41
Transplantation of the Pancreas
James W. Lim
Objectives
1. To review diabetes mellitus (DM) in terms of prevalence, incidence, and costs to society.
2. To identify the classic complications of DM.
3. To review recipient and donor selection.
4. To discuss the three situations in which pancreas transplant is performed.
5. To describe the graft and patient survivals for pancreas transplant.
6. To describe the functions of the pancreas.
7. To describe the different surgical techniques for pancreas transplant.
8. To name the major complications of pancreas transplant.
9. To describe the impact of islet cell transplant.
Case
A 43-year-old Caucasian man with a history of type 1 diabetes melli- tus (DM) since age 5 presents to the emergency room with nausea and vomiting for 72 hours. In addition, he appears to be lethargic and con- fused and has a fever of 39°C. The examination is significant for poor skin turgor, confusion, and right lower extremity cellulitis; he has a blood pressure (BP) of 90/50, a pulse of 125, and a respiratory rate of 35. His lab work is significant for a white blood cell count of 22,000, blood urea nitrogen (BUN)/creatinine of 55/3.4, glucose of 750, and positive serum acetone. The emergency room staff states that this is the fifth time in the past 2 years that this man has come in with similar presentations. What is the diagnosis and how should this patient be treated?
718
Historical Perspective
Pancreas transplant (P Tx)remains the least recognized transplant to the lay public with the exception of small-bowel transplant. Although whole-organ P Tx was first performed in 1966, it remains much of a mystery to healthcare providers at large as well as to the general public because of the paucity of news surrounding it. More kidney transplants (K Tx) have been performed in 1 year in the United States than pancreas transplants worldwide from 1987 to 1999. According to the International Pancreas Transplant Registry (IPTR), 13,372 kidney transplants were performed in the United States alone in 2000, whereas the total number of pancreas transplants performed worldwide from 1966 to 1999 was 12,939.1Two thirds of the pancreas transplants per- formed are done in the United States, with one fourth in Europe (Fig.
41.1). With the advent of Medicare payment for pancreas transplants effective July 1, 1999, it is hoped that financial reimbursement will stimulate an increase in the total number of pancreas transplants performed. In fact, more information about islet cell transplant has emerged with the news of successful islet cell transplant in Edmonton, despite the small numbers and limited follow-up span.
Diabetes Mellitus
Overview
It is estimated that 6.3% or 18.2 million people in the United States have diabetes mellitus (DM). This includes 13 million people who are diagnosed and the estimated 5.2 million people who are undiagnosed.2 Figure 41.1. Number of pancreas transplants reported in the International Pancreas Transplant Registry (IPTR) by continent, 1987–1999. (Reprinted from Cecka JM, Terasaki PI, eds. Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000, with permission.)
1 OPTN/SRTR 2001 Annual Report.
2 Centers for Disease Control and Prevention. National diabetes fact sheet: general infor- mation and national estimates on diabetes in the U.S., 2002. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2003.
The incidence of new cases diagnosed per year is 1.3 million people aged 20 years or older. Approximately one in every 400 to 500 children and adolescents has type 1 DM. Clinical reports and regional studies indicate that type 2 DM is becoming more common among Native American/American Indian, African American, and Hispanic/Latino children and adolescents. Diabetes was the sixth leading cause of death on U.S. death certificates in 2000. Overall, the risk for death among people with DM is about two times that of people without DM. In fact, those patients on dialysis who have DM have the highest rate of mortality on dialysis, approximating 28%
per year. From a strictly economic point of view, it is estimated that direct and indirect expenditures attributable to DM in 2002 were
$132 billion.3Per capita expenditures totaled $13,243 for people with DM and $2,560 for people without DM. Healthcare spending for patients with DM is more than double the spending for patients without DM.
