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Table of Contents
Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 76-80

Acute pancreatitis in a kidney transplant recipient and proposal of a step-wise diagnostic algorithm - A case report

1 Department of Nephrology and Renal Transplantation, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad, Telangana, India
2 Department of Radio-Diagnosis, Niloufer Hospital, Hyderabad, Telangana, India

Date of Submission11-Apr-2020
Date of Acceptance28-Nov-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals and Max Superspeciality Medical Centre, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_32_20

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Acute pancreatitis (AP) is a rarely encountered complication in patients following kidney transplantation and is associated with significant morbidity and mortality. The diagnosis is often difficult due to the lack of classic symptoms and laboratory findings. Herein, we report the case of azathioprine-induced AP leading to acute kidney injury in a kidney transplant recipient, in whom we have encountered diagnostic difficulty. Patient spontaneously recovered after drug withdrawal. We propose a step-wise diagnostic algorithm for the evaluation of AP in kidney transplant recipients.

Keywords: Azathioprine, kidney transplantation, pancreatitis

How to cite this article:
Etta PK, Madhavi T, Parikh N. Acute pancreatitis in a kidney transplant recipient and proposal of a step-wise diagnostic algorithm - A case report. Indian J Transplant 2021;15:76-80

How to cite this URL:
Etta PK, Madhavi T, Parikh N. Acute pancreatitis in a kidney transplant recipient and proposal of a step-wise diagnostic algorithm - A case report. Indian J Transplant [serial online] 2021 [cited 2021 Jul 30];15:76-80. Available from: https://www.ijtonline.in/text.asp?2021/15/1/76/312750

  Introduction Top

Acute pancreatitis (AP) is a rarely encountered complication in patients following kidney transplantation (KT). Several studies have shown that patients with chronic kidney disease (CKD), those on dialysis (peritoneal dialysis [PD] >hemodialysis) and KT recipients (KTRs) have higher rates of AP than the general population. The reported incidence of AP in KTRs varies from 1.2% to 6.8%. The incidence in KTRs has probably reduced in recent years due to restricted use of azathioprine (AZA) in the present era, use of routine pretransplant immunization, and post-KT prophylaxis for infections. The diagnosis is not always straight forward in KTRs as classic clinical features and typical laboratory findings are usually not seen.[1] We report the case of AZA-induced AP leading to acute kidney injury (AKI) in a 27-year-old man 2 years following KT, and in whom we have encountered diagnostic difficulty.

  Case Report Top

A 27-year-old man, with a history of preemptive live-related (one haplomatch) ABO compatible KT with no induction therapy in January 2018 (2 years back), presented with low grade fever, nausea, malaise, and mild pain in the right hypochondriac region of 3 days duration. He had no associated cough, vomiting, and diarrhea. He was on triple immunosuppression (IS) therapy with prednisolone, AZA, and tacrolimus (TAC) at the time of his admission and had normal graft function. His posttransplant period was mostly uneventful, except for recent change in his IS from mycophenolate mofetil (MMF) to AZA around 3 weeks back (due to financial constraints). His basic kidney disease was left solitary kidney with presumed chronic glomerulonephritis. Clinical examination was unremarkable except for mild tenderness in the right hypochondriac region. There was no clinically evident focus of sepsis. The laboratory findings revealed hemoglobin of 11.2 g/dl, total leukocyte count of 12.0 × 103/μL, platelet count of 180 × 103/μL, blood urea of 48 mg/dl, serum creatinine (SCr) of 1.1 mg/dl, total protein of 6.8 g/dl, albumin of 3.2 g/dl, total and direct bilirubin of 2.4 mg/dl and 1.5 mg/dl, aspartate transaminase (AST) and alanine transaminase (ALT) of 644 IU/L (normal 15–37 IU/L) and 186 IU/L (normal 16–63 IU/L), and alkaline phosphatase of 288 IU/L (normal 46–116 IU/L). His urine examination showed 1 + albumin, 3-4 erythrocytes/hpf and 4–5 pus cells/hpf. His serum calcium, phosphorus, and uric acid levels were normal. Lipid profile showed only mild hypercholesterolemia. Serum amylase was 162 U/L (normal 30–110 U/L). Chest radiograph was normal. Ultrasonography showed no obvious pathology in the hepatobiliary tract. Pancreas could not be visualized due to overlying bowel gas. Renal allograft showed normal echogenicity with normal Doppler study. The workup for infective hepatitis such as malaria, leptospirosis, dengue, enteric fever, and scrub typhus was negative. Serology for human immunodeficiency virus, hepatitis B and C was negative. Cytomegalovirus (CMV), hepatitis A and E were not evaluated. Whole blood TAC trough level was optimal. He was given symptomatic and supportive treatment. He had no febrile spikes after admission to the hospital.

