Peptic ulcer disease in kidney transplant recipients

Peptic Ulcer Disease in Kidney Transplant Recipients

Nicholas J. Feduska, MD, San Francisco, California

William J. C. Amend, MD, San Francisco, California

Flavio Vincenti, MD, San Francisco, California

Juliet S. Melter, MD, San Francisco, California

Robert Duca, BS, San Francisco, California

Marvin R. Garovoy, MD, San Francisco, California

Oscar Salvatierra, Jr., MD, San Francisco, California

The pathogenesis of peptic ulcer has not yet been fully defined, but there is a widespread impression that patients treated with corticosteroids are at increased risk [I-5]. Peptic ulcer with hemorrhage is an especially alarming clinical event as it poses an immediate threat to survival and often requires surgical intervention. Furthermore, surgical procedures for patients with peptic ulcer who have been treated with corticosteroids are frequently complicated because of poor quality tissues, impaired wound healing, coagulopathy, and an increased risk of infection. The large number of patients with kidney transplants who have been treated with corticosteroids for immunosuppression provide an ex- cellent opportunity to further define some of the features of peptic ulcer and to evaluate changes in incidence and severity that have been observed with different corticosteroid protocols.

Patients and Methods

From January 1964 through April 1983,1,734 patients received 1,962 kidney transplants at the University of California, San Francisco. The patients ranged in age from 18 months to 65 years (mean 33 years). Corticosteroids and other immunosuppressive drugs were utilized as previously reported, and from September 1972 until April 1983, a protocol was followed in which prolonged use of high doses of corticosteroids was avoided [6].

The data included in this report were collected on a continuing basis and entered into a time-oriented data

From the Tramplant Service and the Immunogenetics and Transplarttation Laboratory, lhdversity of California San Francisco, San Francisco, Cali- fornia.

Requests for reprints shculd be addressed to Nicholas J. Feduska, MD. Transplant Service, Room 984M, University of California San Francisco, San Francisco. California 94143.

Presented at the 55th Annual Meetiq of the Pacific Coast Surgical As- sociation, Newport Beach, California, February 19-22. 1994.

base. They were derived from the patients’ medical histo- ries, letters from referring physicians, and hospitalization summaries. A period of follow-up of at least 4.6 months was available for every patient. All statistical analyses were performed utilizing the BMDP or SAS statistical packages. The diagnosis of peptic ulcer was made by the usual clinical observations, and included all ulcers in the stomach, duo- denum and, though rare, the distal esophagus for which no other diagnosis could be confirmed. Radiographic studies with contrast media and endoscopy were the ~predominant diagnostic methods employed. Hemorrhage was associated with the administration of at least one blood transfusion in most patients. The incidence of peptic ulcer was calculated by comparing the number of patients with this diagnosis to the total number of patients who received transplants, recognizing that a small proportion of the patients received multiple transplants during the period of the study. None of the patients had the diagnosis of peptic ulcer in association with more than one transplant. The incidence of peptic ulcer with and without hemorrhage was determined for related and cadaver transplant recipients, as well as for recipients of first, second, and third transplants. The incidence was also determined for recipients who had type 1 diabetes mellitus as the cause of renal failure. Analyses were performed to evaluate the relationship between the time of transplant&ion and the diagnosis of peptic ulcer, and to determine the incidence of peptic ulcer during the periods from January 1964 through August 1972 and from September 1972 through April 1983 in order to assess the influence of the protocol of immunosuppressive therapy which was followed during the later period. Mortality rates were calculated, and comparisons were made between groups of patients who were treated surgically and medically to evaluate the influence of peptic ulcer requiring these different kinds of treatment on patient and graft survival rates. Patient and graft survival rates were calculated without exclusions by actuarial methods and expressed as percentage survival f standard error. Graft loss was defined as the date of

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Feduska et al

transplant nephrectomy or, if a nonfunctioning graft was not removed, the date of reinstitution of maintenance dialysis. Death of a patient from any cause was also considered to be a graft loss. The primary cause of death was determined, when possible, to further evaluate differences between related and cadaver transplant recipients who were treated surgically or medically. The chi-square test was used to compare frequencies between groups.

