Should Helicobacter pylori infection be treated before kidney transplantation?

Susanna Sarkio1,, Hilpi Rautelin2, Lauri Kyllönen1, Eero Honkanen3, Kaija Salmela1 and Leena Halme1

1 Transplantation and Liver Surgery, Helsinki University Hospital, 2 Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki and Helsinki University Hospital Diagnostics and 3 Department of Internal Medicine, Division of Nephrology, Helsinki University Hospital, Helsinki, Finland



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Before the introduction of modern medication for ulcer disease, gastroduodenal complications were often fatal in recipients of kidney transplants. Helicobacter pylori causes gastritis and is an important risk factor for peptic ulcer disease and gastric malignancies. The aim of this study was to evaluate whether H. pylori infection influences the outcomes of kidney transplantation.

Methods. Between 1991 and 1994, serum H. pylori antibodies were determined in samples taken just before transplantation from 500 consecutive recipients of kidney transplants. Clinical data were collected retrospectively by means of questionnaires sent to the patients and from the national kidney transplantation registry.

Results. The prevalence of seropositivity of H. pylori was 31% in the 500 renal transplant subjects, and the seropositivity increased with age. There were no differences in patient or graft survival between the seronegative and seropositive patients. During the first 3 months after transplantation, five seronegative and one seropositive patient had gastroduodenal ulcers, with bleeding complications in three of the seronegative ones. After 3 months, there were more ulcers in the seropositive group (6 vs 3%) and more oesophagitis in the seronegative group (9 vs 7%). During the 6-year follow-up, two cases of gastroduodenal malignancies were found in the helicobacter-positive group and none in the seronegative group.

Conclusions. Helicobacter pylori infections did not result in significant postoperative gastric complications. Two of the 155 seropositive patients developed gastroduodenal malignancies.

Keywords: Helicobacter pylori; kidney transplantation; malignancy; ulcer



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Before the era of H2 blockers and proton pump inhibitors, peptic ulcer disease commonly led to fatal complications following kidney transplantation; in massive gastrointestinal bleeding, for example, or perforation with peritonitis. Therefore, in some centres, pre-kidney-transplant ulcer surgery was advocated [1]. In 1982, ranitidine was introduced at our centre as ulcer prophylaxis after transplantation, and subsequently, the number of serious upper gastrointestinal complications has decreased dramatically.

The recognition of Helicobacter pylori has largely changed the understanding of the aetiology of peptic ulcer disease. Nowadays, H. pylori is accepted as a major aetiologic factor in gastritis and gastro-duodenal ulceration [2]. Epidemiological studies have demonstrated, moreover, an association between H. pylori and gastric cancer, and in 1994 H. pylori was classified as a group I carcinogen by the International Agency for Research on Cancer [3].

The aim of this study was to determine the presence of H. pylori in a group of recipients of kidney transplants and to evaluate the correlation of upper gastrointestinal complications and dyspeptic symptoms with H. pylori infection in these patients after kidney transplantation. We also wanted to determine if H. pylori infection had any influence on graft or patient survival.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Serum H. pylori antibodies were measured in 500 consecutive patients who underwent cadaveric kidney transplantation at Helsinki University Hospital between August 1991 and November 1994. In 477 (95%) recipients, the transplantation was primary and in 23 (5%) secondary. The median age of the recipients was 42.8 years (range 11.4–69.9); 214 (43%) were women and 286 (57%) were men. All patients were on maintenance dialysis before transplantation, and had on average been on dialysis for 18 months (range 1–181). Other pre-transplantation characteristics of the patients according to their status for H. pylori are given in Table 1Go. The basic immunosuppressive regimen of the recipients consisted of a combination of cyclosporin, methylprednisolone, and azathioprine. Acetylsalicylic acid (ASA) was used for prophylaxis against thrombosis (at a dose of 50–100 mg/day); any use of other non-steroidal anti-inflammatory drugs (NSAID) was prohibited. For infection, a prophylaxis with cefamandole 1 g was used pre-operatively and after 12 h. During their hospitalizations all patients received ranitidine for at least 3 weeks as ulcer prophylaxis. The data on patient outcome and graft survival after transplantation was gathered from medical records and from our national computerised kidney transplantation registry.


