REVIEW J Am Soc Nephrol 13: 277–287, 2002

Gastrointestinal Complications of Transplant Immunosuppression

J. HAROLD HELDERMAN and SIMIN GORAL Department of Medicine, Division of Nephrology, and the Vanderbilt Transplant Center, Vanderbilt University Medical Center, Nashville, Tennessee.

At a time when the judicious use of a broad range of immu- CMV Infection. CMV infection occurs in a large propor- nosuppressive drugs has ensured excellent patient and organ tion of transplant patients and is the most common viral cause survival rates after kidney transplantation, attention is focusing of clinical disorders in these patients. The incidence of enteric on strategies to minimize their side effects. Almost all immu- and/or gastric infection is remarkably high, affecting a sub- nosuppressive medications are associated with some form of stantial portion of patients, especially during the first 6 to 12 gastrointestinal (GI) complication (1–6). The majority of these mo after organ transplantation. Sakr et al. (7) studied 140 liver complications fall into one of several general categories: in- transplant recipients before and after transplantation for the fections, mucosal injury and ulceration, biliary tract diseases, presence and the absence of CMV enteritis. They demonstrated diverticular disease, pancreatitis, and malignancy (Table 1). that, although only one patient had evidence of enteric CMV An understanding of the GI morbidities related to transplan- infection before transplant, the incidence of CMV enteritis tation permits the development of systematic strategies to posttransplant was 27.7% in the cyclosporine (CsA)–treated reduce and manage these disorders. In this article, we provide group and 20% in the tacrolimus-treated group. Interestingly, an overview of the GI complications arising from the use of patients treated with tacrolimus in this particular study had less immunosuppressive medications and review common prophy- severe enteric CMV infection compared with CsA-treated pa- lactic and treatment approaches. tients. CMV-related infections may be systemic, in which case patients typically present with viremia and constitutional Infections symptoms and almost always with accompanying leukopenia; By suppressing the body’s defensive immune functions, all they may be localized or tissue-invasive. CMV can affect any immunosuppressive regimens can lead to increased rates of segment of the GI tract. The symptoms and signs depend on the systemic or localized infections including those of the GI tract. affected gut segment and may include dysphagia, odynophagia, These infections may be bacterial, viral, fungal, or parasitic nausea, vomiting, abdominal pain, GI bleeding, perforation, or and may infect one or more gut segments between the mouth diarrhea. CMV infection can also mimic many other entities and anus. The following discussion is not intended to be such as ischemic colitis, intestinal pseudo-obstruction, toxic comprehensive but will instead indicate those representative megacolon, and colon carcinoma (8). Pancreatitis, especially in infectious entities that most commonly affect transplant recipients of CMV-positive pancreatic allografts, has also been recipients. reported (9). If we look at individual immunosuppressive drugs in detail, Viral Infections it was suggested by several studies that there is an association Infections with cytomegalovirus (CMV) and herpes viruses between mycophenolate mofetil (MMF) and tissue-invasive are very common in transplant recipients. They are very costly CMV, especially of the GI tract (6,10). All three pivotal MMF and can cause significant morbidity and mortality. We are not trials reported information on increase in tissue-invasive CMV going to discuss some other viruses, such as adenoviruses, infection without specific reference to the GI tract (6,11,12). In respiratory syncytial virus, influenza virus, and polyoma virus, the US trial, tissue-invasive CMV disease was more common which can cause serious infections in the immunocompromised in the MMF groups, with rates of 7% for azathioprine (AZA) host, because GI involvement with these viruses is not group, 11% for MMF 2 g/d, and 12% for MMF 3 g/d (11). common. Serious GI events appeared to be more common in the two smaller MMF studies, but interpretation requires a more de- tailed analysis of the raw data (10,13). In one study, 57% of patients treated with MMF had either dose reductions or inter- Received February 8, 2000. Accepted May 30, 2001. ruptions due to adverse events, especially diarrhea, nausea, Correspondence to Dr. Simin Goral, Vanderbilt University Medical Center, vomiting, and leukopenia (13). In addition, 6.5% of patients Division of Nephrology, S-3223 MCN, Nashville, TN 37232. Phone: 615-322- 6976; Fax: 615- 343-7156; E-mail: [email protected] discontinued medication because of noninfectious GI events, 1046-6673/1301-0277 and 6.5% were diagnosed with tissue-invasive CMV of the GI Journal of the American Society of Nephrology tract, compared with 0% for the AZA group. In the other study Copyright © 2001 by the American Society of Nephrology reported by Hebert et al. (10), 21% of patients had gastritis, 278 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 277–287, 2002

