- Email: [email protected]
Tacrolimus Intoxication Resolved by Gastrointestinal Bleeding: Case Report
Tacrolimus Intoxication Resolved by Gastrointestinal Bleeding: Case Report F.C. Renner, A. Staak, L. Bur am Orde, H.-D. Walmrath, and R. Weimer ABSTRACT Tacrolimus is a potent immunosuppressive agent widely used in renal and liver transplantations. Its potential side effects due to overdosing are variable. Most commonly toxic tacrolimus blood levels affect the central and peripheral nervous systems. Once absorbed, tacrolimus binds to plasma proteins and accumulates within erythrocytes. Current treatment strategies to overcome acute intoxications focus on the induction of hepatic cytochrome P450 enzymes to accelerate tacrolimus degradation. We report the case of a 69-year-old renal transplant recipient presenting with acute liver failure, septic shock, and tacrolimus intoxication. The intoxication was resolved by massive gastrointestinal bleeding and subsequent transfusion of packed erythrocytes. We concluded that exchange blood transfusions offer an alternative therapeutic approach for patients with severe liver function impairment and tacrolimus intoxication.
O
N APRIL 27, 2005, a 69-year-old female Caucasian patient was admitted to our intensive care unit with septic shock. In a southern German transplant unit the patient had received a deceased donor kidney graft in September 2004, due to autosomal dominant polycystic kidney disease (ADPKD) with need for hemodialysis since July 2000. Furthermore, the patient suffered hepatic dysfunction, because of multiple hepatic cyst formation resulting in hepatic mass reduction. Coronary artery sclerosis without significant narrowing of coronary vessels was diagnosed by angiography in April 2001. The patient had a complicated clinical course after transplantation with delayed graft function. She developed de novo posttransplantation diabetes mellitus which was intermittently treated with gliquidon. In November 2004, the patient had to be readmitted for urosepsis complicated by pseudomembranous enterocolitis and bullous necrotizing erysipelas on both shanks of unknown origin requiring surgical necrosectomy. The medical history leading to admission to our intensive care unit included severe diarrhea for 3 weeks, progressive physical weakness, and eventually mental confusion and somnolence. The patient had been mildly feverish (up to 38°C) for approximately 1 week preceding admission. Blood pressure was reported as normal (140/85 mm Hg) until admission. The patient became anuric since April 24. The patient had been on tacrolimus (1.5 mg twice daily), prednisolone (5 mg once daily), metoprolol (12.5 mg once daily), digitoxin, torasemid (5 mg once daily), thyroxin
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2006.12.022 522
substitution (100 g once daily), and simvastatin (20 mg once daily). On admission the patient presented with septic shock: hypotension (70/30 mm Hg), tachycardia (100 –110/min), tachypnea (30 – 40/min), reduced vigilance (Glasgow Coma Scale [GCS] score 8), and raised infection parameters (white blood cell count [WCC] 30.1 giga/L; C-reactive protein [CRP] 276.9 mg/L). Her clinical status was further complicated by acute renal failure (serum creatinine 2.9 mg/dL at the day of admission while historical serum creatinine levels were between 1.0 and 1.5 mg/dL) with generalized edema and anuria. Blood liver enzymes were suggestive of severe liver impairment (Table 1). On the left shank ulcer formation with a diameter of approximately 4 cm was found. The patient suffered from watery diarrhea but was not feverish. Diarrhea began 1 week after discontinuation of oral valgancyclovir given as prophylaxis in a cytomegalovirus (CMV) IgG positive donor and negative recipient setting. Clinical suspicion of CMV enterocolitis was confirmed by detection of 400,000 genomes/mL blood From the Renal Transplant Unit (F.C.R., A.S., L.B.a.O., R.W.) and Intensive Care Unit (H.-D.W.), Department of Internal Medicine, University Clinic of Giessen and Marburg, Giessen, Germany. Address reprint requests to Fabrice Christoph Renner, Department of Internal Medicine, University Clinic of Giessen and Marburg, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail: [email protected] © 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 522–525 (2007)
TACROLIMUS INTOXICATION
523 Table 1. Time Course of Relevant Blood Parameters Date
WCC (giga/L) Hemoglobin (g/L) Thrombocyte count (giga/L) Creatinine (mg/dL) LDH (U/L) AST (U/L) APT (U/L) CHE (U/L) CRP (mg/L) Tacrolimus trough level (g/L)
27/04/05
28/04/05
29/04/05
30/04/05
01/05/05
03/05/05
06/05/05
12/05/05
30.1 119 395 2.9 398 76 38 1724 276.9 n.d.