However, on day 3 of hospital admission, his abdominal pain worsened. It was localized to the right hypochondriac and epigastric region. Furthermore, he had several episodes of vomiting, but no hematemesis or melena. His blood investigations were repeated. The total and direct bilirubin were 1.94 mg/dl and 1.59 mg/dl; AST and ALT were 86 IU/L and 64 IU/L; serum amylase and lipase were 186 U/L and 2760 U/L (normal lipase 10–140 U/L); blood urea and SCr were 68 mg/dl and 1.8 mg/dl, respectively. In view of AKI, further evaluation with contrast-enhanced computed tomography (CT) could not be performed. Magnetic resonance cholangiopancreatography (MRCP) was suggestive of AP [Figure 1]. However, from history, we knew that he was a teetotaler and had no biliary tract disease or gall stones in the past. We suspected drug-induced AP, secondary to AZA, as this was started around 3 weeks back which correlated with the latent period. He was managed conservatively with nil by mouth, parenteral fluids, analgesics, and antiemetics. AZA was stopped immediately. The patient showed symptomatic improvement in the next 3 days, after which enteral feeds were restarted. He was shifted back to MMF-based triple IS therapy, as before. At the end of 1 week, his renal allograft function was fully recovered and serum lipase level also returned to normal. He remained asymptomatic at 3 months follow-up.
Figure 1: Axial T2-weighted MR image showing enlarged pancreas with smooth outline and normal parenchymal signal intensity, and mild peripancreatic T2 hyperintense edema with thickening of retroperitoneal fascia (arrows) - suggestive of acute pancreatitis. Note left solitary native kidney is also surrounded by thickened fascia

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  Discussion Top

AP is rare in KTRs and was first described by Starzl in 1964.[2] High index of suspicion is required for early diagnosis as AP may present atypically with frequent lack of classic clinical and laboratory findings. Concurrent use of IS may mask the clinical features, which in turn can delay diagnosis. Atypical abdominal pain, abnormal liver function tests (LFTs), and falsely low amylase levels may be seen, as in our case. The recent drug exposure and resolution of AP after drug withdrawal pointed toward AZA-induced AP in our patient. We have reviewed the literature on AP in patients with kidney diseases including KTRs and propose a step-wise diagnostic algorithm for evaluation of AP in KTRs.

The etiology of AP in KTRs is diverse and not always obvious [Table 1]. Gall stones are the most common cause (40%–70% of cases) of AP in the general population. Patients on dialysis may have silent gall stones, increasing the risk of AP after KT; prophylactic cholecystectomy before KT may be useful.[3] Alcohol is responsible for ~30% of cases of AP in the United States; in India, it may be much higher. These traditional causes, i.e., biliary tract disease (gall stones) and alcoholism are rarely seen in KTRs; and IS drugs and viral infections are the predominant causes.
Table 1: Common causes and risk factors for acute pancreatitis after kidney transplantation

