Objectives: Intestinal perforation remains a clinical challenge and potentially lethal complication in renal transplant recipients. Immunosuppression not only places the patient at risk for intestinal perforation but also masks classic clinical symptoms and signs of acute abdominal pain, leading to delayed diagnosis and proper treatment. The aim of our study is to present the experience of our center on the treatment of intestinal perforation in renal transplant recipients.

Materials and Methods: This study reported 11 patients (0.52%) with intestinal perforation among a group of 2123 patients who received renal transplants in the Transplantation Unit at Laikon General Hospital in Athens, Greece from 1983 to August 2015.

Results: One patient died from septic shock before any surgery, and 3 patients died during the early postoperative period, resulting in a morality rate of 36.3%. All patients who died had a functioning graft. From the patients who were discharged, the mean follow-up was 16 months (range, 4-32 months).

Conclusions: Intestinal perforation after renal transplant is a major and potentially lethal com­plication. Clinical presentation is usually equivocal, and the transplant surgeon should be highly suspicious when treating a renal transplant recipient with acute abdominal pain, even in cases without other predisposing factors (diverticulitis, ischemic colitis, and so forth), so that this condition could be investigated and unmasked.

Key words : Diverticulitis, Immunosuppression

Introduction

Intestinal perforation (IP) after renal transplant is a major and dangerous complication. The interval time between IP and renal transplant varies from days after the transplant to years.¹ Various predisposing factors leading to IP in renal transplant recipients have been suggested: immunosuppression, diverticulosis, uremia with reduced tissue strength and wound healing capacity, chronic constipation, and atherosclerotic changes of the colon.¹ The symptoms and signs of IP are often absent or less impressive due to immunosuppressive therapy; steroids also impair the patient’s ability to localize or contain an abdominal infection, which can lead to delayed diagnosis and devastating clinical outcomes.^1,2  Thus, there is a high mortality rate among renal transplant recipients with IP, ranging from 25% to 68%.3,4 However, recent studies have demonstrated decreased mortality ranges; this can be attributed to multiple factors such as awareness, decreased steroid use and improved antibiotics, better diagnostic tools, and earlier surgical solution.^3-5

The aim of our study is to present the experience of our center on the epidemiology, clinical features, and treatment of IPs in renal transplant recipients.

Materials and Methods

From 1983 to August 2015, our Transplantation Unit at Laikon General Hospital (Athens, Greece) had 2123 patients who underwent renal transplant. Of these patients, 1069 received their grafts from deceased donors and 1054 from living-related donors. Eleven patients presented with IP, and their medical records were reviewed for age, gender, type of primary renal disease, type of renal transplant, immunosuppressive therapy, interval from transplant to colonic perforation, period between onset of symptoms and operative treatment, location of the perforation, clinical presentation, laboratory findings, type of operation, radiographic findings, and outcomes.

Additionally, we took into consideration the 3 eras of immunosuppression: (1) the azathioprine era from 1983 to the late 1980s, (2) the cyclosporine era from the late 1980s to present in which the calcineurin inhibitors cyclosporine and tacrolimus were the mainstay of recipient immunosuppression, and (3) the mammalian target of rapamycin inhibitor era starting in the year 2000.

The usual immunosuppressive regimen ac­cording to our clinic protocol was basiliximab or daclizumab induction and maintenance with methylprednisolone of 20 to 40 mg/d and dose reduction at 4 mg/d over 3 months, mycophenolate mofetil of 1000 to 2000 mg/d, and a calcineurin inhibitor such as cyclosporine (3-5 mg/kg/d) with a preferred level of a preferred level of cyclosporine of 800 to 1000 ng/mL or tacrolimus (0.05-0.1 mg/kg/d) with a preferred level of 6 to 8 ng/mL.

Results

In our unit, IP occurred in 11 patients (0.52%), with male-to-female patient ratio of 2.7/1 among 2123 renal transplant recipients. Mean age was 49 years (range, 33-65 years) at the time of perforation. Six of our patients (55%) had primary renal disease (glomerulonephritis), 2 had adult polycystic kidney disease, 2 had glomerulosclerosis, and 1 had renal hypoplasia.

Most patients (73%) received deceased donor kidney graft, with mean interval from transplant to perforation of 58 months. However, this interval had fluctuations over a wide range (5 days to 18 years).

A lack of classic signs and symptoms of IP in immunosuppressed renal transplant recipients leads to difficulties in diagnosis. Although abdominal pain was present in all of our patients with a wide variation in its severity, leukocytosis and radio­graphic findings pointing to perforation were lacking in 2 patients. Despite these difficulties, in most cases, the diagnosis was immediate and the patient underwent surgical treatment at the onset of symptoms. However, in 3 patients, surgical treatment was delayed from 3 to 8 days due to equivocal clinical picture.

