Pancreas Transplantation at Mayo: III. Multidisciplinary Management

Pancreas Transplantation at Mayo: III. Multidisciplinary Management

JAMES D. PERKINS, M.D.,* Section of Transplantation Surgery; PETER P. FROHNERT, M.D., Division of Nephrology and Internal Medicine; F. J O H N SERVICE, M.D., Division of Endocrinology/ Metabolism and Internal Medicine; MARK P . WILHELM, M.D., MICHAEL R, KEATING, M.D., Division of Infectious Diseases and Internal Medicine; SARA R, DiCECCO, M.S., R.D., Department of Dietetics, Rochester Methodist Hospital; JACQUELINE L. J O H N S O N , M.S.W., Medical Social Service; S T E P H E N R. MUNN, M.D.,t Section of Transplantation Surgery; JORGE A- VELOSA, M.D., Division of Nephrology and Internal Medicine A l t h o u g h p a n c r e a s t r a n s p l a n t a t i o n i s a c o m p l i c a t e d p r o c e d u r e , a g o o d level of s u c c e s s h a s b e e n a c h i e v e d b e c a u s e o f t h e i n t r o d u c t i o n o f c y c l o s p o r i n e for i m m u n o ­ s u p p r e s s i o n , i m p r o v e d m e t h o d s for d i a g n o s i n g rejection, a n d a m u l t i d i s c i p l i n a r y ap­ proach t o management. Our immunosuppressive regimen w a s quadruple therapy w i t h i n d u c t i o n b y u s i n g M i n n e s o t a a n t i l y m p h o b l a s t i c globulin. A b i o p s y t e c h n i q u e w a s instituted i n which t h e pancreas specimens were obtained under cystoscopic d i r e c t i o n d u r i n g e p i s o d e s of h y p o a m y l a s u r i a . T h e c r i t e r i a for rejection e p i s o d e s w e r e n o t o n l y b i o c h e m i c a l a b n o r m a l i t i e s b u t a l s o h i s t o l o g i c c o n f i r m a t i o n a n d a follow-up t o e x c l u d e o t h e r c a u s e s of graft d y s f u n c t i o n . I n f e c t i o u s d i s e a s e m a n a g e m e n t i n c l u d e d u s e of oral s e l e c t i v e b o w e l d e c o n t a m i n a t i o n for 3 w e e k s after t r a n s p l a n t a t i o n . At t h e M a y o Clinic b e t w e e n October 1987 a n d D e c e m b e r 1988,16 p a t i e n t s r e c e i v e d pancreati­ c o d u o d e n a l allografts (both k i d n e y a n d p a n c r e a s i n 13 a n d p a n c r e a s o n l y i n 3 after a prior s u c c e s s f u l k i d n e y t r a n s p l a n t a t i o n ) . I n t w o p a n c r e a s a n d o n e k i d n e y allograft, f u n c t i o n w a s lost. O n e p a t i e n t d i e d o f m u l t i o r g a n failure. T h e c y s t o s c o p i c a l l y d i r e c t e d b i o p s y t e c h n i q u e w a s p e r f o r m e d 23 t i m e s w i t h m i n i m a l c o m p l i c a t i o n s a n d a 93% s u c c e s s rate. T h e m e t a b o l i c r e s u l t s h a v e b e e n excellent; t h e glycosylated h e m o g l o b i n l e v e l w a s n o r m a l 3 t o 6 m o n t h s after t r a n s p l a n t a t i o n . T h e quality of life w a s significantly i m p r o v e d i n a l m o s t all p a t i e n t s . N u t r i t i o n a l a s s e s s m e n t r e v e a l e d little d e t e r i o r a t i o n after t r a n s p l a n t a t i o n . With a m u l t i d i s c i p l i n a r y approach, t h e n e e d e d a n s w e r s a b o u t t h e effect of p a n c r e a s t r a n s p l a n t a t i o n o n t h e d e g e n e r a t i v e complications of diabetes should be forthcoming.

The success rate of pancreas transplantation i s approaching t h a t ofother organ transplantation procedures.^'^ This improved rate c a n be attributed to better selection of patients,^ periopera-

tive a n d operative management,'* a n d postoperative care. Enhanced postoperative care i n eludes not only immunosuppression with u s e of cyclosporine and improved methods for the diag­ nosis of allograft rejection^ b u t also improved metabolic, infectious disease, medical (includ*Current address: University of Washington, Seattle, . ' , . ^ -i' i j · i Washington. ^^S cardiovascular), nutritional, a n d social sertCurrent address: Auckland Hospital, Auckland, New vice care. A s w i t h other organ transplantation, Zealand. postoperative m a n a g e m e n t of pancreas transAddress reprint requests to Dr. J. A. Velosa, Division of Plantation i s best conducted w i t h a multidisciNephrology, Mayo Clinic, Rochester, MN 55905.

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plinary approach. 496

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The primary purpose of pancreas transplan­ tation is t h e restoration of t h e disordered m e ­ tabolism, characteristic of diabetes mellitus, to that of the nondiabetic state. If this goal can be accomplished, the patient will experience the immediate benefit of not only freedom from hy­ poglycemic therapy and the attendant risk of hypoglycemia but also the potential for, al­ though as yet unproved, a salutary effect on the progress of the degenerative complications of diabetes.""** Infections r e m a i n a major cause of morbidity and mortality in the recipients of pancreatic allografts. Although m a n y of the infectious syndromes and etiologic a g e n t s encountered in these patients are similar to those s e e n in recipi­ ents of other solid organ grafts, certain infec­ tious problems are unique to pancreas trans­ plant recipients because of t h e nature of the underlying disease (diabetes mellitus)" and the type of surgical anastomosis performed. N o published experience currently exists t h a t sub­ stantiates the infectious complications in the recipients of whole organ pancreatic allografts placed in an extraperitoneal location. Previous investigators h a v e reported frequent infections attributable to facultative gram-negative bacilli;'° however, t h e s e occurred primarily in pancreas transplant recipients w i t h s e g m e n t a l pancreaticojejunostomies. B e c a u s e of this situ­ ation, as well a s a favorable prior experience in liver transplant p a t i e n t s , " w e elected to use an oral selective bowel decontaminant regimen in our Mayo pancreas transplantation protocol. This regimen is directed at the eradication of potentially pathogenic aerobic or facultative gram-negative organisms from mucosal surfaces while attempting to minimize disturbances of the normal anaerobic flora. In the pancreas transplantation literature, few reports have addressed the nutritional s t a t u s of patients before or after transplantation. One would expect t h e nutritional s t a t u s to improve with better renal function, better glucose m a n ­ agement, and an improved dietary intake (be­ cause of liberalized dietary restrictions), a s similarly reported in the renal transplantation population. •^•'•'^ Any improvements in nutri­

