tacrolimus and Pancreatitis

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies, but are associated with serious adverse events like pancreatitis. Current guidelines are limited to the first step in treating acute ICI-related pancreatitis with steroids but lack treatment advices for steroid dependent pancreatitis. We describe a case series of 3 patients who developed ICI-related pancreatitis with chronic features such as exocrine insufficiency and pancreatic atrophy at imaging. Our first case developed after treatment with pembrolizumab. The pancreatitis responded well after discontinuation of immunotherapy but imaging showed pancreatic atrophy and exocrine pancreatic insufficiency persisted. Cases 2 and 3 developed after treatment with nivolumab. In both, pancreatitis responded well to steroids. However during steroid tapering, pancreatitis recurred and the latter developed exocrine pancreatic insufficiency and pancreatic atrophy at imaging. Our cases demonstrate resemblances with autoimmune pancreatitis based on clinical and imaging findings. In line, both diseases are T-cell mediated and for autoimmune pancreatitis azathioprine is considered as maintenance therapy. Guidelines of other T-cell mediated diseases like ICI-related hepatitis suggest tacrolimus. After adding tacrolimus in case 2 and azathioprine in case 3, steroids could be completely tapered and no new episodes of pancreatitis have occurred. These findings support the idea that the treatment modalities for other T-cell mediated diseases are worthwhile options for steroid dependent ICI-related pancreatitis.

Topics: Autoimmune Pancreatitis; Azathioprine; Exocrine Pancreatic Insufficiency; Expert Testimony; Humans; Immune Checkpoint Inhibitors; Pancreatitis; Steroids; Tacrolimus

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for the management of pancreaticobiliary disorders. The most troublesome ERCP-associated adverse event is post-ERCP pancreatitis (PEP), which occurs in up to 15% of all patients undergoing ERCP. A substantial body of preclinical data support a mechanistic rationale for calcineurin inhibitors in preventing PEP. The findings are coupled with recent clinical data suggesting lower rates of PEP in patients who concurrently use the calcineurin inhibitor tacrolimus (e.g., solid organ transplant recipients). In this review, we will firstly summarize data in support of testing the use of tacrolimus for PEP prophylaxis, either in combination with rectal indomethacin or by itself. Secondly, we propose that administering tacrolimus through the rectal route could be favorable for PEP prophylaxis over other routes of administration.

Topics: Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Cholangiopancreatography, Endoscopic Retrograde; Humans; Pancreatitis; Risk Factors; Tacrolimus

The purpose of this case report is to increase the awareness of tacrolimus-induced acute pancreatitis in renal transplantation patients.. We present a case of tacrolimus-induced acute pancreatitis with positive rechallenge. The 24-year-old male patient underwent kidney transplant and received immunosuppressive therapy with tacrolimus. On day 10 post-transplant, he presented with abdominal pain. A laboratory analysis showed elevated serum amylase and serum lipase levels. An abdominal computed tomography scan showed large-volume ascites and pelvic cavity effusion. These findings led to a diagnosis of acute pancreatitis. After tacrolimus was temporarily stopped and altered with cyclosporine, his symptoms decreased and he was restarted with tacrolimus. On day 61, laboratory tests again revealed significant elevations of serum amylase and serum lipase. A computed tomography scan of the abdomen showed increased pancreatic tail fluid collections. We excluded other possible causes and concluded that tacrolimus was the definite inducer of pancreatitis. The patient was switched from tacrolimus to cyclosporine again. Serum amylase and serum lipase were gradually decreased to normal, and he was discharged home with no relapse.. With the consideration of the wide use of tacrolimus, it is important that healthcare providers are aware of tacrolimus-induced acute pancreatitis. Future studies are needed to confirm and quantify the risk of tacrolimus-induced acute pancreatitis.

Topics: Diagnosis, Differential; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreatitis; Tacrolimus; Tomography, X-Ray Computed; Young Adult

The aim of this review is to evaluate emerging, novel therapies for the prevention of post-ERCP pancreatitis.. Rectal indomethacin reduces the risk of pancreatitis in low- and average-risk patients, who comprise the majority of patients undergoing ERCP. An 8-h protocol of aggressive lactated Ringer's reduces the risk of pancreatitis in average-risk patients. Sublingual nitrate may provide additional benefit to rectal NSAIDs in preventing PEP. A tacrolimus trough > 2.5 ng/mL was recently shown to be associated with a lower risk of PEP in liver transplant patients undergoing ERCP. Routine usage of rectal indomethacin in all patients undergoing ERCP reduces the risk of PEP. Pancreatic-duct stents reduce the risk of PEP in high-risk patients. There is emerging data that aggressive hydration with lactated Ringer's and nitrates may further reduce PEP. Tacrolimus is a promising potential agent to prevent PEP but needs further clinical study.

