski and Joseph von Mering in 1889 demonstrated that pancreatic extirpation in dogs produced severe diabetes, partially reversed by implanting a small portion of pancreas subcutaneously. Dr. P. Watson at the Bristol Royal Infirmary, England, implanted three extracts from a freshly slaughtered sheep into a 15-year old boy with diabetes; unfortunately, due to severe diabetic ketoacidosis the patient expired 3 days later. The identification and isolation of the glycemia-lowering substance contained in pancreatic extracts by Banting, Best, Collip and Macleod, and experimental pancreas allotransplantation in dogs, prepared initial attempts to transplant the pancreas in humans. Drs. William D. Kelly and Richard C. Lillihei performed the first successful human pancreas allograft on December 16th, 1966, at the University of Minnesota. The graft was a pancreatic duct-ligated segmental graft transplanted simultaneously with a kidney in a uremic patient resulting in immediate insulin independence. The patient expired 2 months later due to sepsis with a functioning graft. After this initial transient success, additional cases were reported, primarily using intestine-based exocrine drainage techniques ( Figs. 36.1 and 36.2 ). Of the initial series performed at the University of Minnesota, 11 were performed in uremic patients and 3 in nonuremic patients. Some initial technical successes bolstered enthusiasm and several centers embarked on their own cases in the 1970s and 1980s. As experience expanded, surgical complications began to accumulate, resulting in graft and patient survivals ranging from a few months to 1 year.

Fig. 36.1

A historical technique used for pancreatico-duodenal transplantation, now seldom used. Exocrine drainage of grafts using a cutaneous duodenostomy.

Reproduced from Lillehei, R.C., et al., Pancreatico-duodenal allotransplantation: experimental and clinical experience. Ann Surg 1970;172(3): p. 405–36.

Fig. 36.2

Another historical technique employing enteric drainage via a Roux en Y limb of recipient bowel. Note the long donor duodenum and end to end anastomosis to native jejunum

Reproduced from Lillehei, R.C., et al., Pancreatico-duodenal allotransplantation: experimental and clinical experience. Ann Surg 1970;172(3): p. 405–36

In the mid 80s, Sollinger, Corry, and Ngheim devised the bladder drainage technique, initially with a duodenal button ( Fig. 36.3 ) and then modified to a duodenal segment. For the next decade, the bladder drainage technique with duodenocystostomy was the predominant technique for pancreas transplants. The bladder drainage technique was associated with a low acute complication rate and was useful for measuring urinary amylase level, which helped in monitoring for rejection. At around the same time, use of University of Wisconsin (UW) organ preservation solution and Cyclosporin A (CsA)-based immunosuppression became routine and undoubtedly had a beneficial effect on improving technical success rates and graft survival. However, chronic urologic and metabolic complications frequently plagued patients leading to posttransplant morbidity, and gradually, in the mid 1990s, centers shifted back to enteric drainage, using a graft duodenojejunostomy with or without a Roux-en-Y anastomosis. Today, a duodenojejunostomy without a Roux-en-Y anastomosis continues to be the most commonly used technique for managing exocrine secretions. Portal venous drainage was introduced by Sir Roy Calne in 1984 for segmental pancreas grafts as a potentially more physiologic technique.

Fig. 36.3

A historical technique using duodenal bulb bladder drainage technique.

Reproduced from Sollinger, H.W., et al., One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg 2009;250(4): p. 618–30.

With the introduction of CsA, tacrolimus, and mycophenolate mofetil (MMF), rates of acute rejection dropped dramatically. A number of other strategies such as T cell depleting antibodies, single antigen bead Luminex human leukocyte antigens (HLA) alloantibody determination and virtual crossmatching, pancreatic allograft biopsies, and adoption of a standardized rejection grading schema have contributed to better outcomes in the modern era. Additional history has been detailed elsewhere.

Recent Trends in Pancreas Transplantation

Approximately 900 to 1000 pancreas transplants are performed annually in the US, approximately 90% involving a simultaneous pancreas and kidney (SPK) transplant for patients with IDDM and renal failure. The other 10% of pancreas transplants are equally split between sequential pancreas after kidney transplants (PAK) and pancreas transplants alone (PTA) in patients with preserved renal function and difficult to control diabetes associated with frequent severe hypoglycemia. Analysis of the annual data reports from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR), and International Pancreas Transplant Registry (IPTR) comparing the periods 2005 to 2009 with 2010 to 2014 have demonstrated the number of US pancreas transplants declined by over 20%, whereas the overall number of pancreas transplants performed outside the US has increased ( Fig. 36.4 ). The greatest decline is observed in the PAK population, followed by the SPK population. The PTA population has remained steady at about 200 to 300 transplants per year. The number of active new patients on the waiting list dropped from a high of 2067 in 2004 to 1476 in 2015, the lowest level in the past decade. As a result, the majority (∼70%) of pancreas transplant centers in the US perform 10 or fewer pancreas transplants annually. Data from the Global Observatory on Donation and Transplantation show that 780 pancreas transplants were carried out in 2016 across the 28 countries of the European Union (population 506 million). National transplant rates varied from less than one procedure per million population per year to more than three transplants per million population, as in Norway, the UK, and the Czech Republic. A larger proportion of European transplants are carried out as SPK transplantation than is the case in the US, where the PAK procedure is more common. Patients with life-threatening hypoglycaemia unawareness may be offered either solid-organ PTA or islet transplantation. Most recent data from the UK (2016–2017) show that 76% of all pancreas transplantation (including islets) was in the category of SPK, 8% as PAK and PTA combined, and 16% as islet transplantation. As a proportion of solid-organ pancreas transplants, 91% were SPK.