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tional s t a t u s would be tempered by corticoste­ roid dosages (including bolus therapy for rejec­ tions), infection, and wound healing. Nutri­ tional s t a t u s after transplantation in this group of patients m u s t be a s s e s s e d in order to provide appropriate guidelines for future m a n a g e m e n t in this patient population. The social worker, a vital m e m b e r of any organ transplantation team, can provide infor­ mation to patients and families throughout the course of care through psychosocial a s s e s s m e n t and ongoing contact during hospitalization. The social worker can discuss the necessary adapta­ tions to medical diagnoses, life-style changes, and problems in coping. P a t i e n t s are informed t h a t pancreas transplantation is a complex undertaking that is a type of m a n a g e m e n t rather t h a n a cure. Medications a s well as monitoring of h e a l t h a n d diet become an everyday part of the life of a transplant patient. Patients can feel overwhelmed by the quantity of information disseminated before transplantation, the major concern of transplant candidates usually being quality-of-life i s s u e s . The patient and the family m u s t m a k e the decision about a commitment to transplantation and compliance with all aspects of the follow-up. The primary medical factors of importance after transplantation are related to complica­ tions of diabetes mellitus. In this patient group, the potential for complications—for example, hypertensive complications, amputations, and cardiovascular problems—is substantial. These complications demand constant vigilance in the m a n a g e m e n t of these patients. At the Mayo Clinic, w e have developed a protocol for pancreas transplantation as an evolution of our multidisciplinary experience with t h e postoperative care of other patients who have undergone transplantation. MAYO P A N C R E A S T R A N S P L A N T A T I O N POSTOPERATIVE PROTOCOL Immunosuppressive Therapy.—Patients with kidney and pancreas transplants received a quadruple immunosuppressive regimen that consisted of cyclosporine, corticosteroids (methylprednisolone or prednisone), azathioprine, and

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Minnesota antilymphoblastic globulin (ALG). On the day of transplantation, methylprednisolone (3 mg/kg) w a s given, and azathioprine (5 mg/kg) w a s administered intravenously before transplantation. Immediately after transplan­ tation, 2 mg/kg of methylprednisolone w a s given. Azathioprine w a s t h e n m a i n t a i n e d at 2 to 2.5 mg/kg either intravenously or perorally daily, with adjustments made to m a i n t a i n the leuko­ cyte count at greater t h a n 4,500/mm^. ALG w a s given intravenously the first postoperative day in a dosage of 10 mg/kg and t h e n each subse­ quent day for 7 days in a dosage of 15 mg/kg. ALG w a s administered for a m i n i m u m of 7 days; however, a longer period w a s u s e d if acute tubu­ lar necrosis developed and cyclosporine could not be given. The dose of methylprednisolone w a s rapidly tapered from 2 mg/kg per dose given twice a day intravenously to 0.5 mg/kg per dose twice a day on the fifth postoperative day. Thereafter, prednisone w a s given in a dosage of 0.5 mg/kg per day until 1 m o n t h after transplan­ tation and t h e n rapidly tapered to 0.3 mg/kg per day by 3 m o n t h s after transplantation. A t 1 year, the prednisone dosage w a s 0.2 mg/kg per day and w a s t h e n slowly decreased to 0.1 mg/kg per day thereafter. Cyclosporine therapy w a s instituted in the i m m e d i a t e postoperative pe­ riod w h e n the serum creatinine concentration approached 3 mg/dl. Cyclosporine w a s initially given continuously intravenously to approxi­ mately 6 to 7 mg/h to m a i n t a i n blood levels at approximately 150 to 2 5 0 ng/ml determined by high-performance liquid chromatography. Af­ ter adequate levels were obtained by intrave­ nous administration and w h e n t h e patient w a s tolerating orally administered fluids, the cy­ closporine w a s switched to oral medication given in twice-daily doses. After 3 m o n t h s , the cy­ closporine levels were allowed to decrease to 80 to 140 ng/ml a s m e a s u r e d by high-performance liquid chromatography. For the patients who received only a pancreas transplant, little modification w a s needed in their prior immunosuppressive therapy. ALG w a s given for 7 days, and all patients were maintained on cyclosporine, prednisone, and azathioprine.

Mayo Clin Proc, April 1990, Vol 65

The antirejection immunosuppressive regi­ m e n consisted of methylprednisolone given in­ travenously at 3 mg/kg for 3 days and then tapered to 2 mg/kg for 2 days, 1 mg/kg for 2 days, 0.5 mg/kg for 2 days, and t h e n 0.2 mg/kg for 2 days. The dosages of azathioprine, prednisone, and cyclosporine were not modified. If the rejec­ tion episode failed to respond after 4 days of methylprednisolone therapy, however, the dose of this drug w a s rapidly tapered and 0 K T 3 was instituted at 5 m g intravenously for a m i n i m u m of 10 days. If the rejection episode had not com­ pletely resolved by 10 days (on the basis of both biochemical and histologic criteria), the 0 K T 3 therapy w a s extended through a total of 14 days. During 0 K T 3 therapy, the azathioprine regi­ m e n w a s continued a s previously described along w i t h the prednisone. The cyclosporine regimen, however, w a s discontinued and then resumed 3 days before discontinuation of the 0 K T 3 ther­ apy. For those rejection episodes that were resistant to methylprednisolone treatment and to 0 K T 3 therapy, Minnesota ALG w a s given in 15 to 20 mg/kg doses for a total of 14 days. Biopsy Procedure.—^Allograft biopsy speci­ m e n s were obtained during episodes of graft dysfunction and were evaluated by routine his­ tologic methods. For the recipients with a kid­ n e y and pancreaticoduodenal allograft, speci­ m e n s were obtained from only the organ that demonstrated the greatest dysfunction. Renal biopsy specimens were obtained percutaneously w h e n the serum creatinine concentration in­ creased more t h a n 25% in the absence of an increased cyclosporine level. Biopsy specimens were obtained from the pancreas under cysto­ scopic direction during episodes of hypoamylas­ uria (more t h a n a 50% decrease in urinary amylase excretion rate for longer t h a n 36 hours) without a concomitant decrease in serum amy­ lase value and, for the last five patients, at 10 days after transplantation. The biopsy tech­ nique w a s similar to the procedure we used in a canine pancreaticoduodenal model.* Rejection Criteria.—Rejection w a s diag­ nosed on the basis of the following criteria: biochemical abnormalities, histologic abnormali­ ties, and follow-up t h a t excluded other causes of