Classic Complications
Diabetes mellitus is a chronic, disabling disease that affects all the major organ systems and shortens the life span by 10 years for those people in the United States who are affected by it. The classic complications that occur consist of retinopathy (DM is the most common cause of blindness among adults aged 20 to 74), gastrop- athy/gastroparesis, nephropathy (DM is the most common cause of renal failure), neuropathy, vasculopathy (DM is the most common cause of amputations), labile control, and diabetic ketoacidosis (DKA).4
Strict controlclearly has been shown to delay significantly the devel- opment and slow the progression of the microvascular complications of DM. There appears to be a trend for fewer macrovascular events (strokes, myocardial infarctions, etc.) in patients who are controlled aggressively with insulin. However, this is at the cost of a 10-pound greater weight gain and a threefold higher risk of severe hypoglycemia.
These results were noted with the publication of the Diabetic Control and Complications Trial (DCCT)in the New England Journal of Medi- cine in 1993.5For many patients, however, such aggressive control with its inherent problems proves to be as troublesome as the primary disease itself.
3Reviews/commentaries/position statements report from the American Diabetes Asso- ciation. Diabetes Care 2003;26:917–932.
4Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the U.S., 2002. Atlanta, GA: U.S.
Department of Health and Human Services, Centers for Disease Control and Prevention, 2003.
5DCCT Research Group. The effect of intensive treatment of diabetes on the devel- opment and progression of long-term complications of insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
Pancreas Transplant
Evaluation
With the knowledge that strict control could and did prevent some of the complications associated with DM, the need for a better alternative to insulin arose, laying the foundation for P Tx. Simply put, any patient with DM with complications could be a considered a candidate for P Tx. Most centers would place an age restriction for the recipient of between 18 and 60 years of age; these recipients also would have to have no active contraindications, such as active cancer (CA), illicit drug abuse, HIV, uncorrectable cardiopulmonary disease, inability to afford the medications, and noncompliance. Relative contraindica- tions consist of obesity [body mass index (BMI >35)], amputations (sign of severe peripheral vascular disease), severe gastroparesis (inability to tolerate oral medications postoperatively), and active smoking. Although initially patients with only type 1 DM were deemed candidates, current data from the IPTR support the use of P Tx for patients with type 2 DM as well. The 1-year patient (95% type 1 vs. 93% type 2) and graft (84.8% type 1 vs. 85.2% type 2) survival for both types of DM were not significantly different.
As with any other transplant evaluation, the potential patient is evaluated by a team consisting of a transplant surgeon, transplant nephrologist, transplant coordinator, social worker, and financial coordinator. Laboratory workis done, with the most important values consisting of the serology, i.e., hepatitis (Hep) B or C, HIV, serum cre- atinine, and blood type. The serology helps to determine if patients need further clarification of their hepatitis status (liver biopsy if Hep B or C positive). The serum creatinine determines if the patient needs a K Tx with a P Tx. The blood type determines who the potential cadaver donor may be, since the donor must be blood type compati- ble. Only two programs in the country perform living donor pancreas transplants, and the numbers are small. Most donors are cadaveric. The most important workup of the possible recipient is the cardiac imaging study, be it a nuclear imaging study or a cardiac catheterization. The reason for this is the high rate of cardiac perioperative mortality and morbidity associated with DM.
Once the patient’s testing is finished and the workup is deemed appropriate, the patient can be listed for transplant. Exactly as for a K Tx, the patient waits on a list with people of the same blood type, and those with the longest waiting time are called first. The waiting time for patients on the P Tx list tends to be shorter, since fewer people are on the P Tx list than on the K Tx list. For example, in New Jersey, approxi- mately 200 people are on the P Tx list and 2000 are on the K Tx list.6
Donor Selection
The assessment of a suitable donor is more demanding objectively and subjectively.Unlike for a kidney donor in which serum creatinine
6 OPS New Jersey, personal communication.
is usually the one marker used to rule a potential donor in or out, for a pancreas donor, a number of different markers are used, such as amylase, lipase, and glucose. However, even an elevated serum glucose does not rule out a potential donor, since studies have shown that brain-dead donors often manifest some degree of hyperglycemia, especially when high-dose steroids are given as part of any brain- swelling prevention protocol at many centers in the U.S. Age restric- tionsfor donors usually range from 8 to 50 years of age, with some centers using donors up to age 60. Weight restrictions range from 30 to 100 kg. Donors above 90 kg often manifest increased degrees of fatty infiltration, which, when significant, rules out these donors for whole organ P Tx, but they can be used for recovery for islet cell transplant.
