At a time when the judicious use of a broad range of immunosuppressive drugs has ensured excellent patient and organ survival rates after kidney transplantation, attention is focusing on strategies to minimize their side effects. Almost all immunosuppressive medications are associated with some form of gastrointestinal (GI) complication (1–6). The majority of these complications fall into one of several general categories: infections, mucosal injury and ulceration, biliary tract diseases, diverticular disease, pancreatitis, and malignancy (Table 1). Table 1: Gastrointestinal complications after transplantationAn understanding of the GI morbidities related to transplantation permits the development of systematic strategies to reduce and manage these disorders. In this article, we provide an overview of the GI complications arising from the use of immunosuppressive medications and review common prophylactic and treatment approaches. Infections By suppressing the body’s defensive immune functions, all immunosuppressive regimens can lead to increased rates of systemic or localized infections including those of the GI tract. These infections may be bacterial, viral, fungal, or parasitic and may infect one or more gut segments between the mouth and anus. The following discussion is not intended to be comprehensive but will instead indicate those representative infectious entities that most commonly affect transplant recipients. Viral Infections Infections with cytomegalovirus (CMV) and herpes viruses are very common in transplant recipients. They are very costly and can cause significant morbidity and mortality. We are not going to discuss some other viruses, such as adenoviruses, respiratory syncytial virus, influenza virus, and polyoma virus, which can cause serious infections in the immunocompromised host, because GI involvement with these viruses is not common. CMV Infection. CMV infection occurs in a large proportion of transplant patients and is the most common viral cause of clinical disorders in these patients. The incidence of enteric and/or gastric infection is remarkably high, affecting a substantial portion of patients, especially during the first 6 to 12 mo after organ transplantation. Sakr et al. (7) studied 140 liver transplant recipients before and after transplantation for the presence and the absence of CMV enteritis. They demonstrated that, although only one patient had evidence of enteric CMV infection before transplant, the incidence of CMV enteritis posttransplant was 27.7% in the cyclosporine (CsA)–treated group and 20% in the tacrolimus-treated group. Interestingly, patients treated with tacrolimus in this particular study had less severe enteric CMV infection compared with CsA-treated patients. CMV-related infections may be systemic, in which case patients typically present with viremia and constitutional symptoms and almost always with accompanying leukopenia; they may be localized or tissue-invasive. CMV can affect any segment of the GI tract. The symptoms and signs depend on the affected gut segment and may include dysphagia, odynophagia, nausea, vomiting, abdominal pain, GI bleeding, perforation, or diarrhea. CMV infection can also mimic many other entities such as ischemic colitis, intestinal pseudo-obstruction, toxic megacolon, and colon carcinoma (8). Pancreatitis, especially in recipients of CMV-positive pancreatic allografts, has also been reported (9). If we look at individual immunosuppressive drugs in detail, it was suggested by several studies that there is an association between mycophenolate mofetil (MMF) and tissue-invasive CMV, especially of the GI tract (6,10). All three pivotal MMF trials reported information on increase in tissue-invasive CMV infection without specific reference to the GI tract (6,11,12). In the US trial, tissue-invasive CMV disease was more common in the MMF groups, with rates of 7% for azathioprine (AZA) group, 11% for MMF 2 g/d, and 12% for MMF 3 g/d (11). Serious GI events appeared to be more common in the two smaller MMF studies, but interpretation requires a more detailed analysis of the raw data (10,13). In one study, 57% of patients treated with MMF had either dose reductions or interruptions due to adverse events, especially diarrhea, nausea, vomiting, and leukopenia (13). In addition, 6.5% of patients discontinued medication because of noninfectious GI events, and 6.5% were diagnosed with tissue-invasive CMV of the GI tract, compared with 0% for the AZA group. In the other study reported by Hebert et al. (10), 21% of patients had gastritis, duodenitis, or esophagitis, and 11% had either duodenal or esophageal ulceration. In the same study, CMV disease of the GI tract developed in 11% (2 of 19 patients) after they started receiving MMF. However, as both of these small studies were of graft rescue in refractory acute rejection with high-dose steroid use, higher rates of adverse events are not unexpected. Patients in graft rescue trials tend to be heavily immunosuppressed before switching to the salvage regimen, which may contribute to increased rates of certain infections, including CMV. In addition, MMF-treated patients seemed to experience more upper GI events that required investigation by endoscopy with biopsy in these rescue trials (13). Thus, it is also likely that more MMF patients underwent a biopsy, which might introduce a detection bias for CMV. Recently, two studies have added to the controversy over the link between CMV disease and MMF dosing. A small, uncontrolled study with a total of 62 patients by Kaplan et al. (14) describes patients receiving maintenance MMF therapy (with either CsA or tacrolimus in addition to prednisone) who presented with persistent midepigastric pain. Endoscopy with biopsy revealed that 90% of these patients had evidence of CMV infection in the small intestine or gastric mucosa. The authors demonstrated that an MMF dose of >2 g/d coupled to therapy with tacrolimus versus(CsA) showed a trend toward an increased relative risk for abdominal pain although the association was not statistically significant. Only transplantation from a CMV-positive donor into a CMV-negative recipient and the presence of leukopenia were independent risk factors for the development of abdominal pain in this particular study. In agreement with this observation a case-controlled study of 31 CMV patients matched with 102 control patients demonstrated that that MMF dose of 2 g/d was not an independent risk factor for CMV viremia or tissue invasion in renal allograft recipients (15). The stepwise logistic regression analysis identified the presence of past rejection episodes and a CMV-positive donor as the only significant factors. Information on CMV infection in FK506 studies is incomplete but suggestive of modest rates. In one of the large studies, tissue-invasive CMV, not specified for site, was diagnosed in 6.8% of CsA and 9.3% of FK506 patients (1). In another study, CMV infections were diagnosed in 16.6% of CsA patients and 13.5% of FK506 patients, with 2% of FK506 patients discontinuing study drug because of CMV versus none in the CsA group; possible tissue invasion was not specified (16). Any patient, especially in the early posttransplantation setting or during intensive immunosuppression for rejection, presenting with fever, nausea, vomiting, diarrhea, and laboratory findings of leukopenia and/or increased liver enzymes should undergo endoscopy and biopsy to assess the possibility of CMV enteritis. Failure to identify enteric CMV at an early stage could allow spread to critical organs, such as lung and liver, and perforation of the infected viscus with disastrous consequences (7). Typical endoscopic findings of tissue-invasive CMV of the digestive tract are shallow, erythematous erosions or localized ulcers. However, these visual findings are not specific, so biopsy is essential. CMV inclusion bodies or positive CMV cultures are sometimes from biopsy of patients who are for visual endoscopic the of such biopsy findings is of CMV in by detection of or by a for of early CMV for CMV infection after transplantation was for CMV that on have CMV-positive liver transplant 2 g/d of for after transplantation was in CMV disease incidence was in the group and in the In renal transplant patients who in from to for to mo after transplantation, CMV disease developed in 12 patients the to that other strategies of CMV should be in with have In a of kidney with with during acute rejection and in of graft CMV infections and CMV disease liver transplant patients to either of with or of 12 by the of by was more in CMV infection and disease studies that can be for CMV renal transplant patients to either or of for 12 after renal transplantation, had a significant on the of CMV infections during the first mo of the CMV of donor or recipient and of treatment for acute rejection episodes In another study of kidney transplant patients to either or three for 3 patients had a of CMV infection during a of mo of The infection at 6 mo was for and for were reported in liver transplant recipients A study of and renal transplant patients to either or 2 of for demonstrated that the of CMV disease at 6 mo none of these studies demonstrated that GI involvement of CMV is with general CMV an intensive prophylactic to the morbidity and from CMV infection is and in the patient group. In CMV is the drug of for treatment in all organ by trials of an of will provide information this be for CMV or treatment in transplant recipients. is only to CMV viral that cause clinical infection in transplant patients. as a of the the first 6 after transplantation. can affect many of the GI tract. In addition to especially in the and another common for infection is the with one group in of renal transplant patients over an All developed during the treatment of acute rejection with high-dose and Patients with infection after transplantation present with or as as although the in some patients may after the of Endoscopy can by or and a is a common that symptoms of or in the setting of intensive immunosuppression be without as can to which may be or to esophageal endoscopic may endoscopic biopsy for and viral cultures is have a of during of increased immunosuppression for can be treated with a of and more serious may to be treated with or when there is also CMV or Infections of several risk such as steroid use, and infections are very especially the first of after in transplant recipients. many infections can affect the GI tract, is the most common. 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In this particular study, recipient treatment of rejection with use, and graft increased the incidence of recipients can be of but can also diarrhea, intestinal and toxic with in less severe and in severe is very Infections of immunosuppression is to infection by or are GI infection due to is the most common cause of in patients with et al. in which infection to diarrhea, and in organ transplant recipients. The authors that infection is because is and the is not by patients can infected for several with it has been suggested that transplant recipients with in the posttransplantation should have with a which can with the has been reported to lead to fever, abdominal pain, diarrhea, abdominal nausea, and in renal transplant recipients. patients can present with acute respiratory by the the can and is associated with The should especially be in patients from such as the or the Interestingly, the risk of in transplant recipients in the CsA is that any donor with a of infection with should be for the presence of in and transplantation, treatment with should be the infection is In the case of a transplant or should be for in the liver with drugs there is with are reported drug between and in the but immunocompromised may treatment with this drug for infections to treatment with an in and disease in the general In a study by et al. the of was and in renal transplant recipients and patients, was in of renal transplant patients compared with in patients, other factors to increased of in transplant recipients. et al. renal transplant recipients by endoscopy 2 to mo after transplantation and identified patients with duodenitis, patients with gastritis, and patients with gastric was in the gastric of patients and was associated with gastritis, and ulceration. this was a small study, there was between and either cyclosporine or steroid infection is also transplant but is not higher that in the general et al. studied transplant recipients with endoscopy to assess the infections of the GI tract. was in had gastritis, had duodenitis, had of these patients had GI and infection or in of the patients treated with this is a the general which the possibility of immunosuppression the of We including endoscopy with in patients with possible infection before treatment with and In addition to infectious can be by certain immunosuppressive The three large trials a total of almost patients, that GI side are more common with tacrolimus CsA All three trials increased rates of in two of the the was substantial and All three trials also that and are more common with and also more common with as abdominal pain. to a on adverse events is the that of the tacrolimus patients in the US liver transplant were 12 of or The of GI side is that these GI have a which can be with in the study by et al. none of the patients in the tacrolimus had their study medication discontinued because of a GI In the study by et al. only 3 of tacrolimus patients over to CsA because of GI However, other that GI events due to tacrolimus may be more severe and to In one study, of patients tacrolimus had serious GI with 6 to with the of large trials with MMF demonstrated rates of in the MMF to be between and those in the AZA In many the rates were in the MMF group, which a to The US the rates of drug to GI adverse events were for for MMF 2 g/d, and for MMF 3 g/d at A of possible for have been such as of due to as as of in the are also a of and with use in the of total and/or dose two to of certain immunosuppressive such as MMF and is an to manage GI diarrhea, in transplant recipients. In many patients, such reduce the and of symptoms of the GI factors contribute to in transplant patients. include the of the use of drugs the use of and the possible of due to an or of intestinal In kidney transplantation, a of factors may into such as increased gastric during posttransplantation the possible of during and and The of in is A of a large of patients on by et al. revealed that was a complication of the other another study by et al. demonstrated that there was a trend for those patients treated with for rejection to more or is most likely that the development of in transplant recipients is In the transplant upper GI have an incidence after renal transplantation. in a of renal in patients receiving immunosuppression and as the patients a total of of which and was the 19 were were and were esophageal the incidence is tend to at and is the that the clinical symptoms of other GI and and treatment In many in transplant recipients are In one study, only of patients of with had symptoms However, in of GI perforation and patients, clinical findings of and abdominal pain with some in and in one GI bleeding, when it is to ulceration. liver there were episodes of GI in which endoscopic were these or were the most common cause of of the most common cause enteritis colitis, duodenitis, esophagitis, or of In lung transplant gastric as gastric with a may These large are associated with morbidity and to and may use of factors to these are reported as lung transplantation, high-dose for at after transplantation, high-dose for acute rejection, and CsA A study of kidney transplant recipients by the same authors not gastric it these large are specific to lung transplantation. We that should not be in transplant recipients. are or clinical that identify all patients at increased risk of upper GI ulcers. a of clinical is coupled with a for endoscopy with tissue for and In may be both common and in the renal transplant may cause significant morbidity or when they endoscopy to after transplantation, when are In of the incidence and of in endoscopy in patients is not in transplant recipients. posttransplantation GI may include one or more to reduce or the from the of These include or and one group or for the first 3 mo after transplantation for of and without group reported therapy for at the first after dose three at transplantation and to or by when the medication without a In one of severe GI after renal transplantation with was at as as The such as and a which not any on the of graft In another study, when in with and was more the of and either or with in disease in kidney transplant patients to can immunosuppressive by several CsA may be by of or and may by the of treatment with can of can CsA and both and by upper gut and increase the of with of these possible some transplantation not provide Endoscopy is not only in but also in gastric can be with endoscopic such as of or use of or In a of were of identified is almost always should be only for or of or endoscopic In the of patients who for gastric a and endoscopy may the for the risk of disease has been reported in to of patients with as perforation, or after renal transplantation was reported as in a study by et al. In this particular study, clinical from to has also been reported that renal transplant recipients with kidney disease had increased incidence of gastrointestinal diverticular disease and perforation without any However, when risk factors are complications has In a of renal at we that of patients was in posttransplantation complications in this particular study, we identified of diverticular disease patients, more a of which were associated with of these patients underwent and none developed posttransplantation colon of these patients were at the time of transplantation so not have the of these we the of in patients of should be in certain transplant especially patients with kidney disease, with or symptoms suggestive of diverticular disease by either or of any of the GI tract can in transplant patients, although the colon may be the most common In one of renal patients had a total of episodes of perforation, of which were