Mayo Clin Proc, April 1990, Vol 65

graft dysfunction. Clinical rejection of the renal allograft w a s diagnosed w h e n a s u s t a i n e d in­ crease in serum creatinine concentration of more than 25% w a s present in the absence of an increase in cyclosporine level. Most c a s e s had histologic confirmation. Pancreas allograft re­ jection w a s diagnosed clinically by episodes of hypoamylasuria (as defined in the preceding paragraph); histologic confirmation w a s avail­ able in most cases. The most prominent his­ tologic feature w a s a mixed inflammatory in­ filtrate that involved the pancreatic acinar tissue.'"' Follow-up surveillance w a s conducted for at least 6 w e e k s after biopsy, to monitor for evidence of rejection and to determine the re­ sponse to antirejection therapy. Infectious Disease Management.—Upon notification of donor organ availability, patients were admitted to the hospital and began receiv­ ing a selective decontamination solution that consisted of gentamicin, polymyxin B, and nys­ tatin. In the immediate postoperative setting, this solution w a s administered through a nasogastric tube and w a s applied to the oral cavity in an Orabase medium. The oral selective bowel decontamination solution w a s given every 6 hours and w a s continued for 3 w e e k s after transplantation. Intraoperatively and for a period of 48 hours postoperatively, patients received parenteral prophylaxis with vancomy­ cin and cefotaxime. In addition, the initial 11 patients received parenterally administered metronidazole for 4 8 hours. Acyclovir w a s given prophylactically for 3 w e e k s postoperatively. After resumption of oral intake postoperatively, a prophylactic regimen of co-trimoxazole, one single-strength tablet daily, w a s initiated. Semiquantitative throat, urine, and rectal cul­ tures for aerobic and facultative organisms were obtained immediately before transplantation, before t h e selective decontamination solution w a s administered, and twice per w e e k thereaf­ ter while this regimen w a s continued. In addi­ tion, surveillance blood and urine cultures were performed to detect the presence of cytomega­ lovirus. While hospitalized, all patients had regular follow-up a s s e s s m e n t s by a n infectious disease specialist.

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Metabolic Management.—During the screening period, each potential candidate for pancreas transplantation underwent determina­ tion of hemoglobin Aj, plasma cholesterol, and triglycerides. In addition, p l a s m a glucose and C-peptide responses to a standard t e s t meal (10 kcal/kg; composed of 50% carbohydrates, 35% fat, and 15% protein) consumed after an over­ night fast without concomitant injection of insu­ lin were determined. For follow-up, the fasting plasma glucose level w a s determined with decreasing frequency from daily to twice a week during the first 6 weeks after dismissal from t h e hospital and then week­ ly until the 24th week. Subsequently, it w a s measured every second week until 52 weeks and then monthly thereafter. P l a s m a cholesterol and triglycerides were determined during weeks 1, 2, 6, and 12 and every 3 m o n t h s thereafter. Hemoglobin Aj w a s determined at 3-month inter­ vals. The standard t e s t meal w a s repeated at w e e k s 12, 24, and 52. Nutritional Management.—Nutritional a s s e s s m e n t assisted the dietitians and physi­ cians in providing timely and appropriate nutri­ tional intervention. The nutritional a s s e s s m e n t , which w a s done before transplantation and at 3, 6, 9, and 12 m o n t h s after transplantation, in­ cluded anthropometric a n d biochemical deter­ minations. The anthropometric component in­ cluded height, weight, triceps skinfold, and arm muscle circumference m e a s u r e m e n t s . The tri­ ceps skinfold and arm muscle circumference m e a s u r e m e n t s were done with a Lange skinfold caliper by u s i n g standard techniques (all done by one person), with percentiles calculated from standard tables.'* The basic biochemical mea­ s u r e m e n t s included serum albumin levels. (Nu­ tritional data were analyzed with u s e of a vari­ ety of methods. D a t a are reported as m e a n s ± 1 standard deviation. Comparisons between m e a n s were done w i t h S t u d e n t t tests. Values were considered significant a t the P < 0 . 0 5 level. Because of the small sample size and the small proportion of w o m e n in the sample, all patients were analyzed a s one group.) Before transplantation, patients were in­ structed to follow an appropriate chronic renal