Table 1. Gastrointestinal complications after transplantation senting with fever, nausea, vomiting, diarrhea, and laboratory findings of leukopenia and/or increased liver enzymes should Infections undergo endoscopy and biopsy to assess the possibility of Mucosal injury and ulceration CMV enteritis. Failure to identify enteric CMV at an early Biliary tract diseases stage could allow spread to critical organs, such as lung and Diverticular disease liver, and perforation of the infected viscus with disastrous Perforations consequences (7). Typical endoscopic findings of tissue-inva- Pancreatitis sive CMV of the digestive tract are shallow, erythematous Malignancy erosions or localized ulcers. However, these visual findings are not specific, so biopsy is essential. CMV inclusion bodies or positive CMV cultures are sometimes obtained from biopsy duodenitis, or esophagitis, and 11% had either duodenal or samples of patients who are negative for visual endoscopic esophageal ulceration. In the same study, CMV disease of the findings; the relevance of such biopsy findings is unclear. GI tract developed in 11% (2 of 19 patients) after they started Demonstration of CMV in peripheral blood by direct detection receiving MMF. However, as both of these small studies were of antigenemia or by PCR technique provides a great tool for of graft rescue in refractory acute rejection with high-dose diagnosis of early active CMV infection. Prophylaxis for CMV steroid use, higher rates of adverse events are not unexpected. infection after transplantation was reviewed extensively else- Patients in graft rescue trials tend to be heavily immunosup- where (17). Studies for CMV prophylaxis that rely exclusively pressed before switching to the salvage regimen, which may on acyclovir have produced inconsistent results. Among CMV- contribute to increased rates of certain infections, including positive liver transplant recipients, 2 g/d of oral acyclovir for CMV. In addition, MMF-treated patients seemed to experience 16 wk after transplantation was significantly better than pla- more upper GI events that required investigation by endoscopy cebo in preventing CMV disease (CMV incidence was 5% in with biopsy in these rescue trials (13). Thus, it is also likely the acyclovir group and 27% in the placebo group) (18). In that more MMF patients underwent a biopsy, which might contrast, among 18 renal transplant patients who received oral introduce a detection bias for CMV. acyclovir in dosages from 600 to 4000 mg/d for 4 to 7 mo after Recently, two studies have added to the controversy over the transplantation, CMV disease developed in 12 patients (67%), link between CMV disease and MMF dosing. A small, uncon- leading the researchers to conclude that other strategies of trolled study with a total of 62 patients by Kaplan et al. (14) CMV prophylaxis should be sought (19). Studies using acy- describes patients receiving maintenance MMF therapy (with clovir in combination with ganciclovir have generally pro- either CsA or tacrolimus in addition to prednisone) who pre- duced good results. In a series of 170 consecutive kidney sented with persistent midepigastric pain. Endoscopy with bi- transplantations, prophylaxis with acyclovir, combined with opsy revealed that 90% of these patients had evidence of CMV ganciclovir during acute rejection and in cases of delayed graft infection in the small intestine or gastric mucosa. The authors function, gave good protection against CMV infections and demonstrated that an MMF dose of Ͼ2 g/d coupled to therapy prevented CMV disease (20). Among 167 liver transplant with tacrolimus (versus CsA) showed a trend toward an in- patients randomized to either 120 d of antiviral prophylaxis creased relative risk for abdominal pain although the associa- with acyclovir 800 mg orally four times daily or 14 d of tion was not statistically significant. Only transplantation from ganciclovir (5 mg/kg) intravenously every 12 h followed by a CMV-positive donor into a CMV-negative recipient and the oral acyclovir 800 mg four times daily, the sequence of gan- presence of leukopenia were independent risk factors for the ciclovir followed by acyclovir was more effective than acyclo- development of abdominal pain in this particular study. In vir alone in reducing CMV infection and disease (21). Other agreement with this observation a case-controlled study of 31 studies suggest that ganciclovir can be used effectively alone CMV patients matched with 102 control patients demonstrated for CMV prophylaxis. Among 44 renal transplant patients that that MMF dose of 2 g/d was not an independent risk factor randomized to either placebo or 750 mg of oral ganciclovir for CMV viremia or tissue invasion in renal allograft recipients twice daily for 12 wk after renal transplantation, ganciclovir (15). The stepwise logistic regression analysis identified the had a significant impact on the occurrence of CMV infections presence of past rejection episodes and a CMV-positive donor during the first 9 mo posttransplantation, irrespective of the as the only significant factors. CMV status of donor or recipient and of treatment for acute Information on CMV infection in FK506 studies is incom- rejection episodes (22). In another study of kidney transplant plete but suggestive of modest rates. In one of the large studies, patients randomized to receive either oral acyclovir (800 mg tissue-invasive CMV, not specified for site, was diagnosed in four times daily) or oral ganciclovir (1000 mg three times 6.8% of CsA and 9.3% of FK506 patients (1). In another study, daily) for 3 mo, ganciclovir-treated patients had a much lower CMV infections were diagnosed in 16.6% of CsA patients and rate of CMV infection during a mean of 14.4 mo of follow-up 13.5% of FK506 patients, with 2% of FK506 patients discon- (23). The cumulative infection rate at 6 mo was 35.9% for tinuing study drug because of CMV versus none in the CsA acyclovir and 2.5% for ganciclovir. Similar results were re- group; possible tissue invasion was not specified (16). ported in liver transplant recipients (24). A recent study of Any patient, especially in the early posttransplantation set- valacyclovir among 616 Dϩ/RϪ and Rϩ renal transplant ting or during intensive immunosuppression for rejection, pre- patients randomized to either placebo or2gofvalacyclovir J Am Soc Nephrol 13: 277–287, 2002 GI Complications of Immunosuppression 279 four times daily for 90 d demonstrated that valacyclovir