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Table 1. Patient data

 

Gastrointestinal complications
All living recipients were sent a questionnaire, in which they were asked to write down any upper gastrointestinal complaints they had after kidney transplantation as well as the results of examinations and the treatments they had for those complaints. Data from medical records, with a special interest on macroscopic and microscopic findings of the oesophago-gastro-duodenoscopies performed, were requested (with patients’ written consent) from all hospitals reported by the patient. In the case of deceased patients and of those who did not return their questionnaires, the data was collected from follow-up information sent regularly to the national kidney transplantation registry by the nephrologists responsible for the follow-up of these patients.

Serum analysis
Serum samples were obtained just before kidney transplantation from all the recipients, and were kept frozen at -20°C before analysis. IgG and IgA antibodies for H. pylori were measured by an in-house enzyme immunoassay. The antigen used was an acid glycine extract from H. pylori NCTC 11637. The absorbance readings were converted to reciprocals of the end point titres. Seven hundred was considered positive for IgG and 70 for IgA. The sensitivity and specificity of this test have been shown to be 99 and 97% for IgG and 61 and 99% for IgA [4].

Ethics
The study was approved by the Ethics Committee of Surgical Hospital, Helsinki University Hospital.

Statistics
Pearson's {chi}2 and Mann–Whitney U-test were used to compare groups of patients. Patient and graft survival was evaluated using the life table method.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The prevalence of seropositivity for H. pylori was 31% among the 500 kidney transplant patients in this study, and seropositivity increased with age. The median age of seropositive patients was 47.9 years and of seronegative patients 37.4 years (P<0.01) (Table 1Go). The median follow-up time was 6.2 years (0.2–8.3) in seropositive and 6.4 years (0.0–8.3) in the seronegative patients. During follow-up, 72 (14%) patients (23 (15%) seropositive and 49 (14%) seronegative) died. The causes of death are shown in Table 2Go. None of the deaths were related to H. pylori. Thus, the questionnaire was sent to 428 patients, of whom 335 (78%) responded.


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Table 2. Causes of deaths

 
Graft function
Seropositive patients were older but had fewer systemic diseases than seronegative ones (Table 1Go). During the first 3 months after transplantation, 28 (18%) of the seropositive and 90 (26%) of the seronegative patients were treated for acute rejection (not significant). 128 kidney grafts failed during the follow-up period—the patients who died with a functioning graft are included in this number. The median duration of graft function was 6.1 years (range 0–8.3). There was no difference in patient or graft survival between the seropositive and seronegative patients.

Gastroduodenal complications
Gastroduodenal complications in the first 3 months
oesophago-gastro-duodenoscopy was performed on 17 (3.4%) patients who had gastrointestinal complaints during the first 3 postoperative months after kidney transplantation (Table 3Go). Gastroduodenal ulcer was diagnosed by endoscopy in five seronegative and one seropositive patients during the first 3 months (Table 4Go). All of these patients were treated successfully. Five of the six patients with postoperative ulcers received low-dose ASA prophylaxis. In four of the six ulcer patients the ulcer developed after rejection therapy, and furthermore, one of these patients was diagnosed simultaneously to have a cytomegalovirus (CMV) viraemia (Table 4Go).


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Table 3. OEGD findings in 500 kidney transplant patients

 

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Table 4. Details of gastroduodenal ulcers diagnosed within the first 3 postoperative months

 

Gastroduodenal complications in the follow-up
During follow-up, oesophago-gastro-duodenoscopy was performed on 92 patients (35 seropositive). The findings are presented in Table 3Go. None of the seronegative patients turned out to have H. pylori in the biopsies. There were more ulcers in the seropositive patient group (6 vs 3%), but oesophagitis was more common in the seronegative group (9 vs 7%).

Overall, nine of the 25 ulcer patients (three seropositive) had an acute rejection during the first 3 months. Helicobacter pylori infection was histologically verified in 24 seropositive patients of whom 16 got eradication therapy. During follow-up, 28 (18%) of the H. pylori-positive patients and 59 (17%) of the seronegative patients used proton pump inhibitors or H2 blockers for a period of 6 months. This was done partly because of their former histories of gastroduodenal ulcers and partly because of their dyspeptic complaints.

In the seropositive group there was one ulcer perforation, one year after the transplantation which required laparotomy and ulcer ligation. In both patient groups, one patient underwent fundoplication due to severe reflux oesophagitis after transplantation.