25.1 106 397 3.1 351 42 29 1420 232.1 74.8
16.2 86 208 2.3 333 38 23 2204 143.8 73.2
11.3 119 110 1.3 360 35 n.d. n.d. 63.8 66.0
8.3 73 48 1.1 295 34 16 2964 28.3 24.8
12.4 137 53 1.2 438 32 18 4551 35.5 21.7
17.9 121 64 1.0 431 34 19 2708 54.2 5.8
12.9 105 216 0.9 318 33 34 n.d. 16.5 4.4
n.d. ⫽ not done.
(rt-PCR technique). In blood cultures taken on the day of admission, Pseudomonas aeruginosa was diagnosed. The most probable port of infection was the ulcerous wound on the shank, which was densely colonized by P. aeruginosa. Several technical examinations were performed on the day of admission: chest x-ray showed pleural effusion on the left side and pulmonary edema. Electrocardiography revealed an incomplete left anterior bundle block and sinus tachycardia (100 bpm). Duplex ultrasound of the kidney graft was unable to detect any perfusion of the renal parenchyma, but found a patent renal transplant artery without evidence of stenosis. Initial treatment goals were to overcome the septic shock situation by intravenous (IV) administration of high-dose catecholamines (noradrenaline 13–17 g/min), antibiotics (imipenem and vancomycin) and gancyclovir for CMV treatment. Hemofiltration was performed 6 times during the anuric phase of acute renal failure. One day later, the clinical status of the patient remained unchanged although blood parameters of inflammation declined (WCC 25.1 giga/L; CRP 232.1 mg/L). Liver function parameters were unchanged. We found a tacrolimus trough level of 75 ng/mL and discontinued tacrolimus treatment at once. Hemofiltration treatment was performed daily, but did not result in a significant decline in tacrolimus trough levels (Fig 1). Neurological examination revealed persistent disorientation concerning space, time, and person, somnolence, dysarthria, eye opening only to pain, inadequate motor reactions, and undirected withdrawal of upper and lower limbs to pain. CT scan of the brain did not show signs of cerebral hemorrhage, malignancy, edema, or cortical atrophy. Ammonia blood level was not measured as there was no conclusive evidence for ammonemia from the patient’s history (no tarry stools, no visible blood staining of stools). Drug screening and ethanol blood levels were not done because the patient’s relatives firmly denied that the patient abused drugs or alcohol. Tacrolimus trough levels remained high on April 29 (73 ng/mL). Catecholamine dosage was reduced to 2 to 4 g/min. Blood parameters of inflammation slowly declined.