sig- high-dose steroids or antibodies, and the presence of a Roux- nificantly reduced the occurrence of CMV disease at 6 mo en-Y choledochojejunostomy in patients with liver transplan- (25). Although, none of these studies demonstrated specifically tation. Candida esophagitis usually presents with odynophagia that GI involvement of CMV is decreased with general CMV or dysphagia. Less commonly, patients may present with fever, prophylaxis, an intensive prophylactic strategy to decrease the heartburn, epigastric pain, or GI bleeding. Lesions may include morbidity and mortality from CMV infection is particularly superficial erosions, ulcers, and white nodules or plaques. important and necessary in the high-risk (recipient negative/ Identification of lesions is important because the infection may donor positive) patient group. In established CMV infection, be severe and necrotizing, which may result in perforation (27). ganciclovir is the drug of choice for treatment in all organ Perforation with formation of tracheoesophageal fistulas has transplants followed by foscarnet. Ongoing trials of valganci- also been reported (28). clovir, an orally administered valine ester of ganciclovir, will The responsible species is most commonly either Candida provide information whether this agent would be effective for albicans or Candida tropicalis (4). Fungal infection may occur CMV prophylaxis or treatment in transplant recipients. in conjunction with systemic CMV infection. Of a series of 66 Herpes Simplex Virus. Herpes simplex virus (HSV) is CMV-positive liver transplant recipients, candidal esophagitis second only to CMV among viral agents that cause clinical developed in 3 (29). The diagnosis of candidal infections is infection in transplant patients. It usually presents as a reacti- made by fungal cultures or histopathologic examination of vation of the latent virus mostly within the first 6 wk after appropriate specimens. Therapy includes topical antifungal transplantation. HSV can affect many parts of the GI tract. In preparations (nystatin, amphotericin B oral solutions) and oral addition to mild, ulcer-like mucocutaneous lesions, especially or intravenous antifungal agents. Liposomal amphotericin B in the oral cavity and pharynx, another common site for infec- preparations are less nephrotoxic than the regular amphotericin tion is the esophagus, with one group reporting esophagitis in B but are more expensive. 5 of 221 renal transplant patients (2.2%) over an 8-yr period Different transplant programs have different incidences of (26). All cases developed during the treatment of acute rejec- invasive fungal infections; therefore, prophylaxis may vary tion with high-dose steroids and antilymphocyte preparations. from one program to another. For prophylaxis of upper GI Patients with HSV infection after transplantation usually fungal infection, the use of nystatin swish and swallow every present with odynophagia or dysphagia as well as orocutaneous 6 h for 6 mo after induction and after each rejection treatment HSV lesions, although the orocutaneous complaints in some has been described as well as oral clotrimazole and oral am- patients may develop after the appearance of esophagitis. En- photericin B in renal transplant recipients as effective (5). In doscopy can reveal shallow ulcers surrounded by typical ves- 212 liver transplant recipients who received fluconazole (400 icles, discrete or coalescent ulcers, and pseudomembranous mg/d) until 10 wk after transplantation, fungal colonization lesions mimicking a cutaneous senile lesion. It is a common decreased significantly compared with placebo (28% versus belief that symptoms of odynophagia or dysphagia in the 90%) (30). In addition, proven fungal infection occurred in setting of intensive immunosuppression must be investigated 43% of placebo recipients but in only 9% of fluconazole endoscopically without delay as untreated herpetic ulcers can recipients (P Ͻ 0.001). Interestingly, infection and coloniza- progress to hemorrhage, which may even be fatal, or to esoph- tion by organisms intrinsically resistant to fluconazole did not ageal perforation. Because endoscopic appearance may vary, increase, which is a concern because of the potential for the endoscopic biopsy for histology, immunohistochemistry, and emergence of fluconazole-resistant Candida species in patients viral cultures is necessary. Transplant physicians must have a given prophylactic fluconazole. No hepatotoxicity was ob- high level of suspicion during periods of increased immuno- served in this particular group of patients. It has been recom- suppression for HSV infection. Simple mucocutaneous lesions mended to monitor serum cyclosporine levels closely in pa- can be treated with a short course of oral acyclovir. Extensive tients treated with prophylactic fluconazole because of the and more serious cases may need to be treated with IV acy- interaction between the two drugs. For liver transplant recipi- clovir or ganciclovir when there is also concomitant CMV or ents, it was suggested to use the prophylactic fluconazole only Epstein-Barr virus (EBV) infection. in high-risk groups of patients, such as recipients with previous CMV infection, multiple transfusions, and retransplantation Fungal Infections (31). The optimal duration of prophylaxis and the antifungal Because of several risk factors, such as frequent antibiotic agent are still not standardized. therapy, steroid use, hyperglycemia, indwelling catheters, and impaired cellular immunity, opportunistic fungal infections are Bacterial Infections very common, especially the first couple of months after sur- Bacterial infections of the GI tract are not uncommon in gery in transplant recipients. Although many fungal infections transplant recipients. Examples include Yersinia enterocolitica can affect the GI tract, candidiasis is the