Gastroduodenal malignancies
In the seropositive patient group two patients developed gastroduodenal malignancies. One female patient developed a gastric carcinoma 5 years after transplantation, at the age of 70 and a 64-year-old male was diagnosed to have a carcinoid tumour in the duodenal bulb 3 years after the transplantation. Both patients were treated surgically. In addition, one seropositive patient developed a carcinoma of the hypopharynx, which infiltrated the oesophagus and was diagnosed in oesophago-gastro-duodenoscopy 6 years after the transplantation. No upper gastrointestinal malignancies were found in the seronegative patient group.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Helicobacter pylori infections seem to have negligible influence on the outcomes of patients who have undergone kidney transplantation. Existing data show that patient survival was the same in helicobacter positive and negative patient groups. Our finding that H. pylori was one risk factor for peptic ulcers, but that the frequency of gastroduodenal ulcers or ulcer bleeding within the first 3 months after transplantation was not increased among the helicobacter-positive group, is concordant with an earlier report in which H. pylori infections did not account for the development of ulcerative lesions in kidney allograft patients [5]. Moreover, many seropositive patients have been shown to sero-revert after transplantation when antibacterial and immunosuppressive agents are administered [6].

The number of new H. pylori infections has been shown to be decreasing in developed countries, and consequently, the prevalence of the infection is higher in older age groups [7,8]. In the present series, H. pylori seropositivity was 31%, but the median age of seropositive subjects was significantly higher compared to the seronegative ones. These figures do not differ from another series, which described the age-dependent incidence of H. pylori infection in the general Finnish population [9]. A similar prevalence has also been shown by other authors in renal transplant patients [1012].

Upper gastrointestinal problems were common in kidney transplantation patients before the appearance of modern ulcer medications. In one report from the 1970s, 29% had gastroduodenal complications, of which the biggest group consisted of gastroduodenal haemorrhage. The mortality secondary to upper gastrointestinal haemorrhage was 29% in that study [13]. In a more recent study from the 1990s, the rate of the total gastrointestinal complications was 16%, 9.6% being gastroduodenal complications. In this study the mortality as a result of gastrointestinal complications was about 1% [14].

The fact that despite the ulcer prophylaxis, 9% of our patients had oesophagitis and 5% had gastroduodenal ulcers after the transplantation signifies that there is a potential for a large number of postoperative gastrointestinal problems. Still, the gastrointestinal mortality rate was only 0.4%, which is slightly lower than in the previous study. In our series, six patients, of whom only one was seropositive, experienced gastroduodenal ulcers soon after transplantation. Factors contributing to those were low-dose ASA in five patients, prior rejection therapy with high-dose corticosteroids in four and prior CMV infection in one patient. The association between corticosteroid treatment and ulcer disease has been controversial; but recently, the risk has been considered to be increased only in those who concurrently receive non-steroidal anti-inflammatory drugs [15]. Corticosteroids play a more important role in delaying the healing of lesions caused by non-steroidal anti-inflammatory drugs than in causing de novo ulceration [15,16]. CMV, a common post-organ-transplantation pathogen, which often is activated by rejection therapy, also causes ulcerations in the gastroduodenal mucosa [17,18]. CMV-viraemia was found in one of these six patients, but regrettably, biopsies of ulcers were not systematically examined for CMV.

Kidney transplant recipients have an increased risk of neoplasia, most of the tumours being of cutaneus origin. In a series of 2890 consecutive Finnish kidney transplant patients, 230 post-transplantation malignancies were found. Of these, 39 were of gastrointestinal origin and eight were in the gastroduodenal segment [19]. The two seropositive patients with gastroduodenal malignancies in the present series are included in these figures. Regretably, the H. pylori status of the rest of the patients has not been evaluated. There has been a lot of discussion of the role of H. pylori in the genesis of gastric carcinoma. It now seems that H. pylori is one of the cofactors involved in the development of neoplastic transformation of gastric mucosa [20]. In the present series there were two gastroduodenal malignancies in the seropositive group and none in the negative group. This raises the question whether or not it might be wise to eradicate H. pylori before transplantation.

In conclusion, H. pylori infections are common among kidney transplant patients, but they do not significantly increase the risk of postoperative gastroduodenal complications. During an acute rejection episode effective ulcer prophylaxis seems to be essential in all patients regardless of their H. pylori status, especially in patients who are also receiving prophylactic ASA treatment.



   Acknowledgments
 
This study has been financially supported by the Finnish Kidney Foundation and the Research Foundation of Orion Corporation.