As there was no improvement in the neurological status, we concluded that tacrolimus intoxication played a major role in the central nervous system dysfunction. On April 30, the patient developed an arrhythmia due to atrial fibrillation and was heparinized. On the night from April 30 to May 1, a massive gastrointestinal hemorrhage occurred with peranal outflow of bright red blood. Proctoscopic intervention showed internal hemorrhoids as the source of bleeding. The patient was transfused with 5 red cell concentrates, 4 fresh frozen plasmas, and 2 thrombocyte concentrates. Heparin was stopped. With that, blood loss was halted. On May 1, the tacrolimus trough level had dropped to 25 ng/mL (see Fig 1). The clinical status of the patient dramatically improved on May 1. She was still disoriented in space and time, but was no longer somnolent and showed adequate reactions when spoken to. Dysarthria had disappeared. Renal graft function improved and diuresis started again. Liver function improved, too, with falling liver enzymes in the blood. This development was paralleled by an improvement in inflammation parameters (see Table 1). The last hemofiltration was performed on May 2. On May 3, the patient was transferred from the intensive care unit to the renal transplant unit. On May 8, tacrolimus administration was restarted. DISCUSSION
Tacrolimus (Prograf; Astellas Pharma Inc. Deerfield, Ill, USA) is an immunosuppressive agent indicated for the prophylaxis of organ rejection in liver and kidney transplantation. Following oral application it is rapidly absorbed. In blood tacrolimus is mainly associated with erythrocytes and soluble plasma proteins. The unbound tacrolimus fraction is 1% to 2%. Tacrolimus is metabolized by the cytochrome P450 3A enzyme system subfamily in the liver and the intestine. Most of the metabolites are excreted via the bile into the feces.1 Several cases of intentional or accidental tacrolimus intoxications have been reported (tacrolimus trough levels reported: 27–197 ng/mL).2– 8 The clinical signs and symp-
524
RENNER, STAAK, BUR AM ORDE ET AL
Fig 1. Time course of tacrolimus trough levels and hemoglobin values. ⴱ ⫽ blood taken in the morning; ⴱⴱ ⫽ blood taken in the evening; ⴱⴱⴱ ⫽ blood taken at noon. Arrows indicate time and number of packed erythrocyte transfusions, each arrow representing 1 unit.
toms described were mainly related to the known neurotoxicity, nephrotoxicity, hepatotoxicity, and the immunosuppressive properties of tacrolimus: tonic-clonic seizures, tremor, myalgias, diplopia, cranial nerve palsy, paresthesias, nystagmus, muscular weakness, areflexia, tetraparesis, decrease of epicritic sensitivity, axonal neuropathy, dysmetria, coma, opportunistic infections (pneumonia, sepsis), renal (transplant) failure, nausea, headache, diabetes mellitus, and elevated liver enzymes. Signs of side effects with therapeutic trough levels were reported by Oliverio et al9 and Veroux et al.10 The descriptions of symptoms and especially the severity of clinical signs varied. Variable options of therapy have been proposed. In all reported cases, tacrolimus was temporarily withheld or the dosage significantly reduced. Close clinical observation of intoxicated patients is also recommended by all. Other management options proposed sought to hinder gastrointestinal absorption (gastric lavage, oral administration of activated charcoal to bind ingested tacrolimus) only within 1 hour following ingestion6 or enhanced tacrolimus metabolism by inducing the hepatic P450 CYP3A enzyme system (phenytoin 1.7 mg/kg7; thyroxin5; phenobarbital 5 mg/kg8).