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failure-dialysis diet for diabetic patients. After transplantation, patients were able to e a t once bowel function had returned, and they were advanced as tolerated to a low-bacteria-produc­ ing, low-cholesterol, diabetic, high-protein diet w i t h b e t w e e n - m e a l feedings a s n e c e s s a r y . " Calorie goals were set at Harris-Benedict basal (ideal body weight) plus 30% and a goal of 1.2 g or more of protein per kilogram of ideal body weight. If a patient w a s unable to begin oral intake by day 5 after transplantation, central parenteral nutrition w a s initiated to provide appropriate nutrients. The central parenteral nutrition w a s discontinued once patients were able to eat solid foods and to consume at least 1,000 calories per day. Enteral (tube) feedings were not u s e d during this time. Social Service Management.—One social worker evaluated the psychosocial a s s e s s m e n t for all patients preoperatively and t h e n at 3 , 6 , 9 , and 12 m o n t h s postoperatively. The Karnofsky scale w a s u s e d to a s s e s s the patient's normal activity, health, pattern of daily living, and support systems."' Medical Management.—The medical com­ plications recorded were the number of days hospitalized, the incidence of hypertension and the treatment, and the frequency of cardiovas­ cular abnormalities. RESULTS Sixteen recipients (14 m a l e and 2 female) re­ ceived pancreaticoduodenal allografts at the Mayo Clinic b e t w e e n October 1987 and Decem­ ber 1988." The m e a n age w a s 36 years (range, 2 1 to 47 years). Thirteen transplants were com­ bined kidney and pancreas allografts, and three were pancreas only after a prior successful kid­ ney transplantation. The m e a n follow-up after transplantation w a s 183 days (range, 2 to 3 8 0 days). Only one patient died, at 9 m o n t h s after transplantation (Fig. 1). In two patients, pan­ creas allograft function w a s lost, and resump­ tion ofinsulin therapy w a s necessary (Fig. 1). Of the 13 patients who also received a kidney trans­ plant, only 1 had lost renal function (Fig. 1). Fifteen pancreas transplant recipients have undergone follow-up for more t h a n 30 days. Of

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12 113

03

—

s

3

Patient Pancreaticoduodenal graft Kidney graft

6 9 After transplantation, mo

Fig. L Patient, pancreaticoduodenal graft, and kidney graft survival after pancreas or combined kidney and pan­ creas transplantation.

t h e s e 15 patients, 7 (47%) experienced no rejec­ tion episodes, and 11 pancreas rejection epi­ sodes occurred in the 8 other recipients, 3 expe­ riencing 2 rejection episodes each (Table 1). One patient lost pancreas function as a result of rejection. Only two of the rejection episodes were sensitive to methylprednisolone bolus therapy. Of the 13 recipients who also had a kidney transplant, 12 had follow-up of more t h a n 30 days, and 5 of these 12 (42%) experi­ enced no rejection episodes. Ten episodes of renal rejection occurred in the seven other kid­ ney recipients, three experiencing two rejection episodes each (Table 1). Only one patient lost renal function because of rejection (the same patient who lost pancreas function as a result of rejection). Three rejection episodes were sensi­ tive to methylprednisolone antirejection ther­ apy; the rest necessitated 0 K T 3 therapy, and ALG therapy w a s u s e d in addition to 0 K T 3 in one. Cystoscopically directed pancreas biopsies were performed in 12 of the 16 pancreaticoduo­ denal transplant recipients. In t h e s e 12 recipi­ ents, 23 total biopsies were done, 14 (61%) of which were adequate for histologic diagnosis. (Of the last 13 biopsies, 12 [92%] were adequate.) Only two episodes of hematuria (blood in the urine for more t h a n 12 hours) occurred. Specifi-

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501

Table 1.—Incidence o f P a n c r e a s a n d K i d n e y Rejection, T y p e of Treatment, a n d O u t c o m e in 16 P a t i e n t s Who U n d e r w e n t P a n c r e a s T r a n s p l a n t a t i o n o r C o m b i n e d R e n a l a n d P a n c r e a s T r a n s p l a n t a t i o n at t h e Mayo Clinic (October 1987 T h r o u g h D e c e m b e r 1988)*

Case

FU (days)

No. pancreas rejection episodes

1 2

380 372

0 0

3t 4

300 295

0 2

Days from Txto rejection

Treatment and outcome Graft lost, secondary fibrosis

14 154

0KT3; resolved 0KT3; loss of pan­ creatic function

No. kidney rejection episodes

Days from Txto rejection

Treatment and outcome

Ίό

MP, 0ΚΤ3; resolved 0KT3; loss of renal function

0 0 2

51

5 6t 7

289 275 234

0 0 1

0

35

MP; resolved

2

8 9

182 162

1 2

15 12

10

113

1

21 112

MP; resolved MP; partially resolved OKT3; resolved MP, 0KT3; resolved^

11

103

2

16

12

89

1

98 21

1 1

35 185 15 23

MP; resolved MP; resolved MP; resolved OKT3; resolved

1

112

MP, 0KT3; resolved

1

16

MP, 0KT3; resolved MP, 0KT3; resolved

MP, 0KT3; resolved MP, 0KT3; resolved

2

21 35

13 14t 15 16

63 36 34 2§

0 1 0

MP, 0KT3; resolved 0KT3, ALG; resolved

0 22

MP, 0KT3; resolved 0

*ALG = Minnesota antilymphoblastic globulin; FU = follow-up; MP = methylprednisolone; Tx = transplantation. tThese patients received only a pancreas transplant; all others received both a kidney and a pancreas transplant. tFollow-up for 2 weeks after Jan. 1, 1989. §Follow-up too short.

cally, no episodes of sepsis, pancreatic ascites, tion. Clinical and culture-proven cjd;omegalopseudocysts, or fistulas were noted relative to virus infection occurred in 7 of the 16 patients. All cytomegalovirus episodes occurred between the biopsy technique. Twenty-three episodes of infection occurred in the fourth and ninth postoperative week. The 11 of the 16 patients during t h e follow-up period spectrum ofcjdOmegalovirus disease ranged fi"om (Table 2). A m o n g those patients w i t h at l e a s t 3 fever, viremia, and cjrtopenia to biopsy-proven m o n t h s of follow-up after transplantation (cases organ involvement. Two patients with substan­ 1 through 12), 2 1 infectious episodes occurred in tiated organ involvement (hepatitis, pancreati­ 9 patients. Three patients h a d infections due t o tis) received ganciclovir, although therapy with gram-negative enteric organisms (all due to this agent w a s terminated after 3 days in one EscKericHia coU\ 'mc\uamg p n e u m o m a , perirec­ V>eca\ise οϊ proiouna\euVopen\a anat\\rom\>ocytal abscess, and urinary tract infection with topenia. Both patients recovered. Although bacteremia, all of which occurred after discon­ Candida albicans w a s t h e most common isolate tinuation of oral selective bowel decontamina­ recovered, candidemia developed in only one

502

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Mayo Clin Proc, April 1990, Vol 65