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The various drugs causing AP are classified (Class I-IV) based on the published weight of evidence for each agent and the pattern of clinical presentation; Class I and II drugs have the greatest potential.[4],[5] Among the IS drugs, AZA is thought to have the strongest association with AP and it is one of the drugs for which a causal relationship with AP has been established with rechallenge (Class I drug).[6] AZA is a purine analog and pro-drug, metabolized into the active drug 6-mercaptopurine (6-MP). Most cases of AZA-induced AP were described in patients with Crohn's disease. Consistent latency of AP onset, with an average of 25 days has been found. This adverse effect is neither dose related nor associated with AZA-myelotoxicity or the defect of thiopurine S-methyltransferase enzyme which metabolizes 6-MP; it could be an immune-mediated response. Based on the above classification, the relative risk of AP with each one of the IS drugs can be graded as: AZA and dexamethasone (Class I drugs) >>prednisolone and cyclosporine A (CsA) (Class III) > TAC, MMF and Everolimus (Class IV).[5]

Viral (especially CMV) infections play a major role in the development of AP in developing countries like India.[7] Hypertriglyceridemia (>1000 mg/dL) is both a risk factor for and complication of AP. Serum amylase level can be normal in hypertriglyceridemia as triglycerides interfere with the amylase assay. Lipid abnormalities are common in PD patients and those using corticosteroids, CsA, and mammalian target of rapamycin inhibitors. Hypercalcemia may lead to AP, due to inappropriate activation of enzymes within the pancreatic parenchyma. Hyperparathyroidism, in patients with CKD, may cause inflammatory changes in the pancreas, predisposing to AP.

KTRs have a more insidious onset of illness with fewer signs and symptoms, and the clinical presentation can be misleading. Necrotizing form of AP seems to be more frequent following KT. Jaundice with elevated liver enzymes occurs infrequently and transiently. It is usually due to edema of head of pancreas with compression of the intrapancreatic portion of the common bile duct or passage of biliary stone. AKI is seen in 16%–20% of the AP patients in the general population and occurs mainly in patients with severe AP. The incidence may be much higher in KTRs. AKI can be the result of hypoxemia, impairment of renal microcirculation, decrease in renal perfusion pressure, hypovolemia, endotoxins, and reactive oxygen species.[8] Various local (collection, abscess, pseudocyst, and walled off necrosis) and systemic complications (systemic inflammatory response syndrome [SIRS], shock, acute respiratory distress syndrome, AKI, and disseminated intravascular coagulation) can occur, and delayed diagnosis can be life threatening as the mortality related to AP in KTRs is higher compared with the general population (~50% vs. <10%). Mortality in AP is usually due to SIRS and organ failure (<2 weeks) and sepsis (>2 weeks). The prognosis of drug-induced AP is generally excellent, and mortality is low.

In a systematic review, overall mortality was ~ 5% in the general population, with mortality rates in patients with interstitial and necrotizing AP being 3% and 17%, respectively.[9] In an older review of 1321 KTRs, 23 cases of AP were found and 12 deaths were reported.[10] A study found AP in 10 (7%) of 147 KTRs 1 week to 7½ years after KT. Three had hemorrhagic AP and two of them died.[11] Another study had analyzed 168 RTRs and reported five patients with AP, three of whom died.[12] One case series mentioned the mean incidence and mean mortality rate of post-KT AP as 2.3 and 61.3%, respectively; of the 5 KTRs with AP, three patients died. Two cases of AP occurred in patients with an orthotopic KT.[13] One of the largest retrospective studies attributed AP to IS drugs in all the patients (n = 21). The reported incidence of AP was 1.3%; and 6 out of 21 patients (28%) died.[14] One case series of 9 KTRs had noted the incidence of AP as 2.56%, and 3 out of nine patients (33.3%) died.[15] One case series from South India had attributed AP to viral infections in all of five patients (2 with chicken pox, 2 with CMV, and one patient had hepatitis E). Three out of these five patients had severe disease and died.[7]