Results

A reliable history of peptic ulcer before transplantation was not available for all of the patients included in this report, but among 148 of the 1,734 patients (8.5 percent) with a reliable positive history, 86 (58.1 percent) had peptic ulcer with hemorrhage and 62 (41.9 percent) had peptic ulcer without hemorrhage. Thirty-two of these 148 patients (21.6 percent) had been operated on for peptic ulcer on one or more occasions before transplantation, and the surgical procedures included vagotomy with pyloroplasty (26 patients), gastric resection (7 patients), and oversewing of a bleeding ulcer (3 patients). Only 2 of the 32 patients (6.3 percent) who were operated on were again diagnosed as having peptic ulcer after transplantation, including 1 patient who had undergone vagotomy with pyloroplasty and 1 who had undergone oversewing of a bleeding ulcer.

One hundred sixteen of the 1,734 patients (6.7 percent) were diagnosed as having peptic ulcer after transplantation. They ranged in age from 3 to 70 years (mean 39 years). There were 80 male patients and 36 female patients. The causes of end-stage renal disease among these patients included chronic glo- merulonephritis (42 patients), nephrosclerosis (15 patients), chronic pyelonephritis (9 patients), diabetes mellitus (8 patients), and other or undefined causes (42 patients). No significant difference was observed when the overall incidence of peptic ulcer in related-donor transplant recipients was compared with that for cadaver-donor transplant recipients. Recipients of related-donor transplants had an incidence of peptic ulcer of 5.4 percent (33 of 614 patients), and recipients of cadaver-donor transplants had an incidence of 7.2 percent (83 of 1,152 patients). The incidence of peptic ulcer with hemorrhage was 5.1 percent (89 of 1,734 patients), and of peptic ulcer without hemorrhage 1.6 percent (27 of 1,734 patients). No significant difference was observed in the incidence of peptic ulcer with or without hemorrhage when related and cadaver transplant recipients were compared. The incidence of peptic ulcer with hemorrhage was also without significant difference when recipients of first, second, and third transplants were compared. Similarly, there were no significant differences in the incidence of peptic ulcer without hemorrhage when recipients of first, second, and third transplants were compared.

Comparisons of the incidence of peptic ulcer with hemorrhage among recipients of first and second

related-donor transplants and first and second cadaver-donor transplants also showed no significant differences. There were also no significant differences when comparisons of the incidence of peptic ulcer without hemorrhage were made among these same groups of patients.

The relationship between the time of transplantation and the diagnosis of peptic ulcer was analyzed and revealed the following: diagnosis 1 to 30 days postoperatively 35 patients (30.2 percent), diagnosis 1 to 90 days postoperatively 57 patients (49.1 percent), and diagnosis 1 to 365 days postoperatively 82 patients (70.7 percent). The earliest diagnosis of peptic ulcer was on the first postoperative day, and the latest diagnosis was 5,039 days after transplantation. Additional comparisons were made between related-donor and cadaver-donor transplant recipients to further evaluate the relationship between the time of transplantation and the diagnosis of peptic ulcer, and these comparisons showed a significantly greater incidence of peptic ulcer in cadaver-donor transplant recipients during the first 60 postoperative days. Eight of 33 (24.2 percent) related-donor transplant recipients were diagnosed as having peptic ulcer within the first 60 postoperative days, compared with 43 of 83 (51.8 percent) cadaver-donor transplant recipients (p <0.05).

The clinical factors most commonly seen in association with peptic ulcer after transplantation were identified and the frequency of their occurrence was determined. Ninety-one of the 116 patients (78.4 percent) had been treated for at least one episode of acute rejection. The mean number of episodes for these patients was 1.7 per patient. Sixty patients (51.7 percent) had an episode of sepsis in association with the diagnosis of peptic ulcer, and 52 patients (44.8 percent) had both clinical and biochemical evidence of hepatitis, including an increase in the serum transaminase level, or were determined to have a positive test result for hepatitis B surface antigen or antibody. Thirteen patients (11.2 percent) had clinical and biochemical evidence of pancreatitis, including increases in serum and urine amylase levels. Other features of the patients with peptic ulcer and their frequency included the following: history of peptic ulcer without hemorrhage before transplantation in 12 patients (10.3 percent), history of peptic ulcer with hemorrhage before transplantation in 8 patients (6.9 percent), diabetes mellitus in 8 patients (6.9 percent), clinical and biochemical evidence of hyperparathyroidism, including elevated serum calcium and parathormone levels and related radiographic findings, in 4 patients (3.4 percent), history of biliary tract disease before transplantation in 3 patients (2.6 percent), and history of pancreatitis before transplantation in 2 patients (1.7 percent).