Topics: Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Cholangiopancreatography, Endoscopic Retrograde; Humans; Immunosuppressive Agents; Indomethacin; Nitro Compounds; Pancreatic Ducts; Pancreatitis; Ringer's Lactate; Stents; Tacrolimus

Experimental pancreatic lesions can be induced by a number of different procedures, e.g. pancreatic hyperstimulation, intraductal application of bile acids, feeding choline deficient diet, obstruction of pancreatic duct, or reducing pancreatic blood flow. The pathogenetic mechanisms leading to pancreatic lesions include basolateral enzyme secretion, acinar cell polarisation defect, intracellular activation of proteases, and the production of free radicals and other active metabolites. The importance of these individual mechanisms in the production and progression of different experimentally-induced pancreatic lesions remains speculative. These pathogenetic concepts have inspired the study of a number of substances likely to protect the pancreas and prevent the pancreatic lesions. This paper gives an overview of the pathogenetic concepts of development of and protection against experimental pancreatic lesions produced in animal models. Special mention has been made of an animal model of pancreatic lesion produced by immunosuppressives.

Topics: Animals; Cyclosporine; Pancreas; Pancreatitis; Reactive Oxygen Species; Tacrolimus

Acute pancreatitis remains the most common and morbid complication of endoscopic retrograde cholangiopancreatography (ERCP). The use of rectal indomethacin and pancreatic duct stenting has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP), but these interventions have limitations. Recent clinical and translational evidence suggests a role for calcineurin inhibitors in the prevention of pancreatitis, with multiple retrospective case series showing a reduction in PEP rates in tacrolimus users.. The INTRO trial is a multicenter, international, randomized, double-blinded, controlled trial. A total of 4,874 patients undergoing ERCP will be randomized to receive either oral tacrolimus (5 mg) or oral placebo 1-2 h before ERCP, and followed for 30 days post-procedure. Blood and pancreatic aspirate samples will also be collected in a subset of patients to quantify tacrolimus levels. The primary outcome of the study is the incidence of PEP. Secondary endpoints include the severity of PEP, ERCP-related complications, adverse drug events, length of hospital stay, cost-effectiveness, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of tacrolimus immune modulation in the pancreas.. The INTRO trial will assess the role of calcineurin inhibitors in PEP prophylaxis and develop a foundation for the clinical optimization of this therapeutic strategy from a pharmacologic and economic standpoint. With this clinical trial, we hope to demonstrate a novel approach to PEP prophylaxis using a widely available and well-characterized class of drugs.. NCT05252754, registered on February 14, 2022.

Topics: Acute Disease; Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Calcineurin Inhibitors; Cholangiopancreatography, Endoscopic Retrograde; Humans; Indomethacin; Multicenter Studies as Topic; Pancreatitis; Randomized Controlled Trials as Topic; Retrospective Studies; Tacrolimus

There is an urgent need for safe and targeted interventions to mitigate post-ERCP pancreatitis (PEP). Calcineurin inhibitors (CnIs) offer therapeutic promise as calcineurin signaling within acinar cells is a key initiating event in PEP. In previous proof-of-concept studies using experimental models, we showed that concurrent intra-pancreatic ductal administration of the CnIs, tacrolimus (Tac) or cyclosporine A (CsA) with the ERCP radiocontrast agent (RC) prevented PEP. To translate this finding clinically, we investigated potential toxic effects of intraductal delivery of a single-dose RC-CnI formulation on endocrine pancreas function and systemic toxicities in a preclinical PEP model.. C57BL/6J mice underwent ductal cannulation and received a single, intra-pancreatic ductal infusion of RC or RC with Tac or CsA (treatment groups) or underwent ductal cannulation without infusion ('sham' group). To assess endocrine function, intraperitoneal glucose tolerance test (IPGTT) was performed at two days before infusion and on day 2 and 14 post-surgery. To evaluate off-target tissue toxicities, renal and hepatic function-related parameters including blood urea nitrogen, plasma creatinine, potassium, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were measured at the same time-points as IPGTT. Histological and biochemical indicators of pancreas injury and inflammation were also evaluated.. No abnormalities in glucose metabolism, hepatic or renal function were observed on day 2 or 14 in mice administered with intraductal RC or RC with Tac or CsA.. Intraductal delivery of RC-CnI formulation was safe and well-tolerated with no significant acute or subacute endocrine or systemic toxicities, underscoring its clinical utility to prevent PEP.

Topics: Animals; Calcineurin Inhibitors; Cholangiopancreatography, Endoscopic Retrograde; Contrast Media; Cyclosporine; Mice; Mice, Inbred C57BL; Pancreatitis; Tacrolimus

There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis.. C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated.. Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery.. Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.