Fig. 36.4

Annual number of US transplants. PAK, pancreas after kidney; PTA, pancreas transplant alone; SPK, simultaneous pancreas and kidney transplant.

Reproduced from Kandaswamy R, et al. OPTN/SRTR 2015 Annual Data Report: Pancreas. Am J Transplant 2017;17(Suppl 1):117–73.

In the US, the vast majority of pancreas transplants (∼90%) are performed in patients with insulin-dependent T1D as the underlying disease. However, increasingly insulin-dependent type 2 diabetes (T2D) patients with residual endogenous insulin production (positive fasting serum C-peptide) are receiving pancreas (SPK and PAK) and kidney transplants, as T2D becomes the predominant cause of kidney disease in the US. T2D recipients now account for >10% of SPK transplants, and >6% of PAK and PTA transplants each. Waitlisted T2D candidates increased from a low of 7.3% in 2007 to over 10% currently. Almost all transplants are from deceased donors, with only five living donor cases performed over the past 10 years in the US, and these were performed at only two centers. Living donor pancreas transplantation is more common in Asia.

The reasons for the decline in pancreas transplant volumes in the US are not fully understood, especially in the context of steadily improving patient and graft survival. Potential reasons include improvements in insulin delivery technologies, resulting in delayed progression to advanced diabetic nephropathy, and shift toward more obesity affecting patients with T1D. A recent decrease in donor organ quality is also likely a contributing factor. The US donor population is becoming increasingly aged, obese, and diabetic, all factors that adversely affect pancreatic graft functional outcomes. Despite these adverse trends, overall short-term technical success rates of pancreas transplantation have improved. The trend in pancreas transplantation follows the rule of 90s: 90% are SPKs, 90% are from conventional donors (body mass index [BMI] <30), 90% enteric drainage, 90% systemic venous drainage, 90% receive cell-depleting induction agent, 90% receive tacrolimus and MMF, 90% have T1D, 90% have a PRA <20%, 90% of recipients have a BMI less than 30, and the 1-year and 5-year graft survival is above 90%. And by the rule of 30s: 30% are at least 50 yrs old, 30% experience acute rejection, 30% undergo relaparotomy for postoperative complications, 30% of dual-organ biopsies are discordant, 30% develop donor-specific antibodies, and 30% remain steroid-free long term.

The allocation policies for solid-organ pancreata to patients with diabetes differ across the world and are continually undergoing refinement. In the US, recent changes in the United Network for Organ Sharing (UNOS) Pancreas Allocation System have led to an increase in pancreas transplant volumes (especially SPK transplants) and give priority to utilization of the pancreas as a solid organ over that of islets. The UK pancreas allocation policy is based on four objectives: (1) equality of access irrespective of geographic location or the transplant center at which patients are registered; (2) maximum benefit with respect to utilization of the organ and outcome of the transplant; (3) priority for sensitized and hard-to-match patients; and (4) allocation of suitable donor organs in appropriate numbers to islet transplantation. For every donor organ, all patients on the waiting list are awarded points, based on seven criteria: (1) HLA mismatch; (2) waiting time; (3) degree of sensitization; (4) geography (travel time); (5) donor BMI; (6) dialysis status; and (7) donor to recipient age matching. The algorithm by which points are allocated (including the weighting of each criterion) is based on a series of simulations, designed to achieve the optimum outcome, balancing fairness with utility. The reduction in pancreas transplant activity that has occurred in the US in recent years has not been experienced in Europe, possibly because transplant rates had not previously achieved the same levels. However, pancreas transplant rates in the larger European countries (e.g., the UK) are relatively static. The evidence would suggest that future developments will come as a result of improving outcomes rather than donor organ availability. Early morbidity, mostly associated with reperfusion pancreatitis and later graft failure, probably related to the problems of graft monitoring and undiagnosed rejection, are now the major limiting factors.

Indications and Patient Selection

Simultaneous Kidney and Pancreas Transplantation

Juvenile onset, autoimmune T1D is the principal indication for pancreas transplantation. Patients that develop chronic kidney disease (CKD) stages 3 to 5 are potential candidates for SPK transplantation. According to current UNOS criteria, candidates with an estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m 2 are eligible for listing. Such persons are excellent candidates for an SPK transplant from the same donor because the immunosuppressive medications needed are similar to those for a kidney transplant alone. As long as the cardiac and surgical risks of the dual operation are considered acceptable, the benefits of adding a pancreas transplant to ameliorate diabetes can help prolong the survival of the transplanted kidney by preventing recurrent diabetic nephropathy and is associated with prolonged patient survival compared with a deceased or living donor kidney (LDK) alone in the long term. Moreover, one operation achieves both elimination of dialysis and restoration of normoglycemia. The pancreas donors also generally represent the best 15% to 25% of kidney donors, which implies a high quality cadaver kidney is available for these patients. Depending on the allocation schema, the waiting time for an SPK transplant is usually less than that for a cadaver kidney.