The incidence of peptic ulcer during the periods from January 1964 through August 1972 and from September 1972 through April 1983 was 11 percent

52 The American Journal of Surgery

Peptic Ulcer in Kidney Transplant Recipients

TABLE I Percentage of Patient Survival for Recipients of First Related-Donor and First Cadaver- Donor Transplants With and Without Peptic Ulcer (mean f standard error of mean)

1 Yr 2Yr 5Yr 10 Yr

First related-donor transnlants * Without peptic ulcer

(n = 558) With peptic ulcer

(n = 30)

First cadaverdonor transplants+ Without peptic ulcer

(n = i,OOS) With peptic ulcer

In = 72)

l p <0.0001. t p <0.0001.

95 92 67 76 fl fl f2 f3

67 63 54 39 f9 f9 f10 f 11

91 88 83 fl fl fl

68 62 52 f6 f6 f6

76 f2

37 f8

(43 of 390 patients) for the earlier period and 5.3 percent (73 of 1,367 patients) for the later period. This difference was very statistically significant (p <O.OOOl). When peptic ulcer with hemorrhage and peptic ulcer without hemorrhage were considered, there was no significant difference in the proportions of patients during the earlier period as compared with the later period. The incidence of peptic ulcer among patients with diabetes mellitus as the cause of renal failure was 4.6 percent (8 of 173 patients), compared with an incidence of 6.9 percent (108 of 1,561 patients) among patients who were not diabetic. This did not represent a significant difference. Diabetic recipients of related-donor transplants had an incidence of 2.7 percent (2 of 73 patients) compared with a 6 percent incidence (6 of 100 patients) in diabetic recipients of cadaver-donor transplants. This comparison was also without significant difference. Neither were any significant differences observed when the incidence of peptic ulcer was compared for diabetic and nondiabetic recipients of related-donor transplants or for diabetic and nondiabetic recipients of cadaver-donor transplants.

Analysis of patient survival of recipients of first related-donor and first cadaver-donor transplants showed that patients in both of these groups who had the development of peptic ulcer had significantly poorer survival rates 1 to 10 years after transplantation compared with patients who did not have the development of peptic ulcer (p <O.OOOl) (Table I). There were no significant differences in patient survival when recipients of first related-donor transplants without peptic ulcer were compared with recipients of first cadaver-donor transplants without peptic ulcer, or when recipients of first related-donor transplants with peptic ulcer were compared with recipients of first cadaver-donor transplants with peptic ulcer. Graft survival was significantly poorer for recipients of first related-donor transplants with

TABLE II Percentage Graft Survival for Recipients of First Related-Donor and First Cadaver-Donor Transplants With and Without Peptic Ulcer (mean f standard error of mean)

1 Yr 2 Yr 5 Yr 10 Yr

First relateddonor transplants’ Without peptic ulcer a4 78 70 53

(n = 558) f2 f2 f2 f3 With peptic ulcer 58 50 42 30

(n = 30) f 9 f 10 f 10 f 10

First cadaverdonor transplants? Without peptic ulcer 51 43 30 20

(n = 1.008) f2 f2 f2 f2 With peptic ulcer 48 36 20

(n = 72) f6 f6 f5 A’4

l p <0.002. t p value not significant.

peptic ulcer compared with first related-donor transplants without peptic ulcer (p <0.002) (Table II). No significant differences in graft survival were observed when recipients of first cadaver-donor transplants with peptic ulcer were compared with recipients of first cadaver-donor transplants without peptic ulcer.

Thirty-four separate surgical procedures were performed for 25 of the 116 patients (21.6 percent) in whom peptic ulcer developed after transplantation. These procedures involved 6 related-donor and 19 cadaver-donor transplant recipients. They included the following: vagotomy with pyloroplasty (23 patients), oversewing of the ulcer (9 patients), and gastric resection (2 patients). Three of the related- donor and five of the cadaver-donor transplant recipients had multiple surgical procedures. Ninety- one of the 116 patients (78.4 percent) with peptic ulcer received medical therapy only, including 27 related-donor and 64 cadaver-donor transplant recipients. The mortality rates were as follows: for related-donor transplant recipients treated surgically, 50 percent (3 deaths among 6 patients); for cadaver-donor transplant recipients treated surgically, 52.6 percent (10 deaths among 19 patients); for related-donor transplant recipients treated medically, 55.6 percent (15 deaths among 27 patients); and for cadaver-donor transplant recipients treated medically, 43.8 percent (28 deaths among 64 patients).