most common. and Clostridium difficile colitis. Such infections may be more Candidal Infection. Candidal infection most typically prevalent in patients with systemic CMV infection (29). Yer- presents in the immunosuppressed transplant patient as esoph- sinia septicemia can occur especially in patients with iron agitis with or without oral thrush. Risk factors associated with loading, diabetes mellitus, chronic liver disease, OKT3 use, invasive candidal infections include administration of broad- and high aluminum store, which might contribute an additional spectrum antibiotics, recent treatment for acute rejection with risk factor to immunosuppression (32,33). Patients usually 280 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 277–287, 2002 present with GI symptoms, such as diarrhea and abdominal Helicobacter pylori Infection tenderness, and rarely with erythema nodosum, arthritis, myo- H. pylori plays an important role in gastritis and peptic ulcer carditis, meningitis, and acute renal failure. Antibiotic treat- disease in the general population. In a study by Ozgur et al. ment is efficient to cure the disease. (39), the prevalence of H. pylori was 70% and 60% in renal Although its true incidence among transplant recipients is transplant recipients and hemodialysis patients, respectively. not well known, the overall incidence of C. difficile colitis was Gastritis was seen in 65% of renal transplant patients compared recently reported as 8%, with 16% in the pediatric kidney with 19% in hemodialysis patients, suggesting other factors transplant group, 15.5% in the combined kidney-pancreas contributing to increased levels of gastritis in transplant recip- group, and 3.5% in the adult-kidney only group by West et al. ients. Teenan et al. (40) examined 33 renal transplant recipients (34). In this particular study, young recipient age (Ͻ5 yr), by endoscopy 2 to 4 mo after transplantation and identified 16 female gender, treatment of rejection with monoclonal anti- patients with duodenitis, 10 patients with gastritis, and 4 pa- bodies, antibiotic use, and intra-abdominal graft placement tients with gastric ulcer. H. pylori was found in the gastric increased the incidence of disease. Transplant recipients can be antrum of 16 patients (48%) and was strongly associated with asymptomatic carriers of C. difficile but can also develop symptomatic dyspepsia, gastritis, and peptic ulceration. Al- diarrhea, intestinal obstruction, abscess, and toxic megacolon. though this was a small study, there was no relationship be- Treatment with oral metronidazole in less severe cases and tween H. pylori colonization and either cyclosporine levels or vancomycin in severe C. difficile colitis is very effective. steroid dose. H. pylori infection is also widely prevalent among heart transplant recipients, but its prevalence is not higher than Parasitic Infections that seen in the general population. Huwez et al. (41) studied Another consequence of immunosuppression is susceptibil- 47 heart transplant recipients with endoscopy to assess the ity to infection by protozoan or metazoan parasites. Microspo- opportunistic infections of the GI tract. H. pylori was found in ridia are obligate intracellular protozoan parasites. GI infection 23 (49%) patients; 17% had gastritis, 17% had duodenitis, 30% due to microsporidia is the most common cause of diarrhea in had reflux disease. Eight (35%) of these H. pylori–positive patients with HIV infection. Gumbo et al. (35) described four patients had GI symptoms, and infection recurred or persisted cases in which microsporidial infection led to unexplained in half of the patients treated with triple therapy; this is a lower chronic diarrhea, fatigue, and weight loss in solid organ trans- eradication rate than the general population, which raises the plant recipients. The authors speculated that microsporidial possibility of immunosuppression hindering the clearance of infection is underdiagnosed because suspicion is low and the H. pylori. We recommend full investigation, including endos- organism is not detected by routine stool examination. Since copy with biopsies, in patients with possible H. pylori infection patients can remain infected for several years, with intermittent before treatment with antibiotics. symptomatic periods, it has been suggested that transplant recipients with chronic, unexplained diarrhea in the late post- Mucosal Injury and Ulceration transplantation period should have stools examined with a Diarrhea modified trichrome stain, which can detect microsporidia. In- In addition to infectious causes, diarrhea can be caused by fection with the nematode Strongyloides stercoralis has been certain immunosuppressive drugs. The three large trials involv- reported to lead to fever, abdominal pain, bloody diarrhea, ing tacrolimus, comprising a total of almost 1500 patients, abdominal distension, nausea, and vomiting in renal transplant suggest that GI side effects are more common with tacrolimus recipients. Rarely, patients can present with acute respiratory than CsA (1,2,16). All three trials show increased rates of illness caused by the migration S. stercoralis through the lungs. tacrolimus-associated diarrhea; in two of the three, the differ- Hyperinfection can occur and is associated with high mortality ence was substantial (2.2 times and 1.5 times, respectively) (36). The diagnosis should especially be considered in patients (2,16). All three trials also suggest that nausea and vomiting from endemic areas such as the West Indies or the Far East. are more common with tacrolimus. Dyspepsia and constipation Interestingly, the risk of hyperinfection in transplant recipients also appear somewhat more common with tacrolimus, as does markedly decreased in the CsA era. It is recommended that any abdominal pain. Possibly adding to a dosage-dependent effect potential