Higher degrees of fatty infiltration have led to more successful islet cell recovery.
With respect to whole-organ recovery, the subjective findings of the amount of “fat,” coupled with the texture and “feel” of the poten- tial cadaver donor pancreas, make the procurement of the pancreas rely much more on the experience of the recovering transplant surgeon.More so than with almost any other organ, with the excep- tion of the heart, the experience of the recovery surgeon is crucial, since the decision to accept the pancreas can be a difficult one. The techni- cal aspects of recovery also can be complicated.The donor pancreas is the only organ recovered that has with it other organs attached, in this case the spleen at the tail of the pancreas and the C-loop of the duodenum that comes attached to the head of the pancreas (Fig. 41.2).
Also removed with the donor pancreas are the donor iliac vessels. The spleen is removed either at the end of the procurement process or most commonly when the donor pancreas is prepared on the back table at the recipient hospital. The back-table work consists of cleaning up any
Figure 41.2. The organ is kept in ice-cold solution until transplantation. The kidneys are removed. D, duodenum; Pa, pancreas; SMV, superior mesenteric vein; SA, splenic artery. (Reprinted from Kremer B, Broelsch CE, Bruns DH.
Atlas of Liver, Pancreas, and Kidney Transplantation. New York: Thieme Medical Publishers, 1994. Reprinted by permission.)
extraneous tissue and stapling off the mesenteric vessels and duodenal stumps. The donor common iliac artery with its attached external and internal iliac artery is used as a Y graft to attach to the donor pancreas superior mesenteric artery (SMA) and splenic artery (SA) so as to use the common iliac artery as a conduit for the inflow of the pancreas (Fig. 41.3).
Three Options for Pancreas Transplant
Renal functiondetermines which of the three options potential P Tx candidates will undergo.
Patients with renal failure or pending renal failure receive both a pancreas and kidney transplant, otherwise known as simultaneous pancreas and kidney (SPK) transplant (Table 41.1). Approximately 83% of all pancreas transplants performed in the U.S. are performed in this manner. This patient is then able to come off dialysis, much as a patient who receives a K Tx. This patient, however, would have the added benefit of no longer being a diabetic. The ramifications go
A
B
Figure 41.3. (A) Donor iliac conduit is anastomosed to the splenic artery and the superior mesenteric artery of the pancreas on the back table. (B) Alterna- tively, the blood supply to the donor pancreas can be reconstituted by direct anastomosis of the splenic artery to the superior mesenteric artery. (Reprinted from Harland RC. Pancreas transplantation. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York:
Springer-Verlag, 2001, with permission.)
further, since the natural history of patients with DM who receive only a K Tx indicates they have nearly a 100% recurrence of their DM in the transplant kidney histologically. Fortunately, this is clinically signifi- cant only 5% of the time. As with other transplants, results have improved with time (Table 41.2).
A second subset of patients receives a pancreas after kidney (PAK) transplant.These patients had renal failure because of DM and already have received a K Tx. Because some of the medications that are required posttransplant can exacerbate and worsen glucose control, diabetic complications worsen to the point that these patients now become candidates for PAK. The creatinine clearance (Cr Cl) that defines these patients is >50 cc/min. Approximately 10% of all pancreas transplants are performed in this manner.
Table 41.1. Demographics: U.S. cadaver pancreas transplants, January 1996 to September 1999.