   Notes
 
Correspondence and offprint requests to: Susanna Sarkio MD, Transplantation and Liver Surgery, Helsinki University Hospital, PL 263, FIN-00029 HUS Helsinki, Finland. Email: susanna.sarkio{at}fimnet.fi Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Owens ML, Passaro E, Wilson SE et al. Treatment of peptic ulcer disease in renal transplant patient. Ann Surg1977; 186: 17–21[ISI][Medline]
  2. NIH Consensus conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development. Panel on Helicobacter pylori in peptic ulcer disease. JAMA1994; 272: 65–69[ISI][Medline]
  3. IARC Working group on the evaluation of the carcinogenic risks to humans. Helicobacter pylori. Schistosomes, Liver Flukes and Helicobacter Pylori; Views and Expert Opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon IARC: 1994; 177–240
  4. Oksanen A, Veijola L, Sipponen P, Schauman K-U, Rautelin H. Evaluation of Pyloriset Screen, a rapid whole-blood diagnostic test for Helicobacter pylori infection. J Clin Microbiol1998; 36: 955–957[Abstract/Free Full Text]
  5. Hruby Z, Myszka-Bijak K, Gosciniac G et al. Helicobacter pylori in kidney allograft recipients: high prevalence of colonization and low incience of active inflammatory lesions. Nephron1997; 75: 25–29[ISI][Medline]
  6. Dummer S, Perez-Perez G, Breinig M et al. Seroepidemiology of Helicobacter pylori infection in heart transplant recipients. CID1995; 21: 1303–1305
  7. Talley N, Noak K. The worldwide prevalence of helicobacter pylori: asymptomatic infection and clinical states associated with infection in adults. In: Godwin CS, Worsley BW, eds. Helicobacter Pylori Biology and Clinical Practice. CRC Press Inc, Boca Raton, FL: 1993; 63–83
  8. Sipponen P, Kosunen TU, Samloff IM, Heinonen OP, Siurala M. Rate of Helicobacter pylori acquisition among Finnish adults. Scand J Gastroenterol1996; 31: 229–232[ISI][Medline]
  9. Kosunen T, Aromaa A, Knekt P et al. Helicobacter antibodies in 1973 and 1994 in the adult population of Vammala, Finland. Epidemiol Infect1997; 119: 29–34[ISI][Medline]
  10. Gladziwa U, Haase G, Handt S et al. Prevalence of Helicobacter pylori in patients with chronic renal failure. Nephrol Dial Transplant1993; 8: 301–306[Abstract]
  11. Özgur O, Boyacioglu S, Özdogan M, Gur G, Telatar H, Haberal M. Helicobacter pylori infection in haemodialysis patients and renal transplant recipients. Nephrol Dial Transplant1997; 12: 289–291[Abstract]
  12. Davenport A, Shallcross T, Crabtree J, Davison A, Will E, Heatley R. Prevalence of Helicobacter pylori in patients with end-stage renal failure and renal transplant recipient. Nephron1991; 59: 597–601[ISI][Medline]
  13. Meyers W, Harris N, Stein S et al. Alimentary tract complications after renal transplantation. Ann Surg1979; 190: 535–542[ISI][Medline]
  14. Benoit G, Moukarzel M, Verdelli G et al. Gastrointestinal complications in renal transplantation. Transplant Int1993; 6: 45–49[ISI][Medline]
  15. Weil J, Langman MJS, Wainwright P et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs. Gut2000; 46: 27–31[Abstract/Free Full Text]
  16. Piper JM, Ray WA, Daugherty JR et al. Corticosteroids use and peptic ulcer disease: Role of non steroidal anti-inflammatory drug therapy. Ann Intern Med1991; 114: 735–740[ISI][Medline]
  17. Goodgame RW. Gastrointestinal cytomegalovirus disease. Ann Intern Med1993; 119: 924–935[Abstract/Free Full Text]
  18. Halme L, Höckerstedt K, Salmela K, Lautenschlager I. CMV infection detected in the upper gastrointestinal tract after liver transplantation. Transplant Int1998; 11 [Suppl 1]: 242–244
  19. Kyllönen LE, Salmela KT, Pukkala E. Cancer incidence in a kidney-transplanted population. Transplant Int2000; 13 (Suppl 1): 394–398
  20. Parsonnet J, Friedman G, Vandersteen D et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med1991; 325: 1127–1131[Abstract]
Received for publication: 20. 1.01
Revision received 22. 5.01.



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