Topics: Administration, Rectal; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Mice; Mice, Inbred C57BL; Pancreatitis; Tacrolimus

Calcineurin inhibitors (CNIs) are often associated with abnormalities in glucose and lipid metabolism. Tacrolimus is the most potent CNI which is nowadays used almost universally as a part of triple-drug immunosuppression after kidney transplantation. Tacrolimus can cause islet cell damage and decrease in insulin secretion which can lead to post-transplant diabetes mellitus and rarely diabetic ketoacidosis. Although rare, acute pancreatitis has also been implicated by a few case reports to be associated with tacrolimus. However, tacrolimus-induced acute pancreatitis has not been reported in pediatric kidney transplant recipient till date.. We report the first case of tacrolimus-induced acute pancreatitis in association with hypertriglyceridemia and DKA in a child early after kidney transplant. The patient was managed with supportive treatment, and tacrolimus was stopped for three days and then switched to cyclosporine-based regimen. The patient became euglycemic within 8 weeks of switching to cyclosporine and did not have any recurrence of pancreatitis.. Tacrolimus-induced pancreatitis is rare in the setting of kidney transplants and prompt diagnosis and management can lead to a successful outcome.

Topics: Adolescent; Combined Modality Therapy; Diabetic Ketoacidosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreatitis; Tacrolimus; Tomography, X-Ray Computed

Coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality worldwide in both the general population and kidney transplant recipients. Acute kidney injury is a known complication of COVID-19 and appears to most commonly manifest as acute tubular injury on renal biopsy. Coagulopathy associated with COVID-19 is a known but poorly understood complication that has been reported to cause thrombotic microangiopathy on rare occasions in native kidneys of patients with COVID-19. Here, we report the first case of biopsy-proven thrombotic microangiopathy in a kidney transplant recipient with COVID-19 who developed acute pancreatitis and clinical features of microangiopathic hemolytic anemia. The patient recovered with supportive care alone.

Topics: COVID-19; Creatinine; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreatitis; Platelet Count; SARS-CoV-2; Tacrolimus; Thrombotic Microangiopathies; Transplantation, Homologous

Biliary complications occur in up to 25% of patient following liver transplantation and are often managed by endoscopic retrograde cholangiopancreatography (ERCP). Pancreatitis is the most common adverse event after ERCP (PEP). Tacrolimus and rectal indomethacin have each been reported to reduce risk of PEP. We investigated the incidence of PEP in patients who have undergone ERCP after liver transplantation and the effectiveness of tacrolimus and/or indomethacin in reducing risk of PEP.. We performed a retrospective study of 337 patients who underwent ERCP (n = 937 procedures) for biliary complications after liver transplantation from June 1, 2007 through December 1, 2015. After June 1, 2012, rectal indomethacin (100 mg) was routinely administered at the conclusion of the ERCP unless patients had contraindications. Indomethacin was given after 286 ERCP procedures. After excluding patients with acute/chronic rejection, 323 patients were maintained on a stable dose of tacrolimus prior to ERCP (901 procedures). We collected data on demographic and clinical variables, pre-procedural tacrolimus trough levels, and development of PEP. We calculated adjusted odds ratios (ORs) for the association between tacrolimus and indomethacin use and risk of PEP using mixed-effects multivariable logistic regression. The primary outcome was development of PEP; secondary outcomes included the development moderate-to-severe PEP, cholangitis and bleeding.. PEP occurred after 2.2% of ERCP procedures. A trough level of tacrolimus above 2.5 ng/mL was associated with 79% lower odds of PEP (OR, 0.21; 95% CI, 0.06-0.72; P = .01). Indomethacin was associated with a 91% reduction in risk of PEP (OR, 0.09; 95% CI, 0.01-0.85; P = .03). Indomethacin use did not affect rates of bleeding or cholangitis or decrease in glomerular filtration rate. In patients with trough levels of tacrolimus above 2.5 ng/mL, addition of indomethacin reduced the odds of PEP by 93% compared with patients who were unexposed to indomethacin. (OR, 0.07; 95% CI, 0.01-0.90; P = .04).. In a retrospective study of patients who underwent ERCP for biliary complications after liver transplantation, we found trough levels of tacrolimus above 2.5 ng/mL to significantly reduce risk for PEP. Rectal administration of indomethacin after ERCP significantly decreased rates of pancreatitis, and reduced risk further in patients given tacrolimus. Administration of both drugs prevented patients from developing moderate or severe pancreatitis. Indomethacin did not worsen renal function in patients with chronic kidney disease.