The cause of perforation was diverticulitis in about half of the cases; however, ischemia (1 patient), tuberculosis ileitis (1 patient), perforation after colonoscopy in an ischemic background (1 patient), and spontaneous perforation (2 patients) were found as the remaining causes. Viral examination (Cytomegalovirus, varicella zoster virus, toxoplasma, Epstein-Barr virus) was negative for acute infection at the time of diagnosis.

The most common site of perforation was sigmoid colon (8 patients; 73%), with perforations of the jejunum, cecum, and terminal ileum occurring in the other 3 patients. Almost all patients who required surgical treatment had surgery, with the exception of 1 patient who died on sepsis before any therapeutic intervention.

The Hartmann procedure was performed in 7 of the 8 patients with sigmoid perforation (the other patient was the one who died before reaching surgical intervention). In 2 patients with small bowel perforation, segmental resection at the level of jejunum or terminal ileus with primary anastomosis was performed. In a patient with perforation in the cecum, right hemi-colectomy with ileotransverse anastomosis and loop ileostomy due to ischemic background were performed.

The most common immunosuppression regimen was cyclosporine, azathioprine, and methylpre­d­nisolone (50%); however, cyclosporine and methyl­prednisolone alone or in combination with mycophenolate mofetil were the immunosuppression regimen administered in 3 patients. Nine patients received calcineurin inhibitors (tacrolimus or cyclosporine). Three of the patients had previous acute rejection episodes (treated with ATG), and 4 patients were in chronic rejection status (diagnosis set by Modification of Diet in Renal Disease values and kidney biopsy).

The mortality rate was found to be high (36.4%); 2 patients died during the early postoperative period (30 days) due to septic shock and 1 due to multiple organ failure. One patient has remained (115th postoperative day) in the intensive care unit due to inability to wean from the ventilator. All patients who died had a functioning graft. From the patients who were discharged, the mean follow-up was 16 months (range, 4-32 months). No patient was lost during follow-up.

Table 1 summarizes the epidemiology and the clinical features of the renal transplant recipients who had IP.

Discussion

Intestinal perforation is a rare complication after renal transplant; it is estimated to occur in about 1% to 2%, according to various reports.^6-8 According to Stelzner and associates,¹ acute IP and chronic IP have been described as different clinical patterns. The acute pattern presents a few days or weeks after renal transplant, and it is largely attributable to diverticulitis or Cytomegalovirus.^1,2,6 The chronic pattern presents years after renal transplant, and it is usually associated with diverticulitis or malignancies.^1,6 In our series, most patients had the chronic form (91%), with IP related to posttransplant malignancy in only 1 patient.

Published literature has discussed many factors for IP: constipation, uremia, iatrogenic injuries, nonocclusive arterial ischemic disease, immuno­suppression, and diverticulitis.¹ Diverticulitis is the most frequent cause of colon perforation in renal transplant recipients.^9-13 Various studies reported that the prevalence of colonic diverticulosis is significantly higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population or patients on dialysis for other renal diseases.^4,14-18 Prevalence rates vary from 53.5% to 83%, with the condition attributed to a congenital colonic defect or the secretory action from the renal cysts on the colonic wall.⁸ However, the extent of colonic diverticulitis and perforation does not seem to correlate with the primary renal disease.³

Three studies examined the incidence of progression to diverticulitis among 45 transplant recipients who were known to have diverticulosis before transplant. Diverticulitis with or without perforation occurred in 6% of patients, with 57% of these patients having ADPKD.^15,19,20 In a very recent report, Scotti and associates⁴ described a series of 17 transplant patients with diverticular disease; 47% of these patients had ADPKD. The incidence of perforation was 1.25%, with 44% of these afflicted with ADPKD.⁴ In our series, although diverticulitis was the cause of perforation in half of the cases, only 2% had ADPKD.

Intestinal ischemia is a recognized complication after renal transplant. According to the literature, ischemia was the cause of IP in 15% of patients in a series of 85 cases of IP.⁸ Atherosclerosis and coagulation disorders are some aggravating factors in renal transplant recipients.^8,21 In our series, 2 patients had ischemia as a cause for IP.

Regarding immunosuppressive agents, it is shown that steroids especially contribute to intestinal injury by decreasing connective tissue proliferation and by depressing cell-mediated immunity. Stelzner and associates¹ reported that the incidence and outcome of IP were associated with intensity of immunosuppression. Patients who were exposed to a mean daily dose of corticosteroids that was 3 times higher were more likely to have a fatal outcome versus those who did not.¹ Corticosteroids are now being used at lower doses or are being used only during the immediate postoperative period. The introduction of cyclosporine virtually revolutionized the field of renal transplant. Nevertheless, there has not been a lower incidence of major gastrointestinal complication despite the lower doses of methyl­prednisolone.^3,8 The role of toxic tacrolimus levels contributing to IP is not clear. It is associated with diarrhea rather than constipation or obstruction.¹⁹ In our series, almost all patients (90%) were on calcineurin inhibitors at the time of IP, and all patients received corticosteroids according to our clinic immunosuppression protocol.