Table 2.—Infectious E p i s o d e s in P a t i e n t s Who U n d e r w e n t P a n c r e a s T r a n s p l a n t a t i o n o r Combined Renal a n d P a n c r e a s T r a n s p l a n t a t i o n at t h e Mayo Clinic (October 1987 T h r o u g h D e c e m b e r 1988)* Case

Infectious episodes

1 2

Wound infection Pneumonia CMV syndrome UTI No clinical infection UTI, peritonitis, fungemia

SCN Escherichia coli CMV SCN Candida albicans, enterococcus

3

CMV syndrome

CMV

5

Wound infection

Staphylococcus aureus E. coli, S. aureus, viridans strepto­ cocci C. albicans CMV C. albicans, SCN E. coli CMV

3 4

Perirectal abscess 5 6

7 8

Balanitis CMV syndrome UTI UTI with bacteremia CMV syndrome (primary) Stomatitis UTI CMV syndrome (primary) Wound infection

11 12 13 14 15

CMV syndrome Deep wound infection Herpes labialis CMV syndrome (primary) No clinical infection No clinical infection Wound infection No clinical infection Wound infection

16

No clinical infection

9 10

Organism

Onsett 3 8 9 20

Comment Minor debridement, local treatment only No organ-specific disease; no treatment

10

Peritonitis attributable to ureterovesical disruption involving nonfunctioning intra­ peritoneal renal graft placed 24 mo previously; laparotomy, resection of old renal allograft, amphotericin Β Biopsy-confirmed CMV pancreatitis; ganciclovir Minor debridement, local care

11

Incision and drainage, antibiotics

4 9 9 5 5

No organ-specific disease; no treatment No organ-specific disease; no treatment

HSV type 1 SCN CMV

6 4 7

SCN, enterococcus

5

CMV C. albicans, C. glabrata HSV (presumptive) CMV

6 4 6 6

Vesicular eruption, HSV not culture confirmed Elevated liver function tests, no liver biopsy performed; no treatment

C. albicans. SCN

4

Deep debridement, amphotericin Β

C. albicans

4

Minor incision and drainage, local treatment only

Biopsy-proven hepatitis; ganciclovir Minor incision and drainage, local treatment only No organ-specific disease; no treatment Deep debridement, amphotericin Β

*CMV = cytomegalovirus; HSV = herpes simplex virus; SCN = coagulase-negative Staphylococcus; UTI = urinary tract infection. tWeeks after transplantation. patient, a n d three received parenteral antifun­ gal therapy. E l e v a t e d preoperative l e v e l s of glycosylated hemoglobin w e r e uniformly restored to t h e nor­ mal range at 3 a n d 6 m o n t h s after t r a n s p l a n t a ­ tion (Table 3). In addition, t h e pronounced hyperglycemic response to i n g e s t i o n of a m i x e d m e a l noted preoperatively w a s improved consid­

erably at 3 and 6 m o n t h s — m e d i a n peak post­ prandial r e s p o n s e s of 122 and 135 mg/dl v e r s u s 3 3 9 mg/dl preoperatively (Table 4). In addition, p l a s m a glucose at 180 m i n u t e s w a s restored to near-basal levels in t h e posttransplant studies. C-peptide concentrations were undetectable both basally and in response to ingestion of a mixed meal preoperatively. After transplantation, C-

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Table 3.—Glycosylated H e m o g l o b i n P e r c e n t a g e i n P a t i e n t s Before a n d 3 a n d 6 M o n t h s After Pancreaticoduodenal Transplantation at t h e M a y o Clinic Glycosylated hemoglobin

Preoperative (N = 16)

Median Range

9.7 5.8-21.8

Postoperative 3 mo (N = 7) 6 mo (N = 5) 5.3 3.6-5.6

5.2 5.0-5.9

peptide concentrations were greater t h a n nor­ mal in almost all patients both basally and after ingestion of a m i x e d meal. All patients w h o underwent the mixed meal test, w h e t h e r preop­ eratively or postoperatively, were receiving no insulin. B e c a u s e of the difficulty in scheduling all t e s t s in patients who are w a i t i n g for trans­ plantation, only eight patients u n d e r w e n t pre­ operative tests. Serum cholesterol and triglyceride concentra­ tions were mildly improved after pancreas trans­ plantation (Table 5). N o difference w a s noted in the cholesterol levels b e t w e e n the pancreas and kidney and pancreas-only transplant groups. The pancreas-only group s e e m e d to have lower

triglyceride levels, but the small sample size precluded statistical analysis. After transplantation, patients resumed oral intake at a m e a n of 4.25 ± 2.4 days. Three patients, however, were unable to resume oral intake by day 5 after transplantation and re­ quired central parenteral nutrition for a m e a n of 5 days. A m e a n of 11 ± 7.5 days elapsed before patients were eating their estimated basal re­ quirements (1,592 calories—Harris-Benedict basal), and an additional 5 days (16 ± 11.9 total days) were needed before t h e s e patients were consuming their e s t i m a t e d caloric requirements (2,070 calories—Harris-Benedict basal plus 30%). A m e a n duration of 10 ± 7.5 days w a s needed for patients to consume their estimated minimal protein requirements (mean of 6 8 g of protein, at 1 g/kg). An additional period of 4 days (14 ± 12 total days) of oral intake w a s needed until the full estimated protein n e e d s were being met (mean of 82 g, at 1.2 g/kg). The nutrition a s s e s s m e n t revealed stable results (Table 6). The m e a n w e i g h t before trans­ plantation w a s 68.7 kg (range, 52.6 to 85.9 kg). P a t i e n t s were 100% of their ideal body weight of

Table 4.—^Plasma G l u c o s e R e s p o n s e t o Mixed Meal Test a n d C-Peptide M e a s u r e m e n t s Before a n d After P a n c r e a t i c o d u o d e n a l T r a n s p l a n t a t i o n at t h e Mayo Clinic Postoperative Preoperative (N = 8) 3 mo (N = 6) 6 mo (N = 5) Minutes Median Range Median Range Median Range -10 -5 0 30 60 90 120 150 180 -10 -5 0 30 60 90 120 150 180