Topics: Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Cholangiopancreatography, Endoscopic Retrograde; Humans; Indomethacin; Liver Transplantation; Pancreatitis; Retrospective Studies; Risk Factors; Tacrolimus

Primary nephrotic syndrome (PNS) is one of the most common primary glomerular diseases in children. Patients complicated nephrotic syndrome with pancreatic lesions are rarely reported, and the clinical manifestations in children are atypical. This study has observed the incidence, clinical types, and prognosis of acute pancreatitis (AP) in children with primary nephrotic syndrome, and analyzed its related factors, early diagnosis, and treatment.Seven children with PNS and AP in Shanghai Children's Hospital from January 2015 to December 2017 were reviewed. The clinical data including age, height, weight, body mass index (BMI), diet, biliary tract disease, PNS durations, drugs, proteinuria, creatinine, glucose, glycated hemoglobin, amylase and lipase, albumin, cholesterol, triglyceride, ultrasound, computerized tomography (CT), renal pathology and estimated glomerular filtration rate (eGFR) were retrospectively analyzed. All patients were followed for >2 years.Ten in 589 patients with PNS were detected pancreatic lesions by abdominal ultrasound. Seven were diagnosed as AP, which the incidence was 1.2%. Only 1 of 7 patients had elevated serum amylase. Lesions of pancreas were found by ultrasound and/or enhanced CT. Four of 7 patients had been treated with tacrolimus. All patients with AP were improved after octreotide acetate injection and supportive treatment. Only 1 patient suffered recurrent AP during the relapse of PNS 10 months later.AP in children with PNS is not common, and the clinical manifestations are not typical. Abdominal ultrasound and enhanced CT are of high value in diagnosis. The adverse effects of tacrolimus should be concerned. Early diagnosis and timely treatment can be helpful for a prognosis.

Topics: Adolescent; Child; Child, Preschool; China; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Incidence; Kidney; Male; Nephrotic Syndrome; Octreotide; Pancreatitis; Prognosis; Recurrence; Retrospective Studies; Tacrolimus

Tacrolimus has been widely used for immunosuppressive therapy in solid organ transplantation (SOT) and allo-geneic stem cell transplantation (allo-SCT) over the past 2 decades. Pancreatitis caused by tacrolimus was rarely reported in kidney transplantation previously.. Here we presented a case of a 45-year-old male who underwent kidney transplantation and received immunosuppressive therapy of tacrolimus, on day + 67 after transplantation he developed acute pancreatitis with extremely high blood concentration of tacrolimus. We excluded other possible causes and speculated tacrolimus was the probable inducer of pancreatitis. After tacrolimus was discontinued and alternated with cyclosporine, he gradually recovered and was discharged home with no relapse.. Tacrolimus can be a probable cause of pancreatitis after kidney transplantation. We recommended clinicians to be aware of the possibility of tacrolimus-induced pancreatitis during tacrolimus treatment.

Topics: Cyclosporine; Drug Monitoring; Drug Substitution; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreatitis; Postoperative Complications; Tacrolimus; Treatment Outcome

A 49-year-old man was admitted to our hospital with pancreatitis. He was diagnosed with systemic lupus erythematosus at 34 years of age and was being treated with oral tacrolimus (3 mg/day) and predonine (10 mg/day) for the past 15 months. The computed tomography (CT) scan showed the mass lesion had invaded the pancreatic head via thickening of the duodenal wall. Upper gastrointestinal endoscopy showed the all-round ulcerative lesion from the superior duodenal angle to the descending portion. Histological examination confirmed the diagnosis of diffuse large B cell lymphoma (DLBCL). Tacrolimus therapy was stopped due to the possibility of immunodeficiency-related lymphoproliferative disease; however, the lesion did not improve. Consequently, he was administered rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). After six courses of R-CHOP therapy, a partial response was confirmed on CT. One month after the completion of chemotherapy, a gastrojejunal anastomosis was performed because of duodenal stenosis. He has since been well without recurrence. It was difficult to identify the risk factor for DLBCL; therefore, both the disease activity and immunosuppressive therapy should be taken into consideration as carrying a risk. In the present case, the symptom of pancreatitis enabled an early diagnosis of DLBCL.

Topics: Acute Disease; Anti-Inflammatory Agents; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Duodenal Neoplasms; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Pancreatitis; Prednisolone; Prednisone; Rituximab; Tacrolimus; Vincristine

Pancreatitis after endoscopic retrograde cholangiopancreatography (PEP) is thought to be provoked by pancreatic ductal hypertension, via unknown mechanisms. We investigated the effects of hydrostatic pressures on the development of pancreatitis in mice.. We performed studies with Swiss Webster mice, B6129 mice (controls), and B6129 mice with disruption of the protein phosphatase 3, catalytic subunit, βisoform gene (Cnab. Intraductal pressures of up to 130 mm Hg were observed in the previously reported model of PEP; we found that application of hydrostatic pressures of 100 and 150 mm Hg for 10 minutes consistently induced pancreatitis. Pancreatic tissues had markers of inflammation (increased levels of interleukin [IL] 6, IL1B, and tumor necrosis factor), activation of signal transducer and activator of transcription 3, increased serum amylase and IL6, and loss of tight junction integrity. Transiently high pressures dysregulated Ca. Transient high ductal pressure produces pancreatic inflammation and loss of tight junction integrity in a mouse model of PEP. These processes require calcineurin signaling. Calcineurin inhibitors might be used to prevent acute pancreatitis that results from obstruction.