SPK PAK PTA p value
Frequency 3257 455 183
Recipient age (years) 38.4 ± 7.5 39.9 ± 7.1 37.0 ± 8.6 .0001
Male recipients 58% 58% 39% .001
Retransplants (%) 1% 28% 14% .001
Preservation time (hr) 13.3 ± 5.8 16.3 ± 6.4 16.3 ± 6.8 .0001 Donor age (years) 27.2 ± 11.8 26.7 ± 11.3 25.8 ± 11.3 .167 No. of HLA-A,-B,-DR 4.3 ± 1.2 3.5 ± 1.4 3.4 ± 1.4 .0001
mismatches
Waiting list time (days) 92–415 48–363 48–310 .0005 25–75%
HLA, human leukocyte antigen; PAK, pancreas after kidney (transplant); PTA, pancreas transplant alone; SPK, simultaneous pancreas and kidney (transplant).
Source: Reprinted from Cecka JM, Terasaki PI, eds. Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000, with permission.
Table 41.2. Outcome of U.S. cadaveric pancreas transplants by era of transplant (level II evidence).
1-year patient 1-year pancreas
Type of Tx Era survival (%) graft survival (%)
Simultaneous 1987–1989 90 74
pancreas-kidney 1990–1991 91 75
1992–1993 92 79
1994–1997 94 82
Pancreas after 1987–1989 90 56
kidney 1990–1991 96 51
1992–1993 90 52
1994–1997 95 71
Pancreas transplant 1987–1989 93 46
alone 1990–1991 90 51
1992–1993 80 56
1994–1997 93 62
Source: International Pancreas Transplant Registry (IPTR), Department of Surgery, Uni- versity of Minnesota, Minneapolis, MN. With permission. Reprinted from Harland RC.
Pancreas transplantation. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery:
Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001, with permission.
The third and last subset of patients to receive a P Tx has the most to benefit from this procedure and the most to lose from diabetes. This subset makes up 7% of all the pancreas transplants performed in the U.S. today. These patients have DM and some of the classic complica- tions, most often labile sugar control or hypoglycemic unawareness.
Hypoglycemic unawareness is very uncommon, but it is defined as the inability to sense when the glucose level is nearing dangerously low levels, to the point of losing consciousness. Most diabetics can sense when their glucose levels are getting low and are able to take some sort of “high sugar” tablet or juice to keep them from losing consciousness or going into seizures. Those with hypoglycemic unawareness are not able to detect this and always are fearful that they may do themselves or others harm. However, they do not have renal failure yet or, at worst, they have some early renal insufficiency. These patients receive a pan- creas transplant alone (PTA).The Cr Cl that delineates these patients is 60 to 70 cc/min. Since nearly 35% of all patients with DM go on to suffer renal failure after 15 to 20 years, and since it has been shown that a PTA can reverse all the diabetic changes in the native kidney after 5 to 10 years, this is a very viable option.7
Function of the Pancreas
Before the surgical technique can be explained, the function of the pancreas must be understood. The pancreas has two main functions, one endocrine and the other exocrine. The main endocrine function is insulin production. Insulin is produced mainly in the tail of the pancreas by the beta islet cells and released into the portal vein, from which it then goes to the liver to be metabolized in what is called the first-pass phenomenon. The exocrine function is the production and release of the protease enzymes and bicarbonate.These are released via the pancreatic duct back into the gastrointestinal tract via the ampulla of Vater in the duodenum. The donor pancreas retains these two functions, and the surgical connections are related to these two functions. Hence, the donor portal vein is the conduit by which the insulin produced in the donor pancreas is released into the vascular system in the recipient. Likewise, the attached donor duodenum is the conduit by which the exocrine function is facilitated.
Surgical Techniques
The endocrine function can be drained into the iliac venous system of the recipient (systemic drainage) or into the mesenteric venous system of the recipient (portal drainage). The exocrine function can be drained either into the bladder (bladder drainage) or into the gastrointestinal tract (enteral drainage).