Conventionally, pancreas transplantation was considered suitable only for insulin-dependent T1D, lean, ketosis-prone patients, with absent insulin secretion and C-peptide levels that were extremely low or undetectable. In contrast, patients with T2D are classically obese, insulin resistant, with inappropriately “normal” to elevated C-peptide levels. Data from multiple centers support the notion that pancreas transplantation in insulin-dependent patients with T2D with detectable C peptide, few comorbidities, and reasonable insulin requirements is successful and comparable to T1D recipients of SPK. As the number of uremic T2D patients is increasing, UNOS has issued regulations that define eligibility criteria for patients with measurable C-peptide as a surrogate for T2D. These regulations impose limits by restricting eligibility in those patients having a C-peptide of greater than 2 ng/mL by imposing a maximum allowable BMI (initially 28 kg/m 2 ). UNOS policy mandates a 6-month review process with allowance for reduction (or increase) in the BMI eligibility threshold by plus or minus 2 kg/m 2 depending on the makeup and/or size of the waitlist, to a maximum of 30 kg/m 2 . The majority of T2D are SPK and PAK recipients, but because T2D patients less commonly experience the problematic hypoglycemia and related glycemic lability more often seen in long-standing T1D, non-T1D account for very few PTA transplants performed in the US.

Pancreas After Kidney Transplantation

The second category for pancreas transplantation is patients with IDDM who have received a previous kidney transplant from either a living or deceased donor. This group, along with PTA, accounts for approximately 10% to 15% of patients receiving pancreas transplants. Given the high mortality of waitlisted patients for SPK (46% at 4 years) and the proven benefit of kidney transplant for patients with T1D, pursuing a kidney transplant before pancreas transplant is a viable option for patients in regions with long wait times for SPK or those who have a well-matched living donor kidney. Because PAK patients are already on calcineurin inhibitors (CNIs), the threshold for satisfactory kidney function is much lower than that for PTA patients and many patients can be successfully transplanted with a PAK with an eGFR of approximately 45 to 50 mL/min/1.73 m 2 with an expectation of little change in eGFR after pancreas transplantation. Current literature supports equivalent patient survival and improved GFR in patients who receive a pancreas after a living donor renal transplant (LDRT) versus patients who receive a LDRT alone up to 10 years posttransplant. Factors that may lead to increased odds of kidney loss include pre-PAK GFR <45 mL/min/1.73 m 2 , pre-PAK acute kidney rejection episodes, pre-PAK proteinuria, pancreas transplant interval of >1 year after kidney transplant, and post-PAK pancreas allograft failure. In other words, the ideal patient likely to benefit from PAK is one deemed fit for surgery with minimal immunologic risk, GFR of ≥50 mL/min/1.73 m 2 , without proteinuria or preceding kidney rejection and a recent kidney transplant.

Pancreas Transplant Alone and Kidney Function Evaluation

The third category for pancreas transplantation is in nonuremic, nonkidney transplant patient with insulin-dependent diabetes who typically has hypoglycemia unawareness and/or severe metabolic instability and/or who has failed attempts to manage their diabetes with insulin delivery and glucose-sensing technology. These patients with longstanding diabetes have extremely labile disease such that there is difficulty with day-to-day living, associated with frequent emergency room and inpatient hospitalizations for hypoglycemia or diabetic ketoacidosis. Other patients may have significant difficulty with hypoglycemic unawareness that results in unconsciousness without warning. This can be a devastating condition for these patients that ultimately affects their employment, their ability to keep a license to drive, and concern about suffering lethal hypoglycemia while asleep. The indications for a PTA are currently identical to patients being considered for an islet transplant: recurrent hypoglycemic/hyperglycemic attacks, ketoacidosis, inability to achieve adequate control with exogenous insulin therapy and newer automated technologies, or its failure to mitigate complications.

The perfect candidate for a PTA includes patients with preserved renal function; GFR >80 mL/min/1.73 m 2 and/or serum creatinine <1.5 mg/dL and no proteinuria. In circumstances where a PTA candidate has marginal renal function, a trial of tacrolimus therapy can be used to predict the effect of CNI therapy on postoperative native kidney function. If native kidney functional reserve is deemed insufficient, then the patient is best served by waiting for kidney function to further deteriorate to an eGFR of 20 mL/min/1.73 m 2 or less. The risk of CKD is estimated to be 10% to 15% at 5 years post PTA, with a mean GFR decrease of 33 mL/min/1.73 m 2 . Risk factors associated with renal failure include BMI >30 and age younger than 30 (attributed to enhanced recipient immune status and more frequent rejection episodes).

Extended Indications for Pancreas Transplantation

Indications for pancreas transplantation extend beyond classic insulin-dependent T1D and T2D patients. Pancreas transplantation is sometimes recommended for some patients with IDDM due to pancreatectomy or chronic pancreatitis, including failed total pancreatectomy and islet autotransplantation. This cohort includes diabetes seen after pancreatectomy either for chronic pancreatitis, pancreatic neoplasms (i.e., intraductal papillary mucinous neoplasms), trauma, and various pediatric genetic or congenital abnormalities, and separately, in patients with cystic fibrosis who develop both pancreatic exocrine and endocrine insufficiency. In these postpancreatectomy and cystic fibrosis patients, there is the added benefit of restoring exocrine function with an enteric-drained pancreas graft.