In a recently published largest single-center retrospective study of 39 episodes of AP in 26 KTRs from North India, the authors have identified the following causes for AP: Gall stones (19.3%), structural lesions (11.5%), viral infections (7.8%), and drugs. In 50% patients, AP was presumed to be due to IS drugs. Only two patients had necrotizing AP. AKI was noted in 77% of patients, all showed either partial or complete recovery. In contrast to older studies, patient survival was high (88%).[16] A recent national population-based retrospective cohort study from Taiwan found overall AP incidence rates as 1.71 and 0.61 per 1000 person-years in the KT and non-KT groups, respectively, with corresponding adjusted hazards ratio (aHR [95% confidence interval [CI]]) for AP as 2.48 (1.51–4.09) in the KT group. Recurrent AP risk was significantly higher in the KT group (aHR: 8.19, 95% CI: 2.89–23.2). Patients with post-KT AP demonstrated shorter patient and allograft survival than did those without.[17] Another recent nationwide database from US showed that hypercalcemia was the most common cause of AP in stage 5 CKD, while viral and drug induced AP were more prevalent in the KTRs. Adjusted inpatient mortality was highest in patients with dialysis dependent stage 5 CKD, followed by KTRs, compared to the non-CKD group.[18]

Serum amylase rises within 6–12 h of the onset of AP. Amylase has a short half-life of ~ 10 h and in uncomplicated attacks returns to normal within 3–5 days. Serum amylase is neither sensitive nor specific for AP [Table 2]. Lipase elevations occur earlier (within 4–8 h) and last longer (up to 7–14 days) as compared with elevations in amylase. Though both amylase and lipase levels get elevated in patients with renal dysfunction due to reduced renal clearance, lipase is elevated to a lesser extent than that of amylase. Sometimes, very severe AP can be present in dialysis patients with only slight and nondiagnostic elevation in serum amylase level. Serum lipase is more sensitive and specific marker compared to serum amylase in the diagnosis of AP. Revised Atlanta classification, primarily based on CT findings, is a reliable predictor of severe disease. The various morphological features of AP described are: Interstitial AP, necrotizing AP, acute pancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection and walled-off pancreatic necrosis.[19]
Table 2: Conditions associated with abnormal serum amylase levels

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AP is diagnosed if 2 out of 3 of the following criteria are satisfied: Clinical, laboratory and imaging criteria.[20] We propose a step-wise diagnostic algorithm for evaluation of AP in KTRs [Figure 2]. After exclusion of traditional causes of AP, evaluation for viral infections and drug induced AP is advised. There is no consensus on appropriate treatment of AP in KTRs. Prophylactic antibiotics are not routinely recommended in AP. But, few authors recommend them in KTRs to prevent infection.[21] In patients with advanced renal failure, management of AP is complicated because of limitations in fluid resuscitation. Surgical management may be required for pancreatic necrosis or pseudocysts, especially if infective.[14],[22]
Figure 2: Step-wise diagnostic algorithm for evaluation of acute pancreatitis in kidney transplantation acute pancreatitis, cytomegalovirus, varicella-zoster virus, herpes simplex virus, ultrasonography, magnetic resonance cholangiopancreatography, contrast-enhanced computed tomography, endoscopic retrograde cholangiopancreatography, sphincter of oddi manometry

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In our patient, the initial atypical abdominal pain, deranged LFTs and near normal amylase level masked the underlying AP. Later, elevated lipase, supported by positive MRCP findings confirmed the diagnosis. We managed our patient with conservative and supportive therapy alone. Fortunately, our patient had a mild form of drug induced AP without necrosis or other complications which led to a relatively rapid recovery and normalization of laboratory parameters after drug withdrawal.

  Conclusions Top

AP should be considered as a possibility in all KTRs with unexplained abdominal pain or abnormal LFTs. Classic clinical and laboratory findings may not always be present. Imaging should be performed early in these patients to confirm the diagnosis and look for complications. IS drugs and viral infections are the predominant causes of AP in KTRs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]

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1 Azathioprine
Reactions Weekly. 2021; 1854(1): 73
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