Most centers currently use systemic drainage of the endocrine function, and more and more centers are using enteral drainage of
7 Fioretto P, Steffes, MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropa- thy after pancreas transplantation. N Engl J Med 1998;339:69–75.
the exocrine function (Figs. 41.4 and 41.5).The advantage of systemic drainage is more historical, in that most transplant surgeons were trained to use this method and therefore are more comfortable in its surgical technique and, even more importantly, in its results. This is and remains the preferred technique for most centers. The insulin production goes into the systemic system by way of the donor portal vein into the recipient iliac vein (Fig. 41.6). Thus, the insulin produced does not get metabolized first, since the first-pass phenomenon does not come into play. These patients are, in fact, hyperinsulinemic, much like a type 2 diabetic, but they do not become hypoglycemic because there is still some degree of insulin resistance present.
A few select centers are performing the portal drainage technique.
The insulin production drains back into the portal system by way of the donor portal vein to the recipient’s superior mesenteric vein, thereby preserving the first-pass phenomenon (Fig. 41.7). The advantage of Figure 41.4. Annual number of U.S. BD, cadaver pancreas transplants for which duct management technique is known from 1988–98. (Reprinted from Cecka JM, Terasaki PI, eds. Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000, with permission.)
Figure 41.5. Annual percentage of U.S. cadaver ED pancreas transplants managed with systemic or portal venous drainage, 1996–98. (Reprinted from Cecka JM, Terasaki PI, eds. Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000, with permission.)
Figure 41.6. Bladder-drained pancreas transplant.
(Reprinted from Hickey DP, Bakthauatsalam R, Bannon CA, et al. Urologic complications of pan- creatic transplantation. J Urol 1997;157:2042–2048.
With permission from Lippincott Williams &
Wilkins.)
Figure 41.7. Technique for whole-organ pan- creas transplantation with portal venous and enteric exocrine drainage. (Reprinted from Newall KA, Bruce DS, Cronin DC, et al. Com- parison of pancreas transplantation with portal venous and enteric exocrine drainage to the stan- dard technique utilizing bladder drainage of exocrine secretions. Transplantation: Brief Com- munications 1996;62(9):1353–1356. With permis- sion from Lippincott Williams & Wilkins.)
this method is the theoretical improvement of the lipid profile of the recipient, since there is no longer any hyperinsulinemia. Other advan- tages consist of less rejection episodes and faster operative times.
To date, graft and patient survivals based on systemic versus portal drainage are similar. When portal drainage is used, the exocrine func- tion drains back into the enteric system by way of the recipient loop of small bowel, be it a Roux-en-Y limb or adjacent recipient jejunum.
Hence, this method preserves the physiologic nature of the pancreas by draining the endocrine function back into the portal system and the exocrine function back into the enteric system, hence, the terminology portal/enteral drainage. This is in distinction to systemic/bladder drainage,whereby the endocrine function drains into the iliac venous system and the exocrine functions drains via the bladder.
The advantages of the enteric drainage technique over the bladder drainage technique are many.First, the classic complications associ- ated with draining active enzymes and bicarbonate with the resultant volume loss are alleviated. Therefore, the problems with hematuria, recurrent urinary tract infections (UTIs), reflux pancreatitis (reflux of the urine back into the donor pancreas), acidosis, and hypovolemia are avoided entirely by performing the enteric drainage technique. The ramifications of this cannot be understated. Approximately 12% of all patients drained via the bladder route must be corrected surgically within 2 years of the original P Tx.8The surgical correction consists of taking down the bladder anastomosis and reconnecting the exocrine drainage back into the enteric system (Fig. 41.8).
The main advantage for performing the bladder drainage tech- nique is to measure the urinary amylase produced by the donor pan- creas as a means to diagnose rejection.A decrease of 25% to 60% of the baseline urinary amylase is used by these centers to monitor for rejection. Although the ability to collect the urinary amylase is lost with the enteric drainage technique, direct biopsy of the donor pancreas is used to diagnose rejection definitively. Monitoring of the donor pan- creas is performed by checking serum amylase and lipase. Any persis- tent increase from the baseline serum amylase and lipase is taken as being abnormal, and, if appropriate measures do not indicate infection or technical problems, then a percutaneous U.S.-guided biopsy of the donor pancreas is performed.