Pancreas transplantation is not indicated for the majority of patients with IDDM, such as those who have normal renal function and do not exhibit a labile course, hypoglycemic unawareness, or any evidence of nephropathy. For patients that do have an indication for pancreas transplantation, it is important to rule out significant medical contraindications in a similar manner as applies to other areas of transplantation. These general contraindications include: recent malignancy, active or chronic untreated infection, advanced forms of major extrarenal complications (i.e., uncorrected coronary artery disease [CAD] or severe aortoiliac disease), life expectancy of less than 3 years, morbid obesity with numerous metabolic complications, poor compliance, active substance abuse, and uncontrolled psychiatric disorder.

Recipient Considerations for Success and Cardiovascular Assessment

Advanced CAD is the most important comorbidity to consider in patients with IDDM and DM nephropathy. It has been estimated that uremic, diabetic patients carry a near 50-fold greater risk of cardiovascular events then the general population. Because of the neuropathy associated with diabetes, patients are often asymptomatic because ischemia-induced angina is not perceived. The prevalence of significant (>50% stenosis) CAD in patients with diabetes starting treatment for end-stage renal disease is estimated to be 40% to 60%. As such, screening studies to detect significant and treatable CAD are important. Risk factors such as age, duration of dialysis, duration of diabetes, and smoking and family history should be assessed but are not sufficiently predictive, and standard cardiac risk assessment tools have not been validated widely in this population. Hence, we have adopted an aggressive policy of coronary angiography in nearly all dialysis patients and the majority of nonuremic patients. Techniques for coronary angiography have improved significantly and by avoiding ventriculograms the contrast dye load and consequently the nephrotoxic risk can be reduced considerably. Patients with coronary lesions amenable to angioplasty and/or stenting or bypass grafting should be treated, reevaluated, and then reconsidered for transplantation. The goal of revascularization is to diminish the perioperative risk of significant myocardial ischemia and cardiac events, and to prolong the duration of life after transplantation. Patients should have their cardiac status reassessed at regular intervals (every 1 to 2 years).

Diabetic retinopathy is a nearly ubiquitous finding in patients with diabetes and end-stage renal disease. Significant vision loss may have occurred including blindness. Blindness is not an absolute contraindication to transplantation because many blind patients lead very independent lives. Although rarely a problem, it should be confirmed that a patient with significant vision loss has an adequate support system to help with travel and medication administration if needed. Acute normalization of glycemia has been associated with transient worsening of retinopathy, and stability of retinopathy and its treatment should be ensured before pancreas transplantation; annual ophthalmologic examinations are recommended before and after transplantation.

Autonomic neuropathy is prevalent and may manifest as gastropathy, cystopathy, and orthostatic hypotension. Impaired gastric emptying (gastroparesis) is an important consideration with significant implications in the posttransplant period. Patients with severe gastroparesis may have difficulty tolerating the oral immunosuppressive medications, predisposing to subtherapeutic levels and rejection episodes. Patients typically require motility agents such as metoclopramide or erythromycin and, as such, gastroparesis is not considered a contraindication to pancreas transplantation at many centers. Neurogenic bladder, manifested by inability to sense bladder fullness and empty the bladder, predisposes to urine reflux and high post-void residuals. This may adversely affect renal allograft function, increase the incidence of bladder infections and pyelonephritis, and predispose to graft pancreatitis. The combination of orthostatic hypotension and recumbent hypertension results from dysregulation of vascular tone. This has implications for blood pressure control posttransplant, especially in patients with bladder-drained pancreas transplants that are predisposed to volume depletion. Therefore posttransplant antihypertensive medication must be reassessed. Sensory and motor neuropathies are common in patients with longstanding diabetes. This may have implications for the rehabilitation posttransplant. It also reflects potential risk for injury to the feet and subsequent diabetic foot ulcers.

Uremic, diabetic patients experience an increased rate of vascular complications, including cerebral vascular accidents, transient ischemic attacks, and peripheral vascular disease. Deaths related to cerebral vascular disease are approximately twice as common in patients with diabetes versus no diabetes once end-stage renal disease has occurred. Patients with diabetes suffer strokes more frequently and at a younger age than do age and gender match nondiabetic stroke patients. Hypertension is the major risk factor for stroke followed by diabetes, heart disease, and smoking. Given the high rate of peripheral vascular disease present in the pancreas transplant population, assessing the adequacy of the iliac vessels before transplantation is paramount. A plain computed tomography (CT) scan of the abdomen and pelvis is the best option for assessing target vessels, despite examination findings of palpable femoral pulses. Iliac artery calcifications can be easily detected, as well as aid in operative planning. Additionally, diabetic patients are at risk for amputation of the lower extremity. These problems typically begin with a foot ulcer associated with advanced neuropathy, Charcot foot fractures and pressure ulcers and/or tibioperoneal vascular disease. Significant distal vascular disease or amputation of the lower extremities is not, however, an absolute contraindication to transplantation.

Mental or emotional illnesses including neuroses and depression are quite common. These illnesses may influence the decision of steroid-free/sparing regimens to avoid the deleterious effects of high-dose steroids on mood disorders.