There were no significant differences in patient survival at 1 to 10 year follow-up when recipients of first related-donor transplants treated surgically or medically were compared, and there were also no significant differences at 1 to 10 year follow-up when recipients of first cadaver-donor transplants treated surgically or medically were compared. When graft survival rates at 1 to 10 year follow-up were analyzed for these same groups, it was also observed that there

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TABLE Ill Primary Causes of Death for 56 Patients With Related-Donor or Cadaver-Donor Transplants Treated Surgically or Medically for Peptic Ulcer

Cause of Patients Death (n)

Related-donor transplants treated surgically (n = 3)

Cadaver-donor transplants treated surgically (n = 10)

Related-donor transplants treated medically (n = 15)

Cadaver-donor transplants treated medically (n = 28)

Sepsis Hemorrhage

Sepsis Hemorrhage Pancreatitis Myocardial infarction Not specified

Sepsis Hemorrhage Myocardial infarction Not specified

Sepsis Hemorrhage Liver failure Myocardial infarction Pulmonary embolus Stroke Pancreatitis Metastatic carcinoma Not specified

2 1

5 2

1 2

were no significant differences. The primary causes of death in 56 of the 116 patients (48.3 percent) with peptic ulcer are listed in Table III. Sepsis was the primary cause of death in 22 of the 56 patients (39.3 percent) who died, but a wide spectrum of other causes was also observed. Twelve of the deaths (21.4 percent) were associated with hemorrhage, and of these, only 3 involved patients who were treated surgically. Five patients (8.9 percent) had myocardial infarction as the primary cause of death, and all but one of these patients were treated medically.

Comments

Although the role of exogenous corticosteroids in the pathogenesis of peptic ulcer has not firmly been established, the data in this report support the con- cept of a causal relationship. The overall incidence of 6.7 percent for peptic ulcer in our study is consid- erably greater than that reported earlier by Messer et al [I] in which data were pooled from 71 controlled clinical trials of corticosteroid therapy. In their study, patients who were randomized to systemic corticosteroid or adrenocorticotropic hormone therapy had an incidence of peptic ulcer with hemorrhage of 2.5 percent and peptic ulcer without hemorrhage of 1.8 percent. The data from our large retrospective study with no exclusions show the incidence of peptic ulcer without hemorrhage to be 1.6 percent which is comparable to the incidence in the Messer study. How- ever, the incidence of peptic ulcer with hemorrhage in our study was 5.1 percent, more than twice the

54

incidence of 2.5 percent in the Messer study. A possible explanation is that our renal transplant recipients were probably exposed to a longer period of treatment with higher doses of corticosteroids. Others workers [7] have previously reported that higher doses of corticosteroids increase the likelihood of peptic ulcer.

The wide range of ages (from 3 to 70 years) among patients with peptic ulcer in our study, as well as the wide range of postoperative days from the time of transplantation to diagnosis of peptic ulcer (from 1 to 5,039 days) indicate that transplant recipients are vulnerable to peptic ulcer at virtually any age and at any time. In addition, the occurrence of peptic ulcer as early as the first day after transplantation suggests that the peptic ulcer was either present but not recognized before transplantation or that there was some other explanation for the cause of peptic ulcer other than a high dose of corticosteroids administered over a substantial period of time. Most cases of peptic ulcer occurred early in the period after transplantation, and half of the cases occurred during the first 90 postoperative days, whereas more than 70 percent occurred during the first postoperative year. The higher incidence among cadaver-donor transplant recipients in the first 60 postoperative days, twice that for related-donor transplant recipients, probably reflects greater doses of corticosteroids for the cadaver-donor transplant recipients during this early period when they are known to be more vulnerable to episodes of acute rejection. An important observation was that only 2 of the 32 patients (6.3 percent) who were operated on for peptic ulcer before transplantation were later diagnosed as having peptic ulcer after transplantation. One of these patients had undergone vagotomy with pyloroplasty, whereas the other patient had undergone oversewing of a bleeding ulcer. Hence it appears that earlier or prophylactic ulcer operations may reduce the likelihood of peptic ulcer associated with corticosteroid therapy later, particularly if the operations consist of vagotomy with pyloroplasty or gastric resection, as was the case for 29 of our 32 patients.