The other main advantage of bladder drainage over enteric drainage is that leaks at the donor duodenal anastomosis are tolerated better if urine is leaking rather than enteric contents.Most often, a placement of a Foley catheter to decompress the bladder is enough to control the urinary leak. The main advantage of performing a Roux-en-Y limb anastomosis to the donor duodenum is that, should a leak occur, the enteric contents from a defunctionalized loop of bowel usually can be better controlled than if an adjacent loop of recipient jejunum is used.
8Cecka JM, Terasaki. PI, Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000:68.
Postoperative Complications
The most urgent graft-threatening complications occurring in the perioperative period consist primarily of bleeding or thrombosis of the vascular anastomoses and leak at the duodenal anastomosis.
Bleeding enough to warrant going back to the operating room is uncommon; however, the incidence of blood transfusions either in the original operation or after the procedure approximates 5%. The inci- dence of vascular thrombosis is 12%, with 5% arterial and 7% venous.9 Classically, thrombosis occurs immediately postoperatively and is manifested as a sharp increase in the patient’s blood sugar level. Vas- cular thromboses can be seen as late as 1 month after the procedure. If thromboses are seen after 1 month, they usually are secondary to an immunologic issue rather than a technical one. Unfortunately, by the time this occurs, the graft already is thrombosed, with very little or no chance for salvage. The patient is taken back to the operating room, and, most often, the thrombosed graft is removed, since the incidence of graft thrombectomy to viability is exceedingly rare.
Small bowel
Side-to-side Duodenoenterostomy
Figure 41.8. Procedure of enteric conversion after pancreas transplantation with bladder drainage. CIA, common iliac artery; CIV, common iliac vein.
(Reprinted from Sollinger HW, Sasaki TM, D’Alessandro AM, et al.
Indications for enteric conversion after pancreas transplantation with bladder drainage. Surgery 1992;112:842–846. Copyright © 1992 Mosby. With permission from Mosby.)
9 Troppmann C, Gruessner AC, Benedetti E, et al. Vascular graft thrombosis after pan- creatic transplantation: univariate and multivariate operative and nonoperative risk factor analysis. J Am Coll Surg 1996;182(4):285–316.
Duodenal anastomosisleak occurs in up to 1.4% of all cases, with the highest incidence in enteric drained PTA (Table 41.3). As noted above, a Roux-en-Y connection facilitates control. If undetected, the leaks may lead to deep wound infections that may cause worsening renal or pancreatic function and potential multiorgan dysfunction.
Much of the cause of the leak is secondary to the attenuated donor bowel wall, which may facilitate pulling through of sutures and resul- tant leak. The immunocompromised state does not lend itself to faster or better healing of the duodenal anastomosis. The patient usually has a nasogastric tube to help with the perioperative ileus associated with any intraabdominal procedure.
The usual postoperative course consists of 7 to 10 days of hospitalization, with frequent glucose monitoring in the first 48 hours postoperation. Thereafter, the patient recovers as with any other intraabdominal procedure and proceeds to ambulate as quickly as pos- sible. Some centers keep their patients at bed rest for at least 48 to 72 hours postoperatively so as to minimize any chance of the donor pan- creas moving and potentially kinking at the vascular anastomoses.
Knowledge about immunosuppression medications is imperative, and patients are not discharged until they have proven that they know their medications. (See Immunosuppressive Drugs and Their Toxicities in Chapter 40 for an overview of immunosuppression medications.) The same immunosuppression medications used for K Tx also are used in P Tx, i.e., Prograf (tacrolimus or FK506), Neoral (cyclosporine), Cellcept, and prednisone.
See Algorithm 41.1 for postoperative monitoring.