High BMI T1D and T2D patients are often not offered pancreas transplantation. Currently in the US there is a restriction regarding which patients with T2D can be offered SPK transplantation, whereas there is no similar restriction for PAK or PTA transplantation. Nonetheless, the UNOS pancreas allocation system currently dictates that T2D SPK candidates have to meet the following criteria for accrual of waitlist time for pancreas transplantation: insulin dependence, C-peptide ≤2 ng/mL with no BMI restriction (assumed to be T1D) or on insulin and C-peptide >2 ng/mL with a BMI ≤30 kg/m 2 (assumed to be T2D). However, the BMI qualifier may be eliminated in the future in the US. In the UK, BMI is factored into the allocation algorithm.

Many centers are hesitant to perform a pancreas transplant in patients older than age 50 years. The latest SRTR report shows that pancreas transplants declined sharply in recipients aged older than 50 years, from 244 in 2014 to 185 in 2015. Transplants in younger recipients (age <35 years) increased from 252 in 2014 to 279 in 2015. In the context of improved outcomes and the DM population now living longer, older patients should be considered for pancreas transplantation. Many larger centers in the US and UK are now considering selected older patients to be eligible as long as the patient has a favorable cardiovascular risk profile and does not have additional comorbidities.

From historical retrospective single-center data, obesity has been considered a risk factor for reduced kidney and pancreas graft survival in SPK transplantation for many years. In a recent analysis of the UNOS/SRTR data, the effect of recipient BMI on pancreas transplant outcomes in all three pancreas transplant categories was examined. The authors demonstrated that: (1) overweight and obesity are associated with a moderate increase in early mortality, (2) overweight and obesity are associated with a moderate increase in early pancreas graft loss, (3) obesity, but not overweight, is associated with poorer long-term graft survival, and (4) underweight is associated with poorer long-term patient survival. Although the mechanisms underlying these findings are not understood clearly at this time, multiple single-center studies have demonstrated noninferior patient and graft survival outcomes in obese compared with nonobese patients in both DM categories, but at the expense of a higher surgical complication rate. Based on these data, our recommendation is that each center should determine what recipient BMI they are comfortable with transplanting, it should be individualized to the recipient, and that preoperative weight loss should be strongly encouraged. Given the frequent comorbidities of morbid obesity, few centers will tackle patients with BMI >35. Morbidly obese (World Health Organization [WHO] Class 2) patients could be considered for possible bariatric surgery before transplantation.

Pretransplant assessment of autoimmune markers (e.g., antibodies against glutamic acid decarboxylase, insulinoma-associated antigen-2, zinc transporter-8, and insulin) should be considered to establish a baseline before possible pancreas transplantation. After transplantation, a new or increasing titer of a T1D-specific autoantibody may indicate recurrent autoimmunity as a cause for pancreas graft dysfunction and aid in the evaluation of any new-onset hyperglycemia posttransplant.

Assessment of the degree of hypoglycemic unawareness is crucial. The most common tool used to assess hypoglycemia awareness is the Clarke Hypoglycemia Symptom Questionnaire. The Clarke method comprises eight questions characterizing the patient’s exposure to episodes of moderate and severe hypoglycemia. It also examines the glycemic threshold for, and symptomatic responses to, hypoglycemia. A score of 4 or greater implies impaired awareness of hypoglycemia. Assessment of the frequency and severity of severe hypoglycemia should be part of the evaluation of all patients considering pancreas transplantation.

Donor Selection and Management

Logistic and Technical Aspects to Optimize Organ Viability

Determining donor HLA typing, viral serologies, and crossmatch results with patients on the pancreas transplant waiting list will permit the ideal allocation of the cadaveric pancreas (plus kidney with SPK transplant) before procurement of the organs. This sequence of events has several advantages. It will allow the transplant center performing the pancreas transplant the choice to also procure the pancreas, it will allow patients to be admitted to the hospital and the reevaluation process to begin simultaneously, rather than sequentially, to the procurement of the organs, and it will minimize the cold ischemia time of the pancreas before implantation. It is ideal to revascularize the pancreas within 16 hours from the time of cross clamping at procurement. Finally, it will also allow identification of 0-antigen mismatched donor-recipient pairs to be identified before procurement that will minimize cold ischemia time if the organs need to be transported across the country.

Donor Management and Selection

Identification of suitable deceased organ donors for pancreas transplantation is one of the most important determinants of outcome. The contraindications to use a deceased donor pancreas for transplantation are outlined in Table 36.1 . Optimal management of the donor avoids organ edema and pancreatitis.

Table 36.1

Contraindications to Deceased Pancreas Procurement for Transplantation

History of DM (type 1 and 2)
BMI >35 kg/m 2
Previous pancreatic surgery
Moderate/severe pancreatic trauma
Acute or chronic pancreatitis
Intraabdominal sepsis
Major active infection
Chronic alcohol use
Prolonged hypotension or hypoxemia with significant end-organ damage (kidney, liver, etc.)
Prolonged warm ischemia in DCD donor (>30 min)
Procurement-related injuries
Severe fatty infiltration of pancreatic parenchyma
Severe pancreatic edema
Relative contraindication: presence of replaced right HA off superior mesenteric artery

BMI, body mass index; DCD, donors after cardiac death; DM, diabetes mellitus; HA, hepatic artery.