96 96 97 139 215 260 298 315 339

61-178 63-184 62-196 114-275 138-310 191-366 243-392 283-438 297-484

Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable Undetectable

503

Plasma glucose (mg/dl) 79 61-102 63-101 77 63-100 79 119 92-183 76-191 116 122 71-155 109 70-138 70-127 103 100 70-124 C peptide (mg/ml) 3.3 0.3-6.6 3.5 0.3-5.9 3.6 0.3-4.2 7.7 0.3-22.0 7.7 0.4-27.0 6.2 0.5-23.0 0.5-27.0 7.0 5.7 0.6-17.0 6.4 0.7-23.0

87 83 86 135 121 103 99 93 98

78-105 77-106 78-106 96-154 105-150 91-144 90-148 82-148 85-150

4.8 3.3 3.8 4.6 5.8 6.4 5.2 5.6 4.7

1.8-7.6 2.3-7.6 1.5-7.4 3.5-21.0 3.6-14.0 4.4-12.0 4.0-13.0 3.1-11.0 3.0-9.2

504

PANCREAS TRANSPLANTATION

Mayo Clin Proc, April 1990, Vol 65

Table 5.—Serum Cholesterol a n d Triglyceride M e a s u r e m e n t s Before a n d After P a n c r e a t i c o d u o d e n a l T r a n s p l a n t a t i o n at t h e Mayo Clinic

Ν Preoperative Postoperative 3 mo 6 mo

Total cholesterol (mg/dl) Median Range

Ν

Triglyceride (mg/dl) Median Range

15

207

93-316

15

123

39-307

8 6

203 195

148-237 119-241

8 6

89 97

47-136 52-125

68.7 k g (range, 44.2 to 89.6 kg) before transplan­ tation and remained within the normal range after transplantation. M e a n serum albumin levels remained fairly stable and near or in the normal range w h e n a s s e s s e d throughout the pancreas transplantation process. Before trans­ plantation, 7 of 16 patients (44%) h a d triceps skinfold m e a s u r e m e n t s at greater t h a n the 9 5 t h percentile, and this determination remained stable after transplantation. Overall, arm muscle circumference m e a s u r e m e n t s remained below normal after transplantation (70% at 3 m o n t h s , 86% at 6 m o n t h s , 67% at 9 m o n t h s , and 60% at 12 months). With u s e of the Karnofsky scale, the quality of life w a s shown to be substantially improved postoperatively in this patient population (Table 7). Almost all patients h a d improvement on the basis of this scale, and after transplantation, six patients rated their quality of life as normal. In a comparison of the hospitalization for those patients who received kidney and pan­ creas transplants and those who received a pancreas only, little difference w a s found (Table 8). For the 15 patients with a follow-up that exceeded 30 days, the m e a n initial hospital stay

w a s 15 to 16 days. All t h e s e patients required rehospitalization. The initial hospitalization oc­ curred between 2 and 32 days after the initial dismissal and w a s necessary for surgical compli­ cations including wound complications in al­ most half the patients, for infections in about a fourth, and for treatment of rejection in a fifth. Subsequent rehospitalizations became neces­ sary for t r e a t m e n t of rejection in almost half of the instances. Only two patients had to be rehospitalized for serious cardiovascular prob­ lems—one for severe hypertension and the other for multiple small cerebral infarcts. Before trans­ plantation, all but one recipient required antihy­ pertensive medication or diuretics (or both). A m o n g those patients with more t h a n 30 days of follow-up, only 50% required medication for blood pressure control. This reduction occurred de­ spite the fact that most patients required so­ dium bicarbonate supplementation of 80 to 90 meq daily to maintain acid-base balance. No dif­ ferences in m a n a g e m e n t of hypertension were noted between patients with a previous kidney transplant and those with a kidney transplanted concurrently with the pancreas. During the fol­ low-up period, no amputations were necessary.

Table 6.—Nutrition A s s e s s m e n t D a t a i n P a t i e n t s Before a n d After P a n c r e a t i c o d u o d e n a l T r a n s p l a n t a t i o n at t h e Mayo Clinic Data

Normal

Preoperative

3 mo

Weight (kg)* % IBWt Albumin (g/dl)

68.8 90-110 3.5-5.0

68.7 ± 10.1 100 3.52 ± 0 . 6

67.2 ± 10.3 98 3.31 ± 0 . 6

*Mean ± 1 standard deviation, tideal body weight.

Postoperative 6 mo 9 mo 72.5 ±11.0 98 3.47 ± 0 . 5

71.6 ±12.2 98 3.70 ± 0 . 6

12 mo 82.1 ± 15.1 91 3.65 ± 0 . 6

Mayo Clin P r o c , April 1990, Vol 65

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505

Table 7.—Quality-of-Life A s s e s s m e n t b y t h e Karnofsky S c a l e i n 16 P a t i e n t s Who U n d e r w e n t P a n c r e a t i c o d u o d e n a l T r a n s p l a n t a t i o n at t h e Mayo Clinic Karnofsky scale

Postoperative 1-2 mo 3 mo

Preoperative

1. Normal, no evidence of disease, no complaints, working 2. Minor signs and symptoms of disease, normal activity 3. Activity with effort, some signs or symptoms of disease 4. Cares for self, no work, no activity 5. Occasional assistance, cares for most needs 6. Considerable assistance and frequent medical care

6

3 2

2

2

3

2

3 7

DISCUSSION A longer follow-up interval will be needed to a n s w e r t h e m o s t important question about pancreas t r a n s p l a n t a t i o n — t h a t is, W h a t effect does the procedure h a v e on the progress of t h e degenerative complications of diabetes melli­ tus? Pancreas transplantation restores the dis­ ordered carbohydrate metabolism characteris­ tic of diabetes to t h e nondiabetic state. With the improved success t h a t is now possible w i t h pancreas transplantation, the n u m b e r of longterm recipients will increase and facilitate study of the progression of t h e degenerative complica­ tions of diabetes a s affected by pancreas trans­ plantation. The n e x t step in t h e analysis of pancreas transplantation will be to determine its effect on patient survival. With a longer follow-up period, the incidence of rejection in our series would h a v e b e e n higher.