living donor with a history of infection with S. ster- on adverse events is the fact that 30 of the 268 tacrolimus coralis should be examined for the presence of larvae in stools patients in the US liver transplant trial were 12 yr of age or and urine. Before transplantation, treatment with thiabendazole younger. The severity of tacrolimus-associated GI side effects should be instituted until the infection is eradicated. In the case is uncertain. Some reports suggest that these GI problems have of a transplant recipient, thiabendazole or ivermectin should be a relatively mild course, which can generally be managed with prescribed (37,38). Although thiabendazole competes for me- dosage reduction. For example, in the study by Mayer et al. tabolism sites in the liver with xanthine-type drugs (theophyl- (16), none of the 303 patients in the tacrolimus groups had their line, caffeine), there is no interaction with calcineurin inhibi- study medication discontinued because of a GI event. In the tors. There are no reported drug interactions between study by Pirsch et al. (1), only 3 (1.5%) of 205 tacrolimus ivermectin and calcineurin inhibitors in the literature, but im- patients crossed over to CsA because of GI events. However, munocompromised hosts may require repeated treatment with other reports suggest that GI events due to tacrolimus may be this drug for complete recovery. Microsporidial infections re- more severe and difficult to manage. In one study, 7 (6%) of spond well to treatment with metronidazole (35). 122 patients taking tacrolimus had unusually serious GI out- J Am Soc Nephrol 13: 277–287, 2002 GI Complications of Immunosuppression 281 comes, with 6 requiring prolonged parenteral nutrition to deal thereby delay diagnosis and treatment (5). In fact, many ulcers with the secondary effects of anorexia (42). in transplant recipients are entirely asymptomatic. In one study, Two large trials with MMF demonstrated rates of diarrhea in only 39% of patients (7 of 18) with endoscopically proven the MMF groups to be between 1.3 and 1.9 times those in the ulcers had symptoms (50). However, in cases of GI perforation AZA groups (6,11). In many event categories, the highest rates and peritonitis among steroid-maintained patients, clinical were found in the MMF 3-g/d group, which suggests a dose- findings of fever and abdominal pain develop with some con- dependent effect. According to The US Renal Transplant My- sistency, occurring in 91% and 84%, respectively, in one series cophenolate Mofetil Study, the rates of drug discontinuation (52). specifically attributable to GI adverse events were 6.7% for GI bleeding, when it occurs, is often secondary to ulceration. AZA, 3.6% for MMF 2 g/d, and 8.4% for MMF 3 g/d at 3-yr Among 1000 consecutive liver transplantations, there were 92 follow-up (43). episodes of GI bleeding in which endoscopic diagnoses were A number of possible mechanisms for MMF-associated di- made (53). Of these 92 episodes, ulcers (gastric, duodenal, or arrhea have been proposed, such as inhibition of colonic crypt esophageal) were the most common cause of bleeding (25 of cell division possibly due to immune-mediated mechanism as 92 episodes), the second most common cause being non-CMV well as loss of normal villous structure in the duodenum enteritis (gastritis, colitis, duodenitis, esophagitis, or ileitis): 24 (44,45). There are also a few reports of nausea and diarrhea of 92 episodes. with rapamycin use in the literature (46–48). In lung transplant recipients, giant gastric ulcers (defined as Dose manipulation, reduction of total dosage, and/or dose gastric ulcers with a diameter Ͼ3 cm) may occur. These large splitting (e.g., changing two times daily dosing to four times ulcers are associated with high morbidity and mortality sec- daily) of certain immunosuppressive drugs, such as MMF and ondary to bleeding and may develop despite routine use of tacrolimus, is an important strategy to manage GI toxicities, H2–receptor antagonists (3). Possible factors contributing to particularly diarrhea, in transplant recipients. In many patients, these ulcers are reported as bilateral lung transplantation, high- such manipulations reduce the intensity and duration of symp- dose oral NSAIDs for at least 1 wk after transplantation, toms (6,10,49). high-dose intravenous steroids for acute rejection, and CsA immunosuppression. A retrospective study of kidney transplant Ulceration of the GI Tract recipients by the same authors did not find giant gastric ulcers, Multiple factors contribute to ulcer formation in transplant making it uncertain whether these large ulcers are specific to patients. Examples include the stress of surgery, the use of lung transplantation. We believe that NSAIDs should not be nonsteroidal anti-inflammatory drugs (NSAIDs), the use of used in transplant recipients. steroids, and the possible impairment of native gastroduodenal There are no demographic or clinical features that readily cytoprotection due to an AZA- or MMF-induced slowing of identify all patients at increased risk of upper GI ulcers. There- intestinal cell turnover (50). In kidney transplantation, a num- fore, a high degree of clinical suspicion is called for, coupled ber of additional ulcer-producing factors may come into play, such as increased gastric acid secretion during posttransplan- with a low threshold for endoscopy with tissue sampling for tation dialysis, the possible ulcer-causing effect of heparin used histology, microbiology, and virology (5). In fact, ulcers may during dialysis, and elevated postoperative histamine and gas- be both common and frankly asymptomatic in the renal trans- trin levels (50). plant setting, yet may cause significant morbidity or mortality The role of steroids in peptic ulcer is still controversial. A when they become apparent. One center used routine endos- meta-analysis of a large number of patients on steroids by copy 7 to 14 d after transplantation, even when H2-receptor Conn et al. (51) revealed that peptic ulcer was a rare compli- antagonists are used routinely (50). In view of the decreased cation of corticosteroid therapy. On the other hand, another incidence and severity of peptic ulcer in recent years, routine study by Steger et al. (50) demonstrated that there was a trend endoscopy in asymptomatic patients is not recommended in for those patients treated with methylprednisolone for rejection transplant recipients. to develop more ulcers or inflammatory lesions. It is most Prophylaxis against posttransplantation GI ulceration may likely that the development of peptic ulcer in transplant recip- include one or more methods designed to reduce acid secretion ients is multifactorial. In the modern transplant era, upper GI or protect the mucosa from the effects of acid. These methods ulcers have an overall low incidence after renal transplantation. include H2-receptor antagonists (e.g., ranitidine), proton-pump For example, in a series of 1034 renal transplants in patients inhibitors (e.g., omeprazole), coating agents (e.g., sucralfate or receiving CsA-based immunosuppression and antacids as the bismuth-containing agents), and prostaglandins (misoprostol). sole routine ulcer prophylaxis, 33 patients experienced a total For example, one group used ranitidine, sucralfate, or ome- of 41 endoscopy-proven ulcers, of which 15 bled and 1 (per- prazole for approximately the first 3 mo after transplantation forated) was fatal. Of the 41 ulcers, 19 (46%) were duodenal, (without specifying criteria, if any, for choice of agent and 17 (42%) were gastric, and 5 (12%) were esophageal (5). without giving efficacy data) (10). One pediatric group re- Although the overall incidence is low, ulcers tend to occur at ported using acid-reducing therapy for at least the first year highly variable and unpredictable intervals (5). Further com- after transplantation; specifically, ranitidine 0.8 mg/kg per dose plicating diagnosis is the fact that steroids frequently mask the intravenously three times daily starting at transplantation and clinical symptoms of ulcers (and other GI disorders) and converting to omeprazole or lansoprazole dosed by weight 282 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 277–287, 2002 when the child tolerates oral medication without a nasogastric tified 20 cases of diverticular disease among older patients, feeding tube (54). more than a quarter of which were associated with adult In one series, prophylaxis of severe GI bleeding after renal polycystic disease. None of these 20 patients underwent pre- transplantation with omeprazole was at least as effective as transplantation colectomy, and none developed posttransplan- ranitidine (55). The researchers noted additional advantages, tation symptomatic colon disease. Most of these patients were such as prolonged effect and a simple dosage, which does not younger at the time of transplantation so would not have require any adjustment on the basis of graft function develop- received screening studies. On the basis of these findings, we ment. In another study, misoprostol (prostaglandin E1 ana- recommended abandoning the practice of pretransplantation logue), when used in combination with antacid and ranitidine, colonic screening in asymptomatic patients Ͼ50 yr of age. was more effective than the combination of antacid and rani- Screening should be done selectively in certain transplant tidine, either alone or with bismuth, in preventing peptic ulcer candidates, especially patients with polycystic kidney disease, disease in kidney transplant patients (56). with documented active diverticulitis/complications or symp- Attempts to protect against ulcers can complicate immuno- toms suggestive of diverticular disease by either barium enema suppressive management by several mechanisms. CsA levels or colonoscopy. may be altered by concomitant administration of cimetidine or ranitidine, and cimetidine may falsely elevate serum creatinine Perforations levels by blocking the tubular secretion of creatinine. Routine Perforations of any part of the GI tract can occur in trans- treatment with sucralfate can hinder absorption of CsA. Pro- plant patients, although the colon may be the most common ton-pump inhibitors (e.g., omeprazole) can alter CsA levels, site. In one series of 1401 consecutive renal transplants, 30 and both H2-antagonists and proton-pump inhibitors may, by patients (2.1%) had a total of 34 episodes of colonic perfora- reducing acid secretion, alter upper gut flora and thus poten- tion, 13 (38%) of which were fatal (52). The causation is often tially increase the chance of colonization with undesirable multifactorial, with lower GI perforation often secondary to a organisms (e.g., causing fungal esophagitis) (5). Because of combination of diverticular disease and impairment of GI these possible complications, some transplantation groups do histologic integrity due to NSAIDs, steroids, and other immu- not routinely provide ulcer prophylaxis. nosuppressive agents (8). Endoscopy is important not only in diagnosis but also in Two patterns of lower GI perforation have been reported by treatment. Many bleeding gastric ulcers can be controlled with Stelzner et al. (52) in renal transplant patients, with one pattern endoscopic procedures such as injection of epinephrine or occurring early after transplantation and the other usually oc- alcohol, use of heater probes, or vicaps electrodes (57). In a curring late. In the early pattern, perforation occurs most com- series of 41 consecutive, endoscopy-proven ulcers, 96% were monly in patients with renal failure who are undergoing dial- successfully managed nonsurgically (5). Because medical ysis and have had heavy immunosuppression, particularly with management