The criteria that determine an appropriate donor for pancreas transplantation are more stringent than for kidney or liver donors. Deceased pancreas organ donors are typically between the ages of 10 and 55 years. The lower age limit typically reflects the anticipated small size of the splenic artery that may rarely preclude successful construction of the arterial Y-graft needed for pancreas allograft revascularization. We have performed many transplants from younger and lower weight donors (weight 15–25 kg) and have observed noninferior outcomes in graft and patient survival, with no significant difference in graft loss secondary to technical reasons. The use of older donors has been associated with increased technical failure due to pancreas graft thrombosis, a higher incidence of posttransplant pancreatitis, and decreased pancreas graft survival rates. This may be consequent to reduced tolerability of cold ischemia time, but this has not been rigorously studied. The weight of the cadaveric organ donor is an important consideration. Obese donors over 100 kg are often not suitable. Obese patients may have a history of T2D, or the pancreas may be unsuitable because of a high degree of adipose infiltration. Many transplant surgeons find the pancreas donor risk index (PDRI) a useful tool to gauge whether the donor will provide a suitable pancreas for transplantation.

Hyperglycemia and hyperamylasemia are frequently observed in cadaveric organ donors. Hyperglycemia is not a contraindication to pancreas procurement for patients who are known not to have T1D or T2D. Hyperglycemia is generally benign and caused by a combination of factors including administration of pharmacologic doses of steroids to reduce brain swelling, high rate infusions of glucose-containing solutions (especially in patients with diabetes insipidus), and increased sympathetic activity associated with brain injury. A recent study also showed minimal association of donor HbA1c levels with pancreas graft outcomes. Hyperamylasemia may be concerning but reports have suggested that it has little effect on pancreas graft function posttransplant. It is likely that this finding was due to variable laboratory ranges and/or other nonpancreatic causes for elevated enzymes. If the cause of hyperamylasemia is due to severe hemorrhagic pancreatitis or due to pancreatic injury in the case of a donor with trauma, organ recovery will be ruled out at the time of procurement. However, isolated hyperamylasemia, without hyperlipasemia can also occur in the setting of head trauma and salivary gland injury. The hemodynamic stability and need for inotropic support is an important consideration, as hypotension can cause pancreatitis in addition to acute kidney injury and hepatocellular injury. Donor hypotension may have more influence on the anticipated function of the kidney allograft than it does on initial endocrine function of the pancreas allograft.

Perhaps the most important determinant of the suitability of the pancreas for transplantation is direct examination of the organ during and after the surgical procurement. The experience of the procurement team is important for correct assessment of the suitability of the pancreas graft for transplantation. It is during procurement that judgment regarding the color, degree of fibrosis, adipose tissue around and in between the acinar lobules, firmness or nodularity of the graft, atrophy, hemorrhagic pancreatitis, saponification, donor trauma, and specific vascular anomalies can be accurately assessed. Pancreata with heavy infiltration of adipose tissue are believed to be relatively intolerant of cold preservation, and carry the potential of saponification and reperfusion pancreatitis after revascularization. Fig. 36.5 is an example of a perfect organ in situ before cross clamp.

Fig. 36.5

Example of a high quality pancreas at time of organ recovery, note the color and absence of fatty infiltration of the organ.

The important vascular anomaly that must be evaluated during procurement is the occurrence of a replaced or accessory right hepatic artery (HA) originating from the superior mesenteric artery (SMA). This should also be reassessed ex vivo.

The use of donors after cardiac death (DCD) for pancreas transplantation is well reported. There is a higher rate of ruling out the pancreas for transplantation at the time of DCD procurement than in stable conventional donor after brain death (DBD) organ donors. If the pancreas is deemed suitable, there is the added consideration of the effect of delayed kidney graft function in a uremic SPK candidate. The use of living related and unrelated pancreas donors has also been described. A distal pancreatectomy is performed for a segmental pancreas transplant. Anecdotal cases of combined live donor partial pancreatectomy and nephrectomy have also been reported. These procedures are not widely performed and are confined to one or two pancreas transplant programs, primarily in Asia.

The organ preservation solution may affect pancreas graft survival. In an adjusted analysis of UNOS data comparing the UW solution versus histidine-tryptophan-ketoglutarate (HTK), HTK preservation was independently associated with an increased risk of pancreas graft loss (hazard ratio [HR] 1.30, P = 0.014), especially in pancreas allografts with cold ischemic time ≥12 h (HR 1.42, P = 0.017). This reduced survival was seen in both SPK and PTA transplants ( Fig. 36.6 ). Furthermore, HTK preservation was also associated with 1.54-fold higher odds of early (<30 days) pancreas graft loss compared with UW (odds ratio [OR] 1.54, P = 0.008).

Fig. 36.6

Survival curves for SPK and pancreas alone transplants based on preservative solution. SPK graft survival by HTK versus UW (A), Solitary pancreas graft survival by HTK versus UW (B). HTK, histidine-tryptophan-ketoglutarate; SPK, simultaneous pancreas and kidney UW, University of Wisconsin.