The predominant factors that were associated with peptic ulcer in this study were an earlier episode of acute rejection, sepsis, and hepatitis or hepatitis B surface antigen or positivity. Therefore, aggressive medical prophylactic therapy is particularly indicated for patients who have these high-risk features, as well as the others which were less frequently associated with peptic ulcer. Such prophylactic medical therapy should include the frequent administration of antacids and cimetidine, alone or in combination [8], as well as strict avoidance of potentially ukero- genie drugs, foods, and beverages. Prophylactic ulcer operations appear to have a less frequent, albeit significant, role, as only 17 percent of the patients with peptic ulcer after transplantation had a docu- mented antecedent history of peptic ulcer. We have

The American Journal ol Surgery


used aggressive medical prophylaxis in our patients, particularly since September 1972, and this may have contributed to the dramatic reduction in the incidence of peptic ulcer since that time. Indeed, the more recent incidence of 5.3 percent, compared with the 11 percent earlier incidence, occurred during a period of increased awareness toward peptic ulcer in these patients, as well as of availability of more sen- sitive and reliable diagnostic methods, such as fi- beroptic endoscopy. It was expected that the incidence of peptic ulcer would be higher in patients with diabetes mellitus, as such patients frequently have visceral neuropathy and gastroparesis. However, the incidence was not increased for diabetic patients in this study.

The most significant finding was the striking influence of peptic ulcer on patient survival (Table I). It is obvious that the patients who had the development of peptic ulcer were at greater risk of dying, whether they received their transplants from a related or a cadaver donor. In fact, the influence of peptic ulcer on patient survival was remarkably similar, regardless of the source of the transplant. It appears that peptic ulcer may often be an indicator of a patient’s overall medical complexity and vulnerability, and is not necessarily directly responsible for the higher mortality rate. The magnitude of the relationship, however, underscores that peptic ulcer is a very serious and life-threatening problem, and in kidney transplant recipients, will be associated with hemorrhage 75 percent of the time. Early diagnosis, aggressive medical and surgical treatment, and prompt reductions in the dose of corticosteroids to the lowest acceptable levels are essential if long-term survival is to be achieved. We have previously shown that such adjustments in the intensity of immunosuppressive therapy can result in significant im- provements in patient survival [6]. Graft survival for recipients of first related-donor transplants with peptic ulcer was also significantly poorer (Table II). This finding was not observed among recipients of first cadaver-donor transplants with peptic ulcer.

All of the patients with peptic ulcer who were treated surgically were recipients of first transplants. Eight of the 25 patients required multiple surgical procedures. This high rate of reoperation appears to reflect, at least in part, the type of operation performed. In 9 of the 34 patients, the surgical procedure consisted only of oversewing of the ulcer, and 7 of these 9 patients required reoperation. Only 1 of the 23 patients treated with vagotomy with pyloroplasty required reoperation, and neither of the 2 patients treated with gastric resection did. The high surgical and medical mortality rates of 44 and 56 percent, respectively, for recipients of both related-donor and cadaver-donor transplants were not reflected as significant differences when recipients of first related-donor and first cadaver-donor transplants treated surgically or medically were compared. The

high mortality rate associated with peptic ulcer in certain groups of patients has been recognized previously by others. Increased age, alcoholism, and liver disease are known to be significant risk factors [9], and in kidney transplant recipients, other risk factors undoubtedly contribute. The high frequency of sepsis, hemorrhage, and myocardial infarction, as well as the broad spectrum of other primary causes of death (Table III), emphasize the medical complexity of those who died. Among 56 deaths, 22 were primarily associated with sepsis, 12 with hemorrhage, and 5 with myocardial infarction. Only 3 of the 12 patients for whom death was primarily associated with hemorrhage were treated surgically, suggesting that hemorrhage, in most of these patients, may simply have been accepted as a terminal event or that the patients who died in this fashion were too des- perately ill from other causes for surgical intervention to even be considered. Only one of the five patients who died primarily as a consequence of myocardial infarction (probably in association with hemorrhage) was treated surgically, and similar considerations may have applied to the other four patients with myocardial infarction who were treated without surgery as well.

Summary

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.

References

1. Messer J, R&man D, Sacks HS, Smith H Jr, Chalmers TC. As- sociation of adrenocorticosteroid therapy and peptic-ulcer disease. N Engl J Med 1983;309:21.