Immunosuppression Medications
Recent immunosuppressive regimens have stressed corticosteroid sparing or elimination, with rejection-free survival rates approach- ing 90% at some centers. The PIVOT Study Group compared the conventional 5-day dose of daclizumab (DAC) versus a 2-dose DAC versus no antibody induction in SPK recipients receiving Prograf, Cell- cept, and prednisone. The conclusions were that both DAC regimens significantly reduced the incidence of acuter rejection, with the 2-dose
Table 41.3. Reasons for technical failures: U.S. cadaver pancreas transplants, January 1996 to September 1999.
SPK PAK PTA
BD ED p BD ED p BD ED p
Gft Thr 5.4% 6.6% .215 5.4% 12.7% .009 4.0% 15.1% .01
Infection/pancreatitis 0.6% 1.6% .107 1.7% 3.2% .314 2.0% 1.4% .76
Anastomosis leak 0.4% 1.1% .05 0.0% 0.6% .214 0.0% 1.4% .238
Bleed 0.2% 0.2% .974 0.4% 0.0% .42 0.0% 0.0% —
BD, bladder drained; ED, enteric drained.
Source: Reprinted from Cecka JM, Terasaki PI, eds. Clinical Transplants 1999. Los Angeles: UCLA Immunogenetics Center, 2000, with permission.
DAC regimen showing the highest event-free survival rate.10Kaufman and colleagues11presented their single-center, retrospective experience with a number of different protocols designed to minimize and then eventually withdraw steroids. They concluded that rapid steroid elim- ination can be achieved safely in SPK and PTA patients. Enough data have been reviewed to make some clear-cut recommendations on P Tx.
For SPK, there appears to be very little difference with respect to graft survival using Prograf or Neoral as the first-line medication, whether
Perioperative period Elevated glucose
(above 200)
STAT Doppler ultrasound (US)
+ Flow + Clot in
splenic vein Questionable or no flow
Repeat US within 24 hours
Heparinize
OR
Viable Nonviable
Close and return to floor
Transplant Pancreatectomy
Algorithm 41.1. Algorithm for postoperative monitoring in pancreas transplant.
10 Stratta RJ, Alloway RR, Hoge LA, PIVOT Investigators. One year outcomes in simul- taneous kidney-pancreas transplant recipients receiving an alternative regimen of daclizumab. Program and abstracts of American Transplant Congress 2003, the fourth joint American Transplant meeting, May 30–June 4, 2003, Washington, DC. Abstract 662.
11 Kaufman DB, Leventhal JR, Gallon LG, et al. Pancreas transplantation in the pred- nisone-free era. Program and abstracts of American Transplant Congress 2003, the fourth joint American Transplant meeting, May 30–June 4, 2003, Washington, DC. Abstract 665.
or not Imuran or Cellcept is used as the second-line medication (Table 41.4). However with respect to PAK and PTA, there does appear to be a favorable response with Prograf over Neoral. The higher incidence of potential diabetogenicity seen with Prograf does not offset its use for this subset of P Tx patients.
Islet Cell Transplant
Most recently, a major breakthrough in pancreas islet cell transplant was reported in the New England Journal of Medicine. In the past, 1-year graft survival for islet cell transplant was 8%. In this landmark report, seven of seven patients had 100% success, had no rejection, and were insulin free.12Although the longest follow-up was only 11 months and Table 41.4. Outcomes according to immunosuppression: U.S. pan- creas transplants performed between January 1, 1994, and November 1, 1998.