Reproduced from Stewart ZA, et al. Histidine-tryptophan-ketoglutarate (HTK) is associated with reduced graft survival in pancreas transplantation. Am J Transplant 2009;9(1):217–21.

Models used for Donor Selection

A donor risk index (DRI) derived retrospectively from registry analyses that controls for donor, recipient, and transplant-related factors, has been developed for kidney (KDRI) and liver (LDRI) donors. These DRIs include factors that can be identified at the time of organ allocation and can help predict the risk of early graft failure at 1 year. Such a DRI was constructed for pancreas allografts (PDRI; Fig. 36.7 ) based on data from SPK, PAK, and PTA transplants. The model included 10 donor factors: donor sex, age, black race, Asian race, BMI, cause of death, creatinine, height, and DCD status. The transplant factors included pancreas preservation time and an interaction between PAK and the donor cause of death. The model was stratified by transplant type to allow differing failure rates for each type of pancreas transplant. In summary, the PDRI can be a useful tool in decision making at time of organ offer. In bridging the gap between organ availability and utilization, cautious utilization of higher PDRI donors could be shifted toward recipients with median characteristics awaiting an SPK rather than solitary transplants, whereas aggressive utilization of these high-PDRI donor organs for all transplant categories should be practiced in high-volume centers as their outcomes appear to be noninferior compared with the “perfect” donor. Interestingly, the PDRI has been tested in a European (UK) population, demonstrating that this algorithm is predictive for graft survival of SPK recipients; the range of scores in the UK population (1021 transplants) was greater than that reported in the US cohort, consistent with greater utilization of higher-risk pancreas grafts. Indeed, the UK donor cohort was older (34.9 vs. 26.3 years, P < 0.0001) and comprised a greater proportion of DCD transplants (10.8% vs. 1.4%, P < 0.0001).

Fig. 36.7

(A) Adjusted 1-year graft survival after simultaneous kidney-pancreas (SPK) transplant as a function of the pancreas donor risk index (PDRI). (B) Adjusted 1-year graft survival after pancreas after kidney (PAK) transplant as a function of the PDRI. (C) Adjusted 1-year graft survival after pancreas transplant alone (PTA) as a function of the pancreas donor risk index (PDRI). Curves shown reflect expected survival for an average recipient (41 years old, BMI = 25, male, white, albumin 3.7 g/dL, PRA = 0, private insurance, no prior PTx, and enteric-drained) transplanted with pancreata from each PDRI strata. BMI, body mass index.

Reproduced from Axelrod DA, et al. Systematic evaluation of pancreas allograft quality, outcomes and geographic variation in utilization. Am J Transplant 2010;10(4):837–45.

Another useful tool is the composite risk model devised by the group from the University of Minnesota to predict technical failure (TF). Of the factors analyzed in their multivariable model, donor BMI >30, donor Cr >2.5, donor age >50 yrs, and preservation time >20 hours had the strongest association with technical failure. Bladder drainage of exocrine secretions was protective. In their composite risk model, the presence of one risk factor did not significantly increase risk of TF (HR 1.35, P = 0.35). Two risk factors in combination, however, increased the risk of TF greater than threefold whereas three risk factors increased risk greater than sevenfold (HR 7.66, P ≤ 0.01) ( Fig. 36.8 ).

Fig. 36.8

The University of Minnesota Composite Risk Model prediction of technical failure risk and observed pancreas graft survival. (A) The final Cox analysis was used to generate predictive model of technical failure risk according to the number of risk factors present. The risk model is adjusted for bladder/enteric drainage and history of pancreatitis in the donor. (B) The observed technical failure-free pancreas graft survival in this cohort is depicted according to number of risk factors by univariable Kaplan–Meier survival.

Reproduced from Finger EB, et al. A composite risk model for predicting technical failure in pancreas transplantation. Am J Transplant 2013;13(7):1840–9.

Donor Trends and Procurement-Related Outcomes

Pancreas donor characteristics, as analyzed by the IPTR and SRTR, have changed over the past decade. Deceased pancreas donor demographics show a steady increase in proportions of younger donors (18–34 years), from 49% in 2004 to 64% in 2015. Similarly, the proportion of older donors (age >50 years) decreased from 6% in 2004 to 2% in 2015. Proportions of white donors decreased from 72% in 2004 to 61% in 2015, with a corresponding increase in proportions of black donors from 13% to 22%. Discard rates of pancreata recovered for transplant were highest for donors aged older than 50 years, and for high-BMI donors (>30). The higher discard rates from older and higher-BMI donors reflect the shared experience and published risks associated with these donors. The ratio of male to female donors, and DCD to DBD donors has remained constant. The rate of trauma as cause of donor death increased significantly over time in SPK and PAK transplants, and remained stable in PTA. Proportions of anoxia as a cause of death increased from 10% in 2004 to 27% in 2015. Proportions of cerebrovascular accident decreased from 21% to 11% and of head trauma from 66% to 61%. The preservation time decreased significantly in SPK and PAK. In 2010 to 2014, 62% of all transplants had a preservation time of less than 12 hours, and only 1% reported a preservation time of over 24 hours. A comparison of preservation times in all three categories showed a slightly longer preservation time for PTA compared with SPK because of the higher rate of organ imports.