Immunosuppression can hide the typical symptoms and signs of perforation; steroids inhibit some pyrogenic interleukins and pain-inducing prostaglandins. Such patients may even be totally asymptomatic. Abdominal pain (96%), fever with or without chills (69%), and abdominal tenderness (80%) are the more common symptoms.^22-24 Other more rare symptoms include diarrhea, constipation, nausea, vomiting, and rectal bleeding.^22,23 All of our patients presented with abdominal pain, 40% had fever, and 30% had abdominal tenderness. The radiologic evaluation usually starts with radiographs, with the typical finding being the presence of free intra-abdominal air. Seven of our patients revealed pneumoperitoneum on radiographic imaging. In the literature, pneumoperitoneum is found in approximately 80% of patients with IP.^24,25 However, a computed tomography scan should be required to establish the diagnosis.²⁵

Perforation occurs more often in the sigmoid colon but can also occur in the midsigmoid region, cecum, transverse colon, and descending colon.^14,26 A right side colon perforation after renal transplant is rare.⁶ Half of the patients in the series reported by Puglisi and associates²⁵ showed the sigmoid colon as the perforation site. In our series, the most common site of perforation was also the sigmoid colon (70%).

Because of the possibility of resulting in a life-threatening condition, there is a need for aggressive prevention, including work-up for colonic diverticulosis (colonoscopy or barium enema); further elective colectomy in patients with diverticulosis who will undergo kidney transplant is inevitable.²⁷ Scotti and associates⁴ suggested elective surgery and highlighted the need for abdominal computed tomography in patients who present with fever and abdominal pain, even if mild; these symptoms should prompt a high index of suspicion for early diagnosis and timely surgical treatment.

The optimal surgical approach for complicated colonic disease remains controversial. The lack of bowel preparation, resulting in intraluminal and intraperitoneal fecal contamination at the anastomotic site, is a significant problem when approaching the surgical technique. The most commonly used technique for a perforated sigmoid colon is the Hartmann procedure, which is especially used for cases of severely infected peritonitis.²⁸ Scotti and associates4 used the Hartmann procedure in a series of 9 cases of perforated diverticulitis. Patient outcomes showed 0% mortality rate at 5-year follow-up.⁴ The primary anastomosis had not been performed to avoid the consequences of an anastomotic leak. However, the Hartmann procedure is often permanent and has frequent complications, and the morbidity associated with restoration of the intestinal continuity is high.^3,28

Other techniques have also been used, such as resection and primary anastomosis with or without ileostomy. Golda and associates²⁸ compared the surgical techniques and outcomes in immuno­suppressed patients (79.2% had the Hartmann procedure) versus immunocompetent patients (61.9% had resection and primary anastomosis without ileostomy) undergoing surgery for perforated diverticulitis. Their outcomes suggested worse postoperative morbidity and mortality and higher rates of septic complications in immuno­suppressed patients, in agreement with other studies.^10-12,23 In their series, the mortality rate in immunosuppressed patients was 26.4% (28.1% for those having the Hartmann procedure versus 3.4% in those having resection and primary anastomosis with or without ileostomy) higher than the rate shown in the general population (6.3%), with rates in agreement with the literature (20%-23% for immunosuppressed vs 3% in immunocompromised patients).^10-12,28-32 In our series, 60% of patients had the Hartmann procedure, with 2 deaths due to sepsis.

Before 1980, the reported mortality rate after perforation was very high.^28-32 However, a number of factors such as improved awareness, improved radiologic imaging, early antibiotics, aggressive surgical intervention, and steroid-sparing immuno­suppressant regimens lead to a pattern of decreasing mortality with time.

Sarkio and associates⁵ in a similar series of 18 IPs (spontaneous and iatrogenic) presented a mortality rate of 25%. The mean time of perforation after treatment was 5 months (early posttransplant period), which is different from our data where perforations were a late posttransplant com­plication.⁵ Table 2 summarizes current literature trends about the mortality rates after IP in renal transplant recipients.

Conclusions

Intestinal perforation after renal transplant is a major and potentially lethal complication. Immuno­suppression, diverticulitis, and uremia are suspected as the main causes for this complication. Clinical presentation is usually equivocal, and the transplant surgeon should be highly suspicious when treating a renal transplant recipient with acute abdominal pain, even when other predisposing factors are present (diverticulitis, ischemic colitis), so that the condition can be investigated and unmasked.

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