but the most important issue is graft loss as a result of rejection. Most rejection episodes re­ quired 0 K T 3 antirejection therapy, but even most recipients with two rejection episodes had resolution of their rejection. We lost only one pancreas graft because of chronic rejection. Another pancreas graft w a s lost a s a result of fibrosis, but on several pancreatic biopsy speci­ m e n s , no evidence of rejection w a s present. We believe t h a t the low incidence of graft loss that w e experienced w a s in part due to our cystoscopi­ cally directed biopsy technique.* Forty percent of the episodes of hypoamylasuria are unrelated to a rejection episode. B y u s e of an aggressive protocol for pancreas biopsies, not only are rejec­ tion episodes diagnosed and properly treated but also other c a u s e s of graft dysfunction are determined; t h u s , unnecessary antirejection therapy and serious complications from over-

Table 8.—Follow-Up a n d H o s p i t a l i z a t i o n D a t a i n 15 P a t i e n t s * Who U n d e r w e n t P a n c r e a t i c o d u o d e n a l T r a n s p l a n t a t i o n a t t h e M a y o Clinic

Type of transplant Kidney + pancreas (N = 12) Pancreas only (N = 3)

Initial hospitalization (days)

Rehospital­ ization (no.)

Time in hospital (%)

Followup (days)

Mean

Range

Mean

Range

Mean

Range

34-380

15

11-84

3

1-9

20

2-66

36-298

16

13-16

2

1-3

12

9-35

*One patient with only 2 days of follow-up was excluded from this tabulation.

506

PANCREAS TRANSPLANTATION

immunosuppression can be avoided. One pa­ tient died of multiorgan failure after h a v i n g multiple small cerebral infarcts. Although 11 p a t i e n t s experienced at l e a s t one episode of infection, only 6 h a d major infections. Gram-negative enteric organisms were involved in three infectious episodes, all of which were due to E. coli and occurred at l e a s t 2 w e e k s after oral selective bowel decontamination had b e e n discontinued. All evaluable patients demon­ strated clearing of facultative gram-negative organisms in rectal surveillance cultures within 3 days after the institution of selective bowel decontamination. T h e s e early results s u g g e s t that initiating selective bowel decontamination at the time of transplantation is effective. Initia­ tion of selective bowel decontamination at the time of activation of a patient in a transplant program, which is often several m o n t h s before a suitable donor becomes available, is unlikely to be of additional prophylactic benefit and m a y promote the emergence of resistant strains of bacteria. Several patients h a d minor superficial infec­ tions t h a t occurred primarily in t h e area of incision overljdng t h e pancreatic allograft. Most infections occurred i n t h e setting of underl3dng fat necrosis and were due to organisms of rela­ tively low virulence (coagulase-negative Staphy­ lococcus, Candida species, a n d enterococcus). These organisms did not s e e m to play a primary pathogenic role, and specific antimicrobial ther­ apy w a s not needed. A h i g h incidence of Can­ dida infections associated w i t h several tech­ niques of pancreas transplantation h a s been reported.^" Most such episodes occurred in t h e setting of enteric drainage of the pancreas graft, wherein the allograft contamination infection rate w a s high. Although w e noted several minor infections due to C. albicans, deep fungal infec­ tions that necessitated surgical intervention and antifungal therapy developed in three patients. Many of our patients also h a d low-level urinary tract colonization w i t h Candida species. The drainage of pancreatic secretions into the blad­ der creates a nonacidic environment t h a t m a y promote Candida or bacterial colonization. Early or low-level leakage of colonized urine from the

Mayo Clin Proc, April 1990, Vol 65

donor duodenum m a y play a role in the develop­ m e n t of deep fungal infections. Investigators h a v e demonstrated t h a t the donor duodenal s e g m e n t m a y be colonized with C. albicans}^ In our series of patients, no d e a t h s were attribut­ able to infection. From a metabolic standpoint, our results of pancreas transplantation h a v e been highly suc­ cessful, similar to the results of others.'""^' P l a s m a glucose responses to a standard mixed meal were normal or almost normal at 3 and 6 m o n t h s postoperatively. In addition, glycosyl­ ated hemoglobin w a s restored entirely to the normal range. B a s a l and postnutrient C-pep­ tide concentrations, however, were excessive. The latter finding cannot readily be ascribed solely to t h e systemic appearance of the β-cell secretion and loss of hepatic clearance of firstp a s s insulin or C peptide because C peptide is not cleared by the liver. It m a y reflect the loss of hepatic clearance of insulin and consequently insulin hypersecretion or other factors relating to immunosuppression or renal transplantation. The C-peptide changes were not simply due to renal insufficiency because no correlation w a s found between the C-peptide levels and the serum creatinine concentration. Whether the slight improvement in serum lipids w a s due to improved renal function, glu­ cose control, or dietary influences (or some combination of t h e s e factors) is unclear. The initial nutritional a s s e s s m e n t s e e m s to show t h a t pancreas transplantation h a s a mini­ mal effect on nutritional status. The nutritional s t a t u s of our patient population w a s good before transplantation, and this state continued after­ ward. The minimal long-term w e i g h t gain after transplantation w a s unexpected. Many patients lost weight initially after transplantation but were able to regain it by 3 months. A 6-week a s s e s s m e n t m a y have provided some useful in­ formation on changes during the first 3 months, which were not recorded in this review. Similar instances of minimal w e i g h t gain after renal transplantation in patients with diabetes have been found. Whether this result is due to good patient compliance w i t h t h e weight-control pro­ gram, a change in metabolism, or another factor