Topics: Ampulla of Vater; Amylases; Animals; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Cholangiopancreatography, Endoscopic Retrograde; Disease Models, Animal; Female; Hydrostatic Pressure; Interleukin-1beta; Interleukin-6; Male; Mechanotransduction, Cellular; Membrane Potential, Mitochondrial; Mice, Knockout; Mitochondria; Pancreatitis; STAT3 Transcription Factor; Tacrolimus; Tight Junctions; Time Factors; Tumor Necrosis Factor-alpha

Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain.

Topics: Anilides; Animals; Benzimidazoles; Ceruletide; Cinnamates; Cyclopropanes; Hyperalgesia; Male; Mice; Naphthalenes; Pain; Pancreatitis; Recurrence; Tacrolimus; TRPV Cation Channels

Radiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice.. We exposed mouse and human acinar cells to the radiocontrast agent iohexol (Omnipaque; GE Healthcare, Princeton, NJ) and measured intracellular release of Ca(2+), calcineurin activation (using a luciferase reporter), activation of nuclear factor-κB (NF-κB, using a luciferase reporter), and cell necrosis (via propidium iodide uptake). We infused the radiocontrast agent into the pancreatic ducts of wild-type mice (C57BL/6) to create a mouse model of post-ERCP pancreatitis; some mice were given intraperitoneal injections of the calcineurin inhibitor FK506 before and after infusion of the radiocontrast agent. CnAβ(-/-) mice also were used. This experiment also was performed in mice given infusions of adeno-associated virus 6-NF-κB-luciferase, to assess activation of this transcription factor in vivo.. Incubation of mouse and human acinar cells, but not HEK293 or COS7 cells, with iohexol led to a peak and then plateau in Ca(2+) signaling, along with activation of the transcription factors NF-κB and nuclear factor of activated T cells. Suppressing Ca(2+) signaling or calcineurin with BAPTA, cyclosporine A, or FK506 prevented activation of NF-κB and acinar cell injury. Calcineurin Aβ-deficient mice were protected against induction of pancreatic inflammation by iohexol. The calcineurin inhibitor FK506 prevented contrast-induced activation of NF-κB in pancreata of mice, this was observed by live imaging of mice given infusions of adeno-associated virus 6-NF-κB-luciferase.. Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca(2+) signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis in patients.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Chlorocebus aethiops; Contrast Media; COS Cells; Disease Models, Animal; Gene Expression Regulation; HEK293 Cells; Humans; Iohexol; Male; Mice, Inbred C57BL; Mice, Knockout; Necrosis; NF-kappa B; Pancreas, Exocrine; Pancreatitis; Tacrolimus; Time Factors

More recently, autoimmune pancreatitis (AIP) in association with IgG4-positive cholangitis (IAC) has been recognised as a new and challenging entity. Currently, initiation of high dose steroids (e.g., prednisolone 0.5 - 1 mg/kg/day) followed by a steroid dose taper in combination with purine antagonists (e.g., azathioprine or 6-mercaptopurine) after resolution has been recommended as standard therapy.. A 68-year-old male patient was referred to our institution in February 2012 for therapy evaluation of a steroid-dependent course of autoimmune pancreatitis type 1 with IgG4-associated cholangitis. Since the first diagnosis in March 2011, the patient was treated with high-dose steroids with good response. Whenever steroids were tapered down to a daily dose <20 mg, cholestatic liver enzymes increased dramatically despite concurrent immunosuppressive therapy primarily with azathioprine and 6-MP thereafter. Therefore, we restarted steroid therapy (1 mg/kg/day) in combination with tacrolimus achieving a target level of 5 - 7 ng/mL. During the down-tapering phase, follow-up examinations presented a patient in good general condition without jaundice. Moreover, liver and pancreatic enzymes and also immunoglobulins returned to normal values without any evidence of relapse up today (66 weeks).. In this case, the combination of steroids with tacrolimus seems to be a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis. To date, this is the first description of such a therapeutic approach for this entity.

Topics: Aged; Azathioprine; Cholangitis; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Pancreatitis; Steroids; Tacrolimus; Treatment Failure

New-onset diabetes mellitus after transplant is a well-recognized complication of tacrolimus immunosuppression and commonly occurs as a form of type 2 diabetes mellitus. However, tacrolimus-associated acute pancreatitis causing diabetic ketoacidosis has not been reported in heart transplant patients. We report a 22-year-old women hospitalized owing to diabetic ketoacidosis associated with acute pancreatitis 7 months after a heart transplant. Her immunosuppression included tacrolimus. She was admitted with complaints of polydipsia, anorexia, and abdominal pain of 3 days' duration. Her initial laboratory test revealed a toxic level of tacrolimus (> 30 ng/mL), severe hyperglycemia (39 mmol/L), severe metabolic acidosis (pH 6.9), and ketonuria, although diabetes mellitus had never been diagnosed. Serum amylase and lipase levels and abdominal computed tomography suggested the presence of acute pancreatitis. After correcting the diabetic ketoacidosis and getting the tacrolimus level to the normal range, she was discharged home. Three months later, insulin was replaced with oral hypoglycemic agents. Pancreatitis can present with diabetic ketoacidosis in the recipient of a heart transplant treated with tacrolimus. Clinicians should pay more attention to tacrolimus levels and the risk of pancreatitis.