2. Green SB, Gail MH, Byar DP. Steroids and peptic ulcer. N Engl J Med 1978;294:1291.

3. Kurata JH, Elashoff JD, Wssmm MI. Inadequacy of the iiiature on the relationship between bugs, ulcers, and gastrointestinal bleeding. Gastroenterology 1982;82:373.

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Feduska et al

4. Ballet AJ. Black R, Bunim JJ. Major undesirable side-effects resulting from prednisolone and prednisone. JAMA 1955; 156:459.

5. Spiro HM. Is the steroid ulcer a myth? N Engl J Med 1983;309: 45.

6. Salvatierra 0, Potter D, Cochrum KC, et al. Improved patient survival in renal transplantation. Surgery 1976;79: 166.

7. Conn HO, Blitzer BL. Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N Engl J Med 1976;294:473.

8. Roermund HPC, Tiggeler RGWL, Berden JHM, van Lier HJJ, Koene RAP. Cirnetidine prophylaxis after renal transplantation. Clin Nephrol 1962;18:3’9. . _

9. Brodts JR, Eraklis AJ. Factors affecting the mortalii from peptic ulcer. N Engl J Med 1964;271:803.

Discussion

Thomas V. Berne, MD (Los Angeles, CA): Dr. Feduska and his associates have made a detailed analysis of an important gastrointestinal complication of renal transplantation. The paper reviews a very large experience of almost 2,000 renal transplants. The problem they have studied is one that plagues the transplant surgeon from the day he first sees a potential recipient into the late post-transplant period. The authors have given us new information that can be applied to the care of organ transplant recipients.

As pointed out by Dr. Feduska, one of the ongoing con- troversies in this area has been the role of corticosteroids in the cause of this kind of peptic ulcer disease. Although it may seem obvious that this relationship exists, there are some who strongly believe that there is no association between corticosteroid administration and peptic ulceration. There is slightly conflicting evidence regarding this matter in the authors’ report. First, the evidence supporting the association includes the finding that the preponderance of cases occurred early after the transplant operation, at times when corticoid doses would be high. Also, the incidence of peptic ulcer decreased after 1972 when they adopted a protocol based on much lower total doses of steroids. However, it is possible that the ulcer disease observed in their patients was the result of other factors, such as infection which occurred because of the extracorticost- eroids. Some infections, such as cytomegalovirus, may be easily missed clinically. It has also been our own experience that peptic ulceration after grafting tends to occur in association with sepsis and hepatitis. Therefore, the detection of an ulcer should prompt an all out search for infection.

This paper points out the devastating effect of the development of an ulcer in the posttransplant period. The authors’ finding that only 6 percent of those patients with a previous operative procedure had recurrent ulceration after transplantation is very encouraging-actually it was only 3 percent of those who had ulcer-curative operations and almost all of them were vagotomies and pyloroplasties. Because operative prophylaxis is so good, it is important to consider the area of pretransplant screening and ulcer preventative surgery for potential allograft recipients. For a number of years it has been common practice to recom- mend an ulcer preventative operation for a patient with any previous history of chronic peptic ulcer disease. Dr. Fe- duska, do you think that such a policy is adequate or should all potential recipients have upper gastrointestinal radiographic studies and endoscopy? The fact that one of the ulcers was detected on the first posttransplant day suggests that some active ulcers are being missed. Finally, it is important to point out in the near future, there may be important changes that, hopefully, will reduce the likelihood

of peptic ulcerative disease in allograft recipients. The first change may be that reliance on corticosteroids will significantly diminish because of increasing employment of cy- closporine as the basic immunosuppressive drug. In addition, new antiulcer medications, such as prostaglandins, gastric-specific vagolytic drugs, and the gastric mucosal protectors, may be useful in preventing postgrafting ulcer disease. There is considerable controversy regarding the value of cimetidine in this setting because some believe that the drug is immunostimulatory. With several more new specific Hz blockers being developed, it may be that they will not have this property. Hence, Dr. Feduska, my last question is, do you have any suggestions regarding posttransplant medical prophylaxis, and under what circum- stances would you employ cimetidine or any of the newer antiulcer medications?