Most of the delineated cases of tacrolimus intoxication resolved without sequelae. To our knowledge, this is the first description of a profound reduction of tacrolimus blood concentrations by hemorrhage and transfusion of packed erythrocytes. One may ask why this patient who did not change her drug administration scheme developed tacrolimus intoxication. It is well known that inhibitors of the P450 CYP3A enzyme system, such as diltiazem11 or verapamil, inhibit hepatic degradation of tacrolimus leading to increased tacrolimus blood concentrations. Other drugs like erythromycin interfere with hepatic enzymal detoxification as competent concurrents and hence higher blood levels of tacrolimus. Metoclopramide was described to support enteral absorption in patients suffering from impaired gastric motility.12 However, the patient in our case received none of these drugs. Hochleitner and co-workers13 related increased tacrolimus trough levels (up to 60 ng/mL) with ongoing infectious gastroenteritis. They put forth a reduced presystemic metabolic degradation within bowel mucosa as explanation for the overproportional increase in intestinal absorption of tacrolimus leading to intoxication. In all of their 6 cases, the
TACROLIMUS INTOXICATION
increased trough levels declined with treatment discontinuation.13 We hypothesized that tacrolimus intoxication in our case resulted from a vicious circle where the preexisting liver dysfunction due to the hepatic cysts in the context of ADPKD exacerbated under the growing influence of septicemia led to the accumulation of tacrolimus which itself worsened both liver dysfunction and septicemia. Patients on tacrolimus therapy presenting with new neurological disorders (central or peripheral) should be checked for tacrolimus toxicity. In cases of pronounced liver function impairment in combination with subacute tacrolimus overdose, exchange blood transfusions offer an alternative therapeutic approach. Discontinuation of tacrolimus administration and close clinical surveillance are prerequisites for successful therapy. REFERNCES 1. Wallemacq PE, Reding R: FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects. Clin Chem 39:2219, 1993 2. Boukriche Y, Brugiere O, Castier Y, et al: Severe axonal polyneuropathy after a FK506 overdosage in a lung transplant recipient. Transplantation 72:1849, 2001
525 3. Curran CF, Blahunka PC, Lawrence ID: Acute overdoses of tacrolimus. Transplantation 62:1376, 1996 4. Filler G, Amendt P, von Bredow M, et al: Transient diabetes mellitus and peripheral insulin resistance following tacrolimus intoxication in a child after renal transplantation. Nephrol Dial Transplant 12:334, 1997 5. Haas M, Kletzmayer J, Staudinger T, et al: Hypothyroidism as a cause of tacrolimus intoxication and acute renal failure: a case report. Wien Klin Wochenschr 112:939, 2000 6. Mrvos R, Hodgman M, Krenzelok EP: Tacrolimus (FK506) overdose: a report of five cases. J Toxicol Clin Toxicol 35:395, 1997 7. Yeh CN, Hsieh CH, Hung CM, et al: Case report: acute overdoses of tacrolimus (FK506). Dig Dis Sci 44:1650, 1999 8. Quiros-Tejeira RE, Chang IF, Bristow LJ, et al: Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient. Pediatr Transplant 9:792, 2005 9. Oliverio PJ, Restrepo L, Mitchell SA, et al: Reversible tacrolimus-induced neurotoxicity isolated to the brain stem. Am J Neuroradiol 21:1251, 2000 10. Veroux P, Veroux M, Puliatti C, et al: Severe neurotoxicity in tacrolimus-treated living kidney transplantation in two cases. Urol Int 71:433, 2003 11. Hebert MF, Lam AY: Diltiazem increases tacrolimus concentrations. Ann Pharmacother 33:680, 1999 12. Prescott WA Jr, Callahan BL, Park JM: Tacrolimus toxicity associated with concomitant metoclopramide therapy. Pharmacotherapy 24:532, 2004 13. Hochleitner BW, Boesmueller C, Nehoda H, et al: Increased tacrolimus levels during diarrhea. Transplant Int 14:230, 2001
O