Topics: Acute Disease; Cardiomyopathy, Dilated; Diabetic Ketoacidosis; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Insulin; Pancreatitis; Risk Factors; Sodium Bicarbonate; Tacrolimus; Treatment Outcome; Young Adult

Biliary pancreatitis is the leading cause of acute pancreatitis in both children and adults. A proposed mechanism is the reflux of bile into the pancreatic duct. Bile acid exposure causes pancreatic acinar cell injury through a sustained rise in cytosolic Ca(2+). Thus, it would be clinically relevant to know the targets of this aberrant Ca(2+) signal. We hypothesized that the Ca(2+)-activated phosphatase calcineurin is such a Ca(2+) target. To examine calcineurin activation, we infected primary acinar cells from mice with an adenovirus expressing the promoter for a downstream calcineurin effector, nuclear factor of activated T-cells (NFAT). The bile acid taurolithocholic acid-3-sulfate (TLCS) was primarily used to examine bile acid responses. TLCS caused calcineurin activation only at concentrations that cause acinar cell injury. The activation of calcineurin by TLCS was abolished by chelating intracellular Ca(2+). Pretreatment with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl ester) (BAPTA-AM) or the three specific calcineurin inhibitors FK506, cyclosporine A, or calcineurin inhibitory peptide prevented bile acid-induced acinar cell injury as measured by lactate dehydrogenase leakage and propidium iodide uptake. The calcineurin inhibitors reduced the intra-acinar activation of chymotrypsinogen within 30 min of TLCS administration, and they also prevented NF-κB activation. In vivo, mice that received FK506 or were deficient in the calcineurin isoform Aβ (CnAβ) subunit had reduced pancreatitis severity after infusion of TLCS or taurocholic acid into the pancreatic duct. In summary, we demonstrate that acinar cell calcineurin is activated in response to Ca(2+) generated by bile acid exposure, bile acid-induced pancreatic injury is dependent on calcineurin activation, and calcineurin inhibitors may provide an adjunctive therapy for biliary pancreatitis.

Topics: Acinar Cells; Animals; Bile Acids and Salts; Calcineurin; Calcium; Chymotrypsin; Cytosol; Egtazic Acid; L-Lactate Dehydrogenase; Mice; NF-kappa B; NFATC Transcription Factors; Pancreas; Pancreatitis; Protein Isoforms; Tacrolimus; Taurolithocholic Acid; Time Factors

The present study investigated the treatment effects of the immunosuppressive agent, tacrolimus (FK506), on rats with acute necrotizing pancreatitis (ANP).. We used the taurocholate-induced model of acute necrotizing pancreatitis (ANP) in rats that were divided into seven groups: The sham group included animals that underwent sham operations. The ANP group contained ANP rats induced by taurocholate. The tacrolimus groups contained ANP rats treated with tacrolimus at three different time points (prior to the induction of ANP, immediately after the induction of ANP, one hour after the induction of ANP). The somatostatin group included ANP rats treated with somatostatin. The glucocorticoids group contained ANP rats treated with glucocorticoids. At 3, 6 and 12 hours after the induction of taurocholate, blood samples were collected for TNF-alpha, IL-1beta and amylase assays, and lung and pancreas tissues were harvested for histopathological study and edema evaluation.. Tacrolimus administered prior to the induction of ANP and immediately after the induction of ANP caused a significant decrease in the twenty two-hour mortality rate (p<0.05). However, tacrolimus did not decrease the mortality rate when administered one hour after the induction of ANP (p>0.05). Treatment with all three drugs (tacrolimus, somatostatin and glucocorticoids) resulted in a significant decrease of serum amylase, lung edema, and serum TNF-alpha and IL-1beta levels. Pancreatic and pulmonary morphological alterations were improved.. Tancrolimus can decrease pancreatic and pulmonary injury. The effect of tacrolimus treatment is the same as that of somatostain and glucocroticoids. It is also more effective to administer the drug earlier.