of identified ulcers is almost always successful, corticosteroids. These early perforations are considered to be surgical management should be considered only for primary largely attributable to diverticulitis or CMV colitis. In the late surgical indications (e.g., perforation) or failure of medical or pattern, perforation may occur years after transplantation and is endoscopic therapy. In the subset of patients who require thought to be largely attributable to diverticulosis or malig- surgical intervention for bleeding gastric ulcers, a technique nancy, such as clinically unrecognized lymphoma. The authors involving simultaneous laparotomy and endoscopy may obvi- acknowledge that these patterns are not fully inclusive, and a ate the need for gastrotomy, thus reducing the risk of surgical variety of other factors have been associated with lower GI contamination (57). complications. Steroids have been implicated as a cause of spontaneous colonic perforation in otherwise normal popula- Diverticular Disease tion as well as transplant recipients (62,63). A recent report Diverticular disease has been reported in up to 42% of suggests that MMF may be associated with colonic ulceration patients with ESRD (58). Complicated diverticulitis defined as in a few patients (64). Fungal infections such as mucormycosis diverticulitis involving free perforation, abscess, phlegmon, or have also been reported as a cause of gastric perforation in fistula after renal transplantation was reported as 1.1% in a transplant recipients (65). In recent years, new antibiotics, recent study by Lederman et al. (59). In this particular study, more sensitive diagnostic modalities, such as computed tomog- clinical presentation varied from asymptomatic pneumoperito- raphy scan, early and aggressive surgery, and corticosteroid- neum to generalized peritonitis. It has also been reported that sparing regimens helped to decrease the incidence and severity renal transplant recipients with polycystic kidney disease had of colonic perforation. increased incidence of gastrointestinal diverticular disease and colonic perforation without any clear explanation (59,60). Biliary Tract Disease However, even when risk factors are known, predicting colonic Organ transplant recipients are at high risk for complications complications has proved difficult. In a series of 1186 renal of biliary calculi. Cholecystectomy after transplantation is of- transplants performed at Vanderbilt University, we found that ten carried out emergently and has a high mortality rate (66). In pretransplantation colonic screening of older patients (Ͼ50 yr) a study of 178 heart, lung, or heart-lung transplant recipients, was ineffective in predicting posttransplantation colonic com- 65 (37%) had documented biliary tract disease, including plications (61). For example, in this particular study, we iden- thickened gall bladder wall, sludge, dilated bile ducts, gallblad- J Am Soc Nephrol 13: 277–287, 2002 GI Complications of Immunosuppression 283 der hydrops, and cholelithiasis (66). In patients who underwent transplant recipients. Computed tomography scan usually dem- operation for biliary disease after transplantation, intervention onstrates various degrees of inflammation, edema, necrosis of was mandated by acute complications of biliary tract disease pancreas, extension of edema or fluid in peripancreatic tissue with a mortality rate of 29%. It has been previously reported or multiple fluid collections in the pancreatic region. Treatment that pancreaticobiliary disease occurs 17.4 times more fre- of pancreatitis in transplant recipients include cessation of quently in heart transplant recipients than in the general pop- possible offending agent, fasting, intravenous fluids, parenteral ulation (67). The risk was much higher in the first 2 yr after nutrition if needed, pain management, and surgery, which transplantation in that particular study. Although the etiology might be life-saving in severe cases. of increased biliary tract disease after transplantation is still not very clear and mostly multifactorial, cyclosporine therapy was Gastrointestinal Malignancy shown to be associated with increased incidence of gallstones It has been clearly demonstrated that the risk of cancer in due to an increased cholestasis and reduced bile flow in ani- transplant recipients is higher than in the general population mals (68,69). Cholelithiasis was also reported more frequently (79,80). Although the common types of cancer in the general in a group of renal transplant recipients using cyclosporine/ population, such as carcinomas of the lung, prostate, and breast prednisone compared to a group of patients treated with AZA/ are not increased in transplant patients, certain cancers that are prednisone (70). uncommon in the general population such as lymphomas, skin Current recommendations for the management of biliary cancers, and Kaposi sarcoma occur more often in transplant disease in transplant recipients include eradication of all biliary recipients. In a large study of 62,088 first cadaver kidney calculi, electively, before transplantation and on diagnosis after recipients and 10,988 first heart recipients antedating 1994, transplantation before the patients get really sick, and careful there was no change in the observed incidence of gastric cancer posttransplantation ultrasound surveillance of the biliary tree in transplant recipients compared to general population (81). because of the accelerated development of gallstones after On the other hand, colon cancer was increased, although not transplantation. statistically significantly; rectal cancer was significantly re- duced. Danpanich et al. (82) reported 11 colorectal malignan- Pancreatitis cies (12.6%) in 87 renal transplant recipients. The authors Acute pancreatitis (AP) is an uncommon but a very serious identified that