Nicholas A. Halasz (San Diego, CA): We recently re- viewed the last 150 renal transplantations that we did in San Diego, vis-a-vis the incidence of upper gastrointestinal bleeding. We had a very rigid protocol whereby all patients with a history of ulcer disease within the previous 3 years had a vagotomy and pyloroplasty in order to become acceptable for transplantation. Postoperatively, each patient received antacids every hour during the day and every 2 hours during the night for the first 2 weeks. Then a tapering routine was adopted. In using that approach, there was one bleeding episode after 150 transplantations. I think that shows how highly effective prophylaxis can be. Our steroid doses in the first part of this study were comparable to the authors’. In the second part of the study, for the last 70 patients, we used 0.5 mg/kg rather than the 2 mg/kg, be-

ginning dose, but the initial group did not have any higher incidence of bleeding. I think the big question now is how much of a change should there be now that we have a nonimmunostimulant Hz blocker such as ranitidine available?

We have changed our approach. We have, beginning about 6 months ago, embarked on a study of ranitidine and antacids administered only four times a day. Also, patients with no active ulcer, even though they have a history of ulcer, are being accepted for transplantation without the prophylactic operation. I don’t know yet how this will work, but I csn attest to the fact that routine use of prophylactic operations plus intensive prophylaxis after transplantation can cut the bleeding ulcer rate to less than 1 percent.

Dr. Feduska, what type of prophylaxis did you use in the patients in whom there were complications?

Thomas C. Moore (Torrance, CA): Dr. Feduska and the San Francisco group certainly made a very major contribution to clinical renal transplantation when they both cautioned and practiced restraint in the use of corticost,e- roids in the management of rejection. A number of years ago, I carried out a study with Dr. David Hume of the Medical College of Virginia transplant experience looking at the period and nature of hazard after clinical renal transplantation. We found very awesome incidences of both the occurrence and the mortality of bleeding peptic ulcers. In succeeding years, I maintained an interest in the role of histamine and its formation, metabolism, and excretion in association with transplantation and rejection. The excretion of histamine in urine is probably the most reliable way of determining the formation of histamine, and we found an increase in the urinary excretion of histamine

56 The American Journal of Surgery


after skin, kidney, and heart allografting in rats, dogs, and human subjects. We also found an increase in the activity of histidine decarboxylase, the histamine-forming enzyme that occurs not only in allografts and in host lymphoid tissues but also in host gastric mucosa as well.

These observations have been confirmed recently in an ex vivo model by Dy and Hamburger of Paris who found that a lymphokine associated with transplant rejection was produced which increased the activity of histidine decarboxylase enzyme activity. It also had the fascinating property of appearing to act as a mast cell growth factor. We are going to have to take additional looks at the role of histamine and some of the other very important mediators as we try to sort out the way that we manage their in- volvement and contribution to transplant rejection.

Corticosteroids recently have been demonstrated to have some effect on the cyclooxygenase pathway of arachidonic acid metabolism and may somewhat inhibit the formation of potentially protective prostaglandins. This event also should be borne in mind in the management of rejection.

Nicholas J. Feduska (closing): I would like to begin by saying it is my opinion that in these patients, the presen- tation of peptic ulcer disease with or without hemorrhage is often a clinical indicator and manifestation of their medical complexity and vulnerability. I do not believe that prophylactic operations should be performed routinely. Rather, we should be selective. With regard to making an

assessment of those patients who should have such procedures, I think perhaps the most important item to be considered is that of an accurate medical history reflecting continuing symptoms of peptic ulcer.

It should be emphasized that among those patients in our series, in only 17 percent was an antecedent history of peptic ulcer disease established. Hence, the potential ap- plication of prophylactic operations is limited to a com- paratively small proportion of transplant patients. Fur- thermore, although corticosteroids are recognized as having a masking effect on clinical symptoms, we have neverthe- less been impressed that patients who have peptic ulcer disease are usually quite capable of demonstrating the usual kinds of symptoms that are seen with this problem. Our practice has been to employ rather vigorous antacid therapy routinely: With regard to Dr. Halasz’s question, we have reserved cimetidine for those patients who are at increased risk because of the various risk factors that I have already alluded to. It is possible, but not yet established, that cimetidine utilized in this fashion may be a reasonable substitute for prophylactic operations. It would be very attractive if this were found to be the case because prophylactic surgical procedures in this patient population are not to be taken lightly. These are medically complicated patients, and it should be kept in mind that during the period of dialysis, which is, of course, the time when such operations would be carried out, the annual mortality rate, even without operations, has been between 10 and 15 percent.

volunm 148, July 1984 57

Peptic ulcer disease in kidney transplant recipients

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