Criteria for organ donation tend to be more liberal in European countries than the US, particularly in the UK. Of all deceased donors in the UK, 42% are DCD; pancreas transplantation from this source was first carried out in 2005 and currently represents 25% of the national program. Analysis of the UK experience showed that DCD donors (but not recipients) were selected to minimize other risk factors (e.g., age) and that the graft and patient survival data were similar to contemporary data from DBD donor transplants. Similarly, the maximum acceptable age for donation has increased in the UK, with 23% of transplants from donors older than 50 years. The complications of transplantation are believed to be greater in organs from donors with higher BMI, with very few solid-organ transplants carried out from donors with BMIs greater than 30 kg/m 2 ; the UK organ allocation scheme directs such organs preferentially to islet isolation.

Pancreatic trauma occurring at the time of organ procurement contributes to the growing rate of pancreas discard, with more than 20% of pancreata discarded after recovery in the US due to procurement trauma. The UK transplant registry was analyzed for the frequency of pancreatic injuries, factors associated with damage, and the effects of these injuries on graft survival. More than 50% of recovered pancreata had at least one injury, most commonly a short portal vein (21.5%) and capsular damage (13.6%), and more than 50% of organs retrieved for whole organ or islet transplant purposes were discarded. Liver donation, procurement team origin, HA arising from the SMA, and increasing donor BMI were associated with increased rates of pancreas damage on univariate analyses; on multivariate analysis only the presence of a HA from the SMA remained significant. Overall, there was no difference in graft survival between damaged and undamaged organs; however, graft loss was significantly more frequent in pancreata with arterial damage ( P = 0.04) and in those with parenchymal damage ( Fig. 36.9 ). Damage to the pancreas during organ recovery is more common than liver and kidney recoveries, and hence scrupulous procurement technique and awareness of anatomic variants are essential to reduce rates of procurement-related injuries leading to discard.

Fig. 36.9

Graphical demonstration of pancreas graft survival, stratified by presence and type of pancreas damage. (A) Pancreas graft survival by presence of any damage (damage – gray [ n = 233], no damage – black [ n = 309]; P = 0.28). (B) Pancreas graft survival by presence of arterial damage (arterial damage – gray [ n = 10], no arterial damage – black [ n = 528]; P = 0.04). (C) Pancreas graft survival by presence of parenchymal damage (damage – gray [ n = 9], no damage – black [ n = 529]; P = 0.05).

Reproduced from Ausania F, et al. A registry analysis of damage to the deceased donor pancreas during procurement. Am J Transplant 2015;15(11):2955–62.

Surgical Procedure

Pancreas Procurement

The pancreas must be procured with an intact vascular supply that does not compromise the vascularity of the liver. The pancreas is procured with the spleen and duodenum intact. The organ is perfused with preservation solution and cold-stored. The donor iliac vessels are obtained for revascularization of the arterial supply and sometimes the portal vein. There are two general methods of organ procurement. Many programs prefer to perform an en-bloc removal of the liver and pancreas together and separate the two organs at the back table. Other programs prefer to perform a more deliberate dissection of the pancreas and liver by mobilizing the relevant vasculature before in situ flush preservation, after which the liver and pancreas are separated in situ, ensuring the organs are kept cold and there is rapid extirpation.

The relevant components of the in situ procurement process are briefly described as follows:

  • Long midline incision (± cruciate incision);

  • Mobilization of ascending colon, control of the infrarenal aorta, and identification of superior mesenteric artery;

  • Control of the supraceliac aorta;

  • Identification of HA (ligation of gastroduodenal artery), splenic artery, portal vein, and division of common bile duct;

  • Identification of replaced and/or accessory left and right hepatic arteries;

  • Exposure of the anterior aspect of the pancreas for visual and manual inspection;

  • Mobilization of the spleen by division of short gastric vessels and dissection of its ligamentous attachments;

  • Mobilization of head, tail, and body of the pancreas with minimal manipulation of the organ;

  • Nasogastric (NG) tube positioning into the proximal duodenum and irrigation with antibiotic solution;

  • Removal of NG tube and division of the proximal duodenum proximal to the pylorus (this can be further resected on the back table);

  • Heparinization of the donor and infusion of intraaortic (± intraportal, avoid inferior mesenteric vein (IMV) flush to prevent edema of the pancreas) preservation solution;

  • Division of proximal jejunum, middle colic vessels, superior mesenteric vessels distal to the pancreatic uncinate process;

  • Division of celiac, SMA, splenic arteries; and portal vein;

  • Procurement of liver, pancreaticoduodenosplenic allograft, and kidneys, and reflushing with fresh UW solution ex vivo before packaging. After in situ flushing and during extirpation the organs must be kept cold;

  • Procurement of donor iliac vessels;

  • Closure of incision.

Importance of Ex Vivo Back Table Preparation

The back table preparation of the pancreaticoduodenal allograft for transplantation requires careful and meticulous surgical technique to ensure a properly revascularized pancreas with adequate duodenum and minimal extraneous fibrotic and adipose tissue ( Fig. 36.10 ). The quality of the back table surgical procedure has the greatest effect on the outcome of the transplant surgery.

Dec 26, 2019 | Posted by in NEPHROLOGY | Comments Off on Pancreas and Kidney Transplantation for Diabetic Nephropathy
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