the risk of cancer in renal transplant recipients complication in transplant recipients. The incidence of AP has increases significantly by age at transplantation, pretransplant been reported to be 3 to 5.7% in orthotopic liver transplant splenectomy, a history of invasive cancer pretransplant, and recipients, with a mortality rate of up to 64% (71,72). Under- cigarette smoking. In a study of 174 liver transplant recipients lying factors to each episode of pancreatitis were identified as who survived at least 1 yr, 12% of patients developed de novo biliary manipulation, history of recent ingestion of alcohol, malignancies, including three patients (all transplanted for pri- hepatitis B infection, and malignancy in the region of the mary biliary cirrhosis) with colon cancer (83). The relative risk pancreas. In renal transplant recipients, AP was reported to be for colon carcinoma was 12.5, which was statistically signifi- 1 to 2.3% with a high mortality rate up to 100% (73,74). CMV, cant. Since several transplant centers reported increased inci- hypercalcemia, alcohol, cholelithiasis, and immunosuppression dence of colon cancer in patients with primary sclerosing are the most common precipitating factors for AP. A 30-fold cholangitis and ulcerative colitis, regular screening with annual difference in the incidence of AP between the heart transplant surveillance colonoscopy after transplantation in these partic- recipients and nontransplant cardiopulmonary bypass patients ular patients is recommended (84,85). (3.0 versus Ͻ0.1%; P Ͻ 0.05) in a recent study reported by Posttransplantation lymphoproliferative disorder (PTLD) Herline et al. (75). There was an eightfold difference in mor- can involve GI tract up to 10% of transplant recipients. Un- tality between the transplant patients with and without pancre- fortunately, PTLD involvement of the GI tract is not readily atitis (33% versus 4%), although this did not reach statistical accessible as abnormal lymph node enlargements for early significance in this particular study. It has been reported in diagnosis. Acute abdomen from perforation or obstruction and both animal studies and human clinical trials of transplantation GI bleeding can occur late in the disease process. In a retro- and GI diseases, such as Crohn disease, that there is a possible spective study of 172 pediatric liver transplant recipients, GI association between azathioprine and AP (76,77). Soderdahl et symptoms occurred in 38.5% of EBV-infected patients and al. (78) compared the incidence of pancreatitis between 327 43% of patients with GI symptoms (mostly GI bleeding) de- renal transplant recipients treated with azathioprine and ste- veloped PTLD (86). O’Connor et al. (87) evaluated 24 pedi- roids (AZA group) and 321 patients who received cyclosporine atric liver transplant recipients with abdominal pain, vomiting, and low-dose steroid (CsA group). The incidence of pancre- hematemesis, anemia, growth failure, and suspected PTLD. In atitis decreased from 4.6% in the AZA group to 1.2% in the six patients, endoscopy revealed the characteristic finding of CsA group (P Ͻ 0.05). There are also reports implicating CsA, raised, rubbery, and erythematous lesion with a central ulcer- especially high serum trough levels, and steroids in AP, but ation (B lymphocytes ϩ EBV on biopsy) located predomi- without convincing experimental or clinical evidences. Drug- nately in the colon or stomach. Authors recommended endos- induced pancreatitis in transplant recipients can be severe, copy and biopsy in transplant recipients who have GI sometimes lethal. Computed tomography plays a very impor- symptoms associated with positive EBV serologies to rule out tant role in the diagnosis and follow-up of pancreatitis in PTLD. 284 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 277–287, 2002

Low-grade, gastric mucosa-associated lymphoid tissue– duce the consequences of these management problems in trans- type lymphomas are also reported in transplant recipients plant recipients. (88). These lymphomas are rare, can be associated with H. pylori, and are treated with a variety of modalities, including reduction of immunosuppression, antibiotics, surgery, and References chemotherapy. 1. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS: A A clinical suspicion is mandatory for the diagnosis of PTLD comparison of FK506 (FK506) and CsA for immunosuppression after cadaveric renal transplantation. Transplantation 63: 977– in transplant recipients, especially in the GI tract. Endoscopy is 983, 1997 the most useful tool for diagnosis and treatment of PTLD 2. The U.S. Multicenter FK506 Liver Study Group: A comparison involving GI tract as well as monitoring the response to ther- of FK506 (FK506) and CsA for immunosuppression in liver apy. 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The Tricontinental Mycophenolate Mofetil Renal Transplanta- relative frequency of GI side effects among immunosuppres- tion Study Group: A blinded, randomized clinical trial of myco- sants have to some extent been skewed by reduced rates of phenolate mofetil for the prevention of acute rejection in cadav- toxicities of some of the newer immunosuppressive drugs, eric renal transplantation. Transplantation 61: 1029–1037, 1996 which could lead to greater clinical emphasis on the GI events 7. Sakr M, Hassanein T, Gavaler J, Abu-Elmagd K, Fung J, Gordon R, Starzl T, Van Thiel D: Cytomegalovirus infection of the upper by both physician and patient. GI tract following liver transplantation—Incidence, location, and Whatever immunosuppressive regimen is used, certain pre- severity in CsA- and FK506-treated patients. Transplantation 53: cepts of GI prophylaxis and management apply to reduce the 786–791, 1992 incidence and impact of the clinical entity. Antiviral and/or 8. 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