Topics: Amylases; Animals; Anti-Inflammatory Agents; Ascites; Disease Models, Animal; Interleukin-1beta; Lung; Organ Size; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Tacrolimus; Tumor Necrosis Factor-alpha

The premature activation of digestive proenzymes, specifically proteases, within the pancreatic acinar cell is an early and critical event during acute pancreatitis. Our previous studies demonstrate that this activation requires a distinct pathological rise in cytosolic Ca(2+). Furthermore, we have shown that a target of aberrant Ca(2+) in acinar cells is the Ca(2+)/calmodulin-dependent phosphatase calcineurin (PP2B). In this study, we hypothesized that PP2B mediates in vivo protease activation and pancreatitis severity. To test this, pancreatitis was induced in mice over 8 h by administering hourly intraperitoneal injections of the cholecystokinin analog caerulein (50 microg/kg). Treatment with the PP2B inhibitor FK506 at 1 and 8 h after pancreatitis induction reduced trypsin activities by greater than 50% (P < 0.005). Serum amylase and IL-6 was reduced by 86 and 84% relative to baseline (P < 0.0005) at 8 h, respectively. Histological severity of pancreatitis, graded on the basis of pancreatic edema, acinar cell vacuolization, inflammation, and apoptosis, was reduced early in the course of pancreatitis. Myeloperoxidase activity from both pancreas and lung was reduced by 93 and 83% relative to baseline, respectively (P < 0.05). These data suggest that PP2B is an important target of the aberrant acinar cell Ca(2+) rise associated with pathological protease activation and pancreatitis.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Ceruletide; Enzyme Activation; HSP70 Heat-Shock Proteins; Interleukin-6; Lung; Male; Mice; Mice, Inbred Strains; Pancreas; Pancreatic alpha-Amylases; Pancreatitis; Peptide Hydrolases; Peroxidase; Tacrolimus; Trypsin

Ischemia reperfusion (I/R)-associated early graft pancreatitis is a major complication after pancreas transplantation. The influence of immunosuppressants on graft pancreatitis remains unclear. The aim of this study was to evaluate ciclosporin and tacrolimus in experimental pancreatic I/R.. Moderate pancreatitis was induced in rats by I/R injury. Animals were assigned to 4 groups: (1) control without I/R, (2) I/R without therapy, (3) I/R + ciclosporin, or (4) I/R + tacrolimus. After 24 hours, pancreatic damage was evaluated by amylase, endothelin 1, thromboxane A2, and histology. Additionally, microcirculation was evaluated 12 hours after reperfusion by intravital microscopy.. I/R significantly increased amylase compared with controls, with maximum levels after ciclosporin treatment. Histology showed comparable tissue injury in control and tacrolimus-treated animals. Ciclosporin-treated animals developed significantly (P < 0.05) more inflammation and necrosis compared with the other groups. Erythrocyte velocity evaluated by intravital microscopy was reduced in all animals after I/R. This was significantly pronounced after ciclosporin application. There was a significant increase of adherent leukocytes and platelets in ciclosporin-treated animals compared with both other groups.. Tacrolimus does not negatively influence I/R-induced pancreatitis, whereas ciclosporin aggravates pancreatic tissue damage after I/R. These effects should be evaluated in the clinical setting of pancreas transplantation.

Topics: Acute Disease; Animals; Blood Pressure; Cyclosporine; Disease Models, Animal; Heart Rate; Immunosuppressive Agents; Pancreas; Pancreas Transplantation; Pancreatitis; Rats; Reperfusion Injury; Tacrolimus

Topics: Acute Disease; Aged; Cerebral Hemorrhage; Dementia, Vascular; Endothelial Cells; Humans; Male; Neurotoxicity Syndromes; Pancreatitis; Peripheral Blood Stem Cell Transplantation; Tacrolimus; Transplantation, Homologous

Topics: Acute Disease; Bone Marrow Transplantation; Child; Granulomatous Disease, Chronic; Humans; Immunosuppressive Agents; Male; Pancreatitis; Tacrolimus; Transplantation, Homologous

Topics: Acute Disease; Cadaver; Fatal Outcome; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pancreatitis; Tacrolimus

Topics: Bile Duct Diseases; Bile Ducts, Intrahepatic; Carbamazepine; Child, Preschool; Cholestasis; Hepatitis B; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Methylprednisolone; Pancreatitis; Stevens-Johnson Syndrome; Tacrolimus

We have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. In this study, we examined the effects of FK506 in this mouse model in preventing autoimmune pancreatitis and investigated its action on calcium signalling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treated with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mononuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltration associated with destruction of acini and partial fatty changes were observed in 25-week-old control mice. In contrast, FK506 treated mice showed almost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-treated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using naive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppressive effect of FK506 on Bcl-2 production but not on Bax production was confirmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its beneficial effect on aly autoimmune pancreatitis.

Topics: Animals; Apoptosis; Autoimmune Diseases; bcl-2-Associated X Protein; Calcium Signaling; Cells, Cultured; Immunosuppressive Agents; Mice; Pancreatitis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Antigen, T-Cell; T-Lymphocytes; Tacrolimus

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg x kg(-1) x day(-1) but not 0.025 mg x kg(-1) x day(-1) of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.

Topics: Animals; Apoptosis; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Corticosterone; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Pancreatitis; Rats; Rats, Wistar; T-Lymphocytes; Tacrolimus

Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient.