N APRIL 27, 2005, a 69-year-old female Caucasian patient was admitted to our intensive care unit with septic shock. In a southern German transplant unit the patient had received a deceased donor kidney graft in September 2004, due to autosomal dominant polycystic kidney disease (ADPKD) with need for hemodialysis since July 2000. Furthermore, the patient suffered hepatic dysfunction, because of multiple hepatic cyst formation resulting in hepatic mass reduction. Coronary artery sclerosis without significant narrowing of coronary vessels was diagnosed by angiography in April 2001. The patient had a complicated clinical course after transplantation with delayed graft function. She developed de novo posttransplantation diabetes mellitus which was intermittently treated with gliquidon. In November 2004, the patient had to be readmitted for urosepsis complicated by pseudomembranous enterocolitis and bullous necrotizing erysipelas on both shanks of unknown origin requiring surgical necrosectomy. The medical history leading to admission to our intensive care unit included severe diarrhea for 3 weeks, progressive physical weakness, and eventually mental confusion and somnolence. The patient had been mildly feverish (up to 38°C) for approximately 1 week preceding admission. Blood pressure was reported as normal (140/85 mm Hg) until admission. The patient became anuric since April 24. The patient had been on tacrolimus (1.5 mg twice daily), prednisolone (5 mg once daily), metoprolol (12.5 mg once daily), digitoxin, torasemid (5 mg once daily), thyroxin
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2006.12.022 522
substitution (100 g once daily), and simvastatin (20 mg once daily). On admission the patient presented with septic shock: hypotension (70/30 mm Hg), tachycardia (100 –110/min), tachypnea (30 – 40/min), reduced vigilance (Glasgow Coma Scale [GCS] score 8), and raised infection parameters (white blood cell count [WCC] 30.1 giga/L; C-reactive protein [CRP] 276.9 mg/L). Her clinical status was further complicated by acute renal failure (serum creatinine 2.9 mg/dL at the day of admission while historical serum creatinine levels were between 1.0 and 1.5 mg/dL) with generalized edema and anuria. Blood liver enzymes were suggestive of severe liver impairment (Table 1). On the left shank ulcer formation with a diameter of approximately 4 cm was found. The patient suffered from watery diarrhea but was not feverish. Diarrhea began 1 week after discontinuation of oral valgancyclovir given as prophylaxis in a cytomegalovirus (CMV) IgG positive donor and negative recipient setting. Clinical suspicion of CMV enterocolitis was confirmed by detection of 400,000 genomes/mL blood From the Renal Transplant Unit (F.C.R., A.S., L.B.a.O., R.W.) and Intensive Care Unit (H.-D.W.), Department of Internal Medicine, University Clinic of Giessen and Marburg, Giessen, Germany. Address reprint requests to Fabrice Christoph Renner, Department of Internal Medicine, University Clinic of Giessen and Marburg, Klinikstrasse 36, D-35392 Giessen, Germany. E-mail: [email protected] © 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 522–525 (2007)
TACROLIMUS INTOXICATION
523 Table 1. Time Course of Relevant Blood Parameters Date
WCC (giga/L) Hemoglobin (g/L) Thrombocyte count (giga/L) Creatinine (mg/dL) LDH (U/L) AST (U/L) APT (U/L) CHE (U/L) CRP (mg/L) Tacrolimus trough level (g/L)
27/04/05
28/04/05
29/04/05
30/04/05
01/05/05
03/05/05
06/05/05
12/05/05
30.1 119 395 2.9 398 76 38 1724 276.9 n.d.
25.1 106 397 3.1 351 42 29 1420 232.1 74.8
16.2 86 208 2.3 333 38 23 2204 143.8 73.2
11.3 119 110 1.3 360 35 n.d. n.d. 63.8 66.0
8.3 73 48 1.1 295 34 16 2964 28.3 24.8
12.4 137 53 1.2 438 32 18 4551 35.5 21.7
17.9 121 64 1.0 431 34 19 2708 54.2 5.8
12.9 105 216 0.9 318 33 34 n.d. 16.5 4.4
n.d. ⫽ not done.
(rt-PCR technique). In blood cultures taken on the day of admission, Pseudomonas aeruginosa was diagnosed. The most probable port of infection was the ulcerous wound on the shank, which was densely colonized by P. aeruginosa. Several technical examinations were performed on the day of admission: chest x-ray showed pleural effusion on the left side and pulmonary edema. Electrocardiography revealed an incomplete left anterior bundle block and sinus tachycardia (100 bpm). Duplex ultrasound of the kidney graft was unable to detect any perfusion of the renal parenchyma, but found a patent renal transplant artery without evidence of stenosis. Initial treatment goals were to overcome the septic shock situation by intravenous (IV) administration of high-dose catecholamines (noradrenaline 13–17 g/min), antibiotics (imipenem and vancomycin) and gancyclovir for CMV treatment. