Portal de Periódicos da CAPES

Gastrointestinal Complications of Transplant Immunosuppression

2002; American Society of Nephrology; Volume: 13; Issue: 1 Linguagem: Inglês

10.1681/asn.v131277

1533-3450

J. Harold Helderman, Simin Göral,

Renal Transplantation Outcomes and Treatments

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 obtained from biopsy samples of patients who are negative for visual endoscopic findings; the relevance of such biopsy findings is unclear. Demonstration of CMV in peripheral blood by direct detection of antigenemia or by PCR technique provides a great tool for diagnosis of early active CMV infection. Prophylaxis for CMV infection after transplantation was reviewed extensively elsewhere (17). Studies for CMV prophylaxis that rely exclusively on acyclovir have produced inconsistent results. Among CMV-positive liver transplant recipients, 2 g/d of oral acyclovir for 16 wk after transplantation was significantly better than placebo in preventing CMV disease (CMV incidence was 5% in the acyclovir group and 27% in the placebo group) (18). In contrast, among 18 renal transplant patients who received oral acyclovir in dosages from 600 to 4000 mg/d for 4 to 7 mo after transplantation, CMV disease developed in 12 patients (67%), leading the researchers to conclude that other strategies of CMV prophylaxis should be sought (19). Studies using acyclovir in combination with ganciclovir have generally produced good results. In a series of 170 consecutive kidney transplantations, prophylaxis with acyclovir, combined with ganciclovir during acute rejection and in cases of delayed graft function, gave good protection against CMV infections and prevented CMV disease (20). Among 167 liver transplant patients randomized to either 120 d of antiviral prophylaxis with acyclovir 800 mg orally four times daily or 14 d of ganciclovir (5 mg/kg) intravenously every 12 h followed by oral acyclovir 800 mg four times daily, the sequence of ganciclovir followed by acyclovir was more effective than acyclovir alone in reducing CMV infection and disease (21). Other studies suggest that ganciclovir can be used effectively alone for CMV prophylaxis. Among 44 renal transplant patients randomized to either placebo or 750 mg of oral ganciclovir twice daily for 12 wk after renal transplantation, ganciclovir had a significant impact on the occurrence of CMV infections during the first 9 mo posttransplantation, irrespective of the CMV status of donor or recipient and of treatment for acute rejection episodes (22). In another study of kidney transplant patients randomized to receive either oral acyclovir (800 mg four times daily) or oral ganciclovir (1000 mg three times daily) for 3 mo, ganciclovir-treated patients had a much lower rate of CMV infection during a mean of 14.4 mo of follow-up (23). The cumulative infection rate at 6 mo was 35.9% for acyclovir and 2.5% for ganciclovir. Similar results were reported in liver transplant recipients (24). A recent study of valacyclovir among 616 D+/R− and R+ renal transplant patients randomized to either placebo or 2 g of valacyclovir four times daily for 90 d demonstrated that valacyclovir significantly reduced the occurrence of CMV disease at 6 mo (25). Although, none of these studies demonstrated specifically that GI involvement of CMV is decreased with general CMV prophylaxis, an intensive prophylactic strategy to decrease the morbidity and mortality from CMV infection is particularly important and necessary in the high-risk (recipient negative/donor positive) patient group. In established CMV infection, ganciclovir is the drug of choice for treatment in all organ transplants followed by foscarnet. Ongoing trials of valganciclovir, an orally administered valine ester of ganciclovir, will provide information whether this agent would be effective for CMV prophylaxis or treatment in transplant recipients. Herpes Simplex Virus. Herpes simplex virus (HSV) is second only to CMV among viral agents that cause clinical infection in transplant patients. It usually presents as a reactivation of the latent virus mostly within the first 6 wk after transplantation. HSV can affect many parts of the GI tract. In addition to mild, ulcer-like mucocutaneous lesions, especially in the oral cavity and pharynx, another common site for infection is the esophagus, with one group reporting esophagitis in 5 of 221 renal transplant patients (2.2%) over an 8-yr period (26). All cases developed during the treatment of acute rejection with high-dose steroids and antilymphocyte preparations. Patients with HSV infection after transplantation usually present with odynophagia or dysphagia as well as orocutaneous HSV lesions, although the orocutaneous complaints in some patients may develop after the appearance of esophagitis. Endoscopy can reveal shallow ulcers surrounded by typical vesicles, discrete or coalescent ulcers, and pseudomembranous lesions mimicking a cutaneous senile lesion. It is a common belief that symptoms of odynophagia or dysphagia in the setting of intensive immunosuppression must be investigated endoscopically without delay as untreated herpetic ulcers can progress to hemorrhage, which may even be fatal, or to esophageal perforation. Because endoscopic appearance may vary, endoscopic biopsy for histology, immunohistochemistry, and viral cultures is necessary. Transplant physicians must have a high level of suspicion during periods of increased immunosuppression for HSV infection. Simple mucocutaneous lesions can be treated with a short course of oral acyclovir. Extensive and more serious cases may need to be treated with IV acyclovir or ganciclovir when there is also concomitant CMV or Epstein-Barr virus (EBV) infection. Fungal Infections Because of several risk factors, such as frequent antibiotic therapy, steroid use, hyperglycemia, indwelling catheters, and impaired cellular immunity, opportunistic fungal infections are very common, especially the first couple of months after surgery in transplant recipients. Although many fungal infections can affect the GI tract, candidiasis is the most common. Candidal Infection. Candidal infection most typically presents in the immunosuppressed transplant patient as esophagitis with or without oral thrush. Risk factors associated with invasive candidal infections include administration of broad-spectrum antibiotics, recent treatment for acute rejection with high-dose steroids or antibodies, and the presence of a Roux-en-Y choledochojejunostomy in patients with liver transplantation. Candida esophagitis usually presents with odynophagia or dysphagia. Less commonly, patients may present with fever, heartburn, epigastric pain, or GI bleeding. Lesions may include superficial erosions, ulcers, and white nodules or plaques. Identification of lesions is important because the infection may be severe and necrotizing, which may result in perforation (27). Perforation with formation of tracheoesophageal fistulas has also been reported (28). The responsible species is most commonly either Candida albicans or Candida tropicalis (4). Fungal infection may occur in conjunction with systemic CMV infection. Of a series of 66 CMV-positive liver transplant recipients, candidal esophagitis developed in 3 (29). The diagnosis of candidal infections is made by fungal cultures or histopathologic examination of appropriate specimens. Therapy includes topical antifungal preparations (nystatin, amphotericin B oral solutions) and oral or intravenous antifungal agents. Liposomal amphotericin B preparations are less nephrotoxic than the regular amphotericin B but are more expensive. Different transplant programs have different incidences of invasive fungal infections; therefore, prophylaxis may vary from one program to another. For prophylaxis of upper GI fungal infection, the use of nystatin swish and swallow every 6 h for 6 mo after induction and after each rejection treatment has been described as well as oral clotrimazole and oral amphotericin B in renal transplant recipients as effective (5). In 212 liver transplant recipients who received fluconazole (400 mg/d) until 10 wk after transplantation, fungal colonization decreased significantly compared with placebo (28% versus 90%) (30). In addition, proven fungal infection occurred in 43% of placebo recipients but in only 9% of fluconazole recipients (P < 0.001). Interestingly, infection and colonization by organisms intrinsically resistant to fluconazole did not increase, which is a concern because of the potential for the emergence of fluconazole-resistant Candida species in patients given prophylactic fluconazole. No hepatotoxicity was observed in this particular group of patients. It has been recommended to monitor serum cyclosporine levels closely in patients treated with prophylactic fluconazole because of the interaction between the two drugs. For liver transplant recipients, it was suggested to use the prophylactic fluconazole only in high-risk groups of patients, such as recipients with previous CMV infection, multiple transfusions, and retransplantation (31). The optimal duration of prophylaxis and the antifungal agent are still not standardized. Bacterial Infections Bacterial infections of the GI tract are not uncommon in transplant recipients. Examples include Yersinia enterocolitica and Clostridium difficile colitis. Such infections may be more prevalent in patients with systemic CMV infection (29). Yersinia septicemia can occur especially in patients with iron loading, diabetes mellitus, chronic liver disease, OKT3 use, and high aluminum store, which might contribute an additional risk factor to immunosuppression (32,33). Patients usually present with GI symptoms, such as diarrhea and abdominal tenderness, and rarely with erythema nodosum, arthritis, myocarditis, meningitis, and acute renal failure. Antibiotic treatment is efficient to cure the disease. Although its true incidence among transplant recipients is not well known, the overall incidence of C. difficile colitis was recently reported as 8%, with 16% in the pediatric kidney transplant group, 15.5% in the combined kidney-pancreas group, and 3.5% in the adult-kidney only group by West et al. (34). In this particular study, young recipient age ( 3 cm) may occur. These large ulcers are associated with high morbidity and mortality secondary to bleeding and may develop despite routine use of H2–receptor antagonists (3). Possible factors contributing to these ulcers are reported as bilateral lung transplantation, high-dose oral NSAIDs for at least 1 wk after transplantation, high-dose intravenous steroids for acute rejection, and CsA immunosuppression. A retrospective study of kidney transplant recipients by the same authors did not find giant gastric ulcers, making it uncertain whether these large ulcers are specific to lung transplantation. We believe that NSAIDs should not be used in transplant recipients. There are no demographic or clinical features that readily identify all patients at increased risk of upper GI ulcers. Therefore, a high degree of clinical suspicion is called for, coupled with a low threshold for endoscopy with tissue sampling for histology, microbiology, and virology (5). In fact, ulcers may be both common and frankly asymptomatic in the renal transplant setting, yet may cause significant morbidity or mortality when they become apparent. One center used routine endoscopy 7 to 14 d after transplantation, even when H2-receptor antagonists are used routinely (50). In view of the decreased incidence and severity of peptic ulcer in recent years, routine endoscopy in asymptomatic patients is not recommended in transplant recipients. Prophylaxis against posttransplantation GI ulceration may include one or more methods designed to reduce acid secretion or protect the mucosa from the effects of acid. These methods include H2-receptor antagonists (e.g., ranitidine), proton-pump inhibitors (e.g., omeprazole), coating agents (e.g., sucralfate or bismuth-contai