Topics: Adult; Female; Fetal Blood; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Multiple Organ Failure; Pancreatitis; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

To find out if two immunomodulatory drugs used in organ transplantation (FK506 (tacrolimus) and OKT3 (Orthoclone) would reduce early inflammatory complications in experimental acute pancreatitis.. Laboratory study.. University hospital, Germany.. 36 Balb/c mice.. Pancreatitis induced by 7 intraperitoneal injections of cerulein 50 microg/kg at hourly intervals followed by FK506 0.32 mg/kg, OKT3 0.6 mg/kg, or 0.9% sodium chloride (controls) (n = 12 in each group). 12 hours after induction of pancreatitis the animals were killed.. Serum amylase activity and interleukin-6 (IL-6) concentrations; histological damage to pancreas and lungs, apoptotic cells in pancreas; and myeloperoxidase activity in lungs.. No animal died during the experiment. At 12h serum amylase activity and IL-6 concentrations were increased in all 3 groups, but highest in the OKT3 group. The pancreatic histological score, apoptosis, and inflammatory infiltration were lower in the two experimental groups than controls, but the degree of vacuolisation of acinar cells was similar. Packed cell volume was higher in the control than the experimental groups, and pulmonary damage and myeloperoxidase activity were less in the experimental groups than the controls.. Single therapeutic doses of FK506 and OKT3 reduced the early severity of pancreatitis, pulmonary damage, and haemoconcentration in mice. Single doses of FK506 or OKT3 may therefore be effective in preventing the early complications of pancreatitis.

Topics: Acute Disease; Amylases; Animals; Apoptosis; Ceruletide; Female; Immunosuppressive Agents; Interleukin-6; Lung; Mice; Mice, Inbred BALB C; Muromonab-CD3; Pancreas; Pancreatitis; Peroxidase; Tacrolimus

Topics: Adolescent; Adult; Chronic Disease; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreas Transplantation; Pancreatitis; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

To use mice to examine the effects of cyclosporine and tacrolimus (FK 506) on two forms of acute pancreatitis often seen after clinical organ transplantation.. In the first experiment, male CD-1 mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously once a day for 10 days. On the 11th day, acute edematous pancreatitis was induced by ceruletide (cerulein). In the second experiment, female ICR mice were fed with a choline-deficient, ethionine-supplemented (CDE) diet for 72 hours to induce necrotizing pancreatitis. After 30 hours on the CDE diet, the mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously twice daily for 3 days.. The pancreatic dry-to-wet weight ratios after ceruletide injections significantly decreased in mice treated with cyclosporine but did not with tacrolimus. Cyclosporine also significantly increased serum amylase levels, but tacrolimus did not. Cyclosporine or tacrolimus alone did not produce pancreatitis. In the CDE diet groups there was a significant difference in survival among the cyclosporine-treated, the tacrolimus-treated, and the control groups.. Cyclosporine or tacrolimus given alone does not induce acute pancreatitis. In contrast, cyclosporine can adversely affect the course of acute edematous pancreatitis, and both immunosuppressants may worsen the survival of mice with acute hemorrhagic necrotizing pancreatitis. This study also demonstrated that the deteriorating effect of tacrolimus is less potent than that of cyclosporine.

Topics: Acute Disease; Animals; Ceruletide; Choline Deficiency; Cyclosporine; Edema; Ethionine; Female; Male; Mice; Necrosis; Pancreatitis; Tacrolimus

We investigated the acute effects of the immunosuppressive agent, tacrolimus (FK-506), on the exocrine pancreas, in rats with or without stimulation of the pancreas, and evaluated the protective effects exerted by gabexate mesilate (FOY). While an intravenous injection of FK-506 did not change serum amylase levels during the 5-h observation period, this agent increased pancreatic amylase and protein content, and decreased the content of pancreatic DNA. Histologically, we observed intra-acinar vacuolization and individual cell necrosis. When the pancreas was stimulated by two intraperitoneal injections of caerulein (5 micrograms/kg) at 1-h intervals, however, which treatment did not induce any evident pancreatic change, FK-506 significantly increased serum amylase, pancreatic wet weight, and pancreatic amylase and protein, and decreased pancreatic DNA. Histologically, there were significant dose-related differences in the severity of intra-acinar vacuolization, interstitial edema, neutrophil infiltration, individual cell necrosis, and hemorrhage. Levels of intrapancreatic elastase were elevated and local pancreatic blood flow was reduced. Treatment with FOY improved the FK-506-induced acute pancreatitis, but did not increase the pancreatic blood flow. These findings indicate that FK-506 enhances abnormal pancreatic enzyme secretion and suggest that therapeutic doses of this agent can induce acute pancreatitis when the pancreas is stimulated. A protease inhibitor may protect the exocrine pancreas in patients who receive FK-506 after organ transplantation.

Topics: Amylases; Animals; Ceruletide; Gabexate; Male; Pancreas; Pancreatic Elastase; Pancreatitis; Rats; Rats, Wistar; Tacrolimus