Mayo Clin Proc, April 1990, Vol 65

is unknown. Patients required a prolonged period in order to consume the planned a m o u n t of food. This finding w a s attributable to decreased appe­ tite and level of activity along w i t h probable gastroparesis and perhaps an overestimation of their needs. Despite this, w o u n d healing w a s not substantially affected. T h e serum albumin levels remained at or near the normal range throughout the transplantation follow-up pe­ riod. These levels were lower overall in compari­ son with those described previously in the dia­ betic renal transplantation population. The triceps skinfold m e a s u r e m e n t s indicated t h a t many patients have increased body fat stores before transplantation, and t h e s e remained i n about the s a m e proportion afterward. A greater percentage of our patient population had arm muscle circumferences below the fifth percentile in comparison w i t h t h e findings of others, a result t h a t indicates a decreased m u s c l e m a s s that is disproportionate to the serum albumin levels.'^ T h u s , in a relatively well-nourished diabetic population w i t h chronic renal failure, pancreas and renal transplantation does not adversely affect the nutritional status. CONCLUSION Patients who receive a pancreas transplant or a combined kidney and pancreas transplant un­ dergo a long a n d difficult process t h a t involves a substantial a m o u n t of t i m e i n t h e hospital. Potential recipients m u s t be informed about the time-consuming c o m m i t m e n t e v e n after pan­ creas transplantation. Despite the difficulty of the process, m o s t patients choose to undergo t h e procedure in an effort to achieve a better quality of life. P a t i e n t s can overcome frustration, de­ pression, and fear of episodes of rejection with the help of a social worker, who can encourage the s e t t i n g of realistic goals and provide emo­ tional support. Patience and tolerance are nec­ essary for all family m e m b e r s throughout this process. The transition from being seriously ill to h a v i n g a relatively normal life is s o m e t i m e s a slow process, but it can eventuate. Although a good level of success h a s been achieved with pancreas transplantation, the procedure is not without risks. N o n e t h e l e s s , a s

PANCREAS TRANSPLANTATION

507

more patients receive a pancreas transplant, more opportunities will be available for study of t h e effect on the degenerative complications of diabetes and finally the resulting effect on pa­ tient survival. Only by a multidisciplinary approach will t h e s e much needed a n s w e r s about pancreas transplantation be obtained. ACKNOWLEDGMENT We are indebted to the nursing staff of our transplantation unit and to Joyce A. Overman, R.N., director of the unit, for their outstanding role in our transplantation program.

REFERENCES 1. Sutherland DER, Moudry KC, Fryd DS: Results of pancreas-transplant registry. Diabetes 38 (Suppl l):46-54,1989 2. Sollinger HW, Stratta RJ, Kalayoglu M, Pirsch JD, Belzer FO: Pancreas transplantation with pancreaticocystostomy and quadruple immunosuppres­ sion. Surgery 102:674-678, 1987 3. Velosa J A, Frohnert PP, Perkins JD, Zimmerman BR, Fromme GA, Geerdes PA: Pancreas transplantation at Mayo: I. Patient selection. Mayo Clin Proc 65:475482, 1990 4. Perkins JD, Fromme GA, Narr BJ, Southern PA, Marsh CL, Munn SR, Engen DE, Sterioff S: Pancreas transplantation at Mayo: II. Operative and periop­ erative management. Mayo Clin Proc 65:483-495, 1990 5. Marsh CL, Perkins JD, Barr D, Miller AR, Carpenter HA: Cystoscopically directed biopsy technique in canine pancreaticoduodenal transplantation. Trans­ plant Proc 21:2816-2817, 1989 6. Bohman S-0, Tyden G, Wilczek H, Lundgren G, Jaremko G, Gunnarsson R, Ostman J, Groth CG: Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man. Diabetes 34:306308, 1985 7. Wilczek H, Solders G, Gunnarsson R, Tyden G, Persson A: Effects of successful combined pancreatic and renal transplantation on advanced diabetic neuropa­ thy: a one-year follow-up study. Transplant Proc 19:2327-2328, 1987 8. Ramsay RC, Goetz FC, Sutheriand DER, Mauer SM, Robison LL, Cantrill HL, Knobloch WH, Najarian JS: Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mel­ litus. Ν Engl J Med 318:208-214, 1988 9. Raith L, Csato M, Dobozy A: Decreased Candida albicans killing activity of granulocytes from patients with diabetes mellitus. Mykosen 26:557-564, 1983 10. Hesse UJ, Sutherland DER, Simmons RL, Najarian JS: Intra-abdominal infections in pancreas trans­ plant recipients. Ann Surg 203:153-162, 1986

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Wiesner RH, Hermans PE, Rakela J, Washington JA Π, Perkins JD, DiCecco S, Krom R: Selective bowel decontamination to decrease gram-negative aerobic bacterial and Candida colonization and prevent in­ fection after orthotopic liver transplantation. Trans­ plantation 45:570-574, 1988 Rosenberg ME: Nutrition and transplantation. Kidney 18:19-22, 1986 Miller DG, Levine SE, D'Elia JA, Bistrian BR: Nutri­ tional status of diabetic and nondiabetic patients after renal transplantation. Am J Clin Nutr 44:6669, 1986 Carpenter HA, Barr D, Marsh CL, Miller AR, Perkins JD: Sequential histopathologic changes in pancreati­ coduodenal allogreift rejection in dogs. Transplanta­ tion 48:764-768, 1989 Grant A, DeHoog S: Nutritional Assessment and Support. Third edition. Seattle, Anne Grant and Susan DeHoog, 1985 Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH: The use of nitrogen mustard in the palliative

M a y o Clin Proc, April 1990, Vol 65

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treatment of carcinoma: with particular reference to bronchogenic carcinoma. Cancer 1:634-656, 1948 Munn SR, Engen DE, Barr D, Carpenter HA, Perkins JD: Differential diagnosis of hypoamylasuria in pancreas allograft recipients with urinary exocrine drainage. Transplantation 49:359-362, 1990 Potter van Loon BJ, Lichtendahl AT, Mulder SS, Van Houten H, Gooszen HG, Van den Broek PJ: Microbial contamination of donor duodenum in whole-pancreas transplantation (poster summary). Diabetes 38 (Suppl l):242-243, 1989 Sutherland DER, Goetz FC, Elick BA, Najarian JS: Experience with 49 segmental pancreas transplants in 45 diabetic patients. Transplantation 34:330-338, 1982 Tyden G: What can be achieved by pancreatic trans­ plantation? Transplant Proc 18 (Suppl 3):55-57,1986 Ostman J, Bolinder J, Gunnarsson R, Brattstrom C, Tyden G, Wahren J, Groth C-G: Effects of pancreas transplantation on metabolic and hormonal profiles in IDDM patients. Diabetes 38 (Suppl l):88-93,1989