The is with GI perforation to a of diverticular disease and of GI due to and other immunosuppressive (8). of GI perforation have been reported by et al. in renal transplant patients, with one early after transplantation and the other In the early perforation occurs most commonly in patients with renal who are and have had with These early are to be to or CMV In the perforation may after transplantation and is to be to or such as The authors that these are not and a of other factors have been associated with GI have been as a cause of perforation in as as transplant recipients A that MMF may be associated with in a patients infections such as have also been reported as a cause of gastric perforation in transplant recipients In more such as early and and regimens to the incidence and of transplant recipients are at risk for complications of biliary after transplantation is and has a In a study of or transplant had biliary tract disease, including and In patients who underwent for biliary disease after transplantation, was by acute complications of biliary tract disease with a of has been reported that disease occurs more in transplant recipients in the general The risk was higher in the first 2 after transplantation in that particular study. the of increased biliary tract disease after transplantation is not very and cyclosporine therapy was to be associated with increased incidence of due to an increased and in was also reported more in a group of renal transplant recipients compared to a group of patients treated with for the of biliary disease in transplant recipients include of all biliary before transplantation and on after transplantation before the patients and posttransplantation of the biliary because of the development of after transplantation. is an but a very serious complication in transplant recipients. The incidence of has been reported to be 3 to in liver transplant with a of to factors to of were identified as biliary of of and malignancy in the of the In renal transplant was reported to be to with a to CMV, and immunosuppression are the most common factors for A in the incidence of between the transplant recipients and patients versus in a study reported by et al. was an in between the transplant patients with and without versus although this not in this particular study. has been reported in both studies and clinical trials of transplantation and GI diseases, such as disease, that there is a possible association between azathioprine and et al. compared the incidence of between renal transplant recipients treated with azathioprine and and patients who cyclosporine and steroid The incidence of from in the AZA group to in the CsA group are also especially and in but without or clinical in transplant recipients can be sometimes a very in the and of in transplant recipients. of of of or in tissue or in the pancreatic of in transplant recipients include of possible pain and which might be in severe Gastrointestinal has been demonstrated that the risk of in transplant recipients is higher in the general the common of in the general such as of the and are not increased in transplant patients, certain that are in the general such as and more in transplant recipients. In a large study of first kidney recipients and first recipients there was in the incidence of gastric in transplant recipients compared to general the other colon was although not statistically was et al. reported in renal transplant recipients. The authors identified that the risk of in renal transplant recipients by at transplantation, a of and In a study of liver transplant recipients who at 12% of patients developed including three patients for biliary with colon The relative risk for colon carcinoma was which was statistically significant. several transplant reported increased incidence of colon in patients with and colitis, with after transplantation in these particular patients is can GI tract to of transplant recipients. involvement of the GI tract is not as for early from perforation or and GI can in the disease In a study of liver transplant GI symptoms in of patients and of patients with GI symptoms GI developed et al. liver transplant recipients with abdominal pain, vomiting, and In patients, endoscopy revealed the of and erythematous with a on in the colon or endoscopy and biopsy in transplant recipients who have GI symptoms associated with positive to gastric are also reported in transplant recipients These are can be associated with and are treated with a of including of and A clinical is for the of in transplant especially in the GI tract. Endoscopy is the most for and treatment of GI tract as as the to is treatment or of and as as such as treatment with or The discussion of treatment of in is the of this are several GI complications of immunosuppressive that are in transplant recipients. between the large immunosuppressive drug trials in such as of events, and drug and the possibility that data not indicate relative rates of GI adverse may also be that the relative of GI side have to some been by rates of of some of the immunosuppressive which could lead to clinical on the GI events by both and immunosuppressive is certain of GI and to reduce the incidence and of the clinical and/or as as should be always with of the side of these approaches. most transplant patients are which can or clinical a of is especially in patients receiving high-dose to to detailed GI with clinical GI should be as a endoscopy with Failure to identify but can have such as enteric or other GI events drug is not such as dose and can reduce the to In regimens MMF or drug by allow a patient to on an and immunosuppressive after kidney transplantation might be another to with addition of very such as MMF and to transplant in patients with serious GI We as experience with immunosuppressive to that and treatment of GI complications will also and reduce the consequences of these in transplant recipients.
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Helderman et al. (2002) studied this question.
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