Simultaneous pancreas-kidney (SPK) transplants
Pancreas graft function at one year
Type of immunosuppression % n
Cyclosporine, azathioprine 81 1170
Cyclosporine, mycophenolate mofetil 86 850
Tacrolimus, azathioprine 80 516
Tacrolimus, mycophenolate mofetil 83 740
Pancreas after kidney (PAK) transplants
Pancreas graft function at one year
Type of immunosuppression % n
Cyclosporine, azathioprine 58 88
Cyclosporine, mycophenolate mofetil 63 59
Tacrolimus, azathioprine 73 55
Tacrolimus, mycophenolate mofetil 79 160
Pancreas transplants alone (PTA)
Pancreas graft function at one year
Type of immunosuppression % n
Cyclosporine, azathioprine 54 40
Cyclosporine, mycophenolate mofetil 54 14
Tacrolimus, azathioprine 63 37
Tacrolimus, mycophenolate mofetil 73 85
Source: International Pancreas Transplant Registry (IPTR), Department of Surgery, University of Minnesota, Minneapolis, MN. With permission. Reprinted from Harland RC. Pancreas Transplantation. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery:
Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001, with permission.
12 Shapiro J, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type I diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–238.
the total number of patients reported was exceedingly small, this pre- liminary report gives hope that potentially greater and bigger things will follow. As of mid-2003, a total of 49 transplants (36 patients at nine international sites) had been performed. The immunosuppression pro- tocol included daclizumab, sirolimus, and Prograf. Median follow-up at that time was 9.4 months. The eligibility criteria are quite strict and consist of the following: presence of type 1 DM with stable require- ments, weight limit of 70 kg or less, Cr Cl greater than 80 mL/min, and no progressive diabetic complications. Of those who completed the transplant, 82.3% are insulin-free, with 52% of those who received any transplant being insulin-free. Most patients required two transplants, and some required three transplants. No deaths have been reported;
however, there is a wide variation of success, with results as high as 90% at Edmonton to as low as 23% at some of the other sites.
Other centers have picked up the Edmonton protocol and, with their own variations, also have had some success. Long-term issues that need to be addressed involve the ability to achieve success with only one transplant as opposed to the two usually required. Also, the cost of starting up an islet cell transplant program is prohibitive for many centers, and therefore certain centers may become the regional center for all the prospective patients in that area. Finally, the inability to monitor for rejection delays any therapeutic measures until it is too late. The long-term question of potentially increasing patients’ anti- body level to the extent that it makes them untransplantable should they need a K Tx in the future is another issue that can be addressed only with time.
Although solid organ P Tx still is considered to have the superior outcome for more people, the realization of successful islet cell trans- plant is closer than ever. The ability to avoid major surgery and yet undergo successful P Tx via percutaneous placement of these islet cells indeed would be a major breakthrough in the field of transplant.
Although immunosuppression medications still would be required, any method that would decrease the known morbidity and mortality of an operative procedure could be considered only an advantage.
Case Discussion
The patient in the case presented exhibits the classic complications associated with someone who has DM with a severe infection. Most often, the infection is not noticed because of the lack of sensation in the lower extremities. These patients often become very ill very quickly and appear septic. Often, they are dehydrated as manifested by the elevated BUN and creatinine. In addition, as they lose their ability to control their sugars with routine subcutaneous doses of insulin, they can go into ketoacidosis, as manifested by the serum acetone. The treat- ment consists of an insulin drip and adequate intravenous hydration with empiric antibiotic coverage. The patient should be admitted and, when stable, have an imaging study to evaluate for possible osteomyelitis.
Summary
The realization of successful islet cell transplant forever has changed the face of P Tx. No longer are the prospects for islet cell transplant
“just around the corner.” The success of islet cell transplant after so many years of futility has spawned new interest in hepatocyte trans- plant for liver transplant as well as in the potential of stem cells. Not lost in this great surge of cell research are the ever improving results for solid-organ P Tx. Clearly, results have improved from era to era.
Technical failure rates have improved much over the years, but they still remain the number-one reason for graft loss. Improvements in immunosuppression have helped reduce the added complication rate in the care of the immunosuppressed patient. It is hoped that, as advances continue to be made in the field of islet cell and whole-organ P Tx, more potential patients are made aware that their options are no longer restricted to insulin alone. Percutaneous insulin is not the answer for many patients, and, as more news surrounding the improved results of P Tx become known, more healthcare providers will be better able to inform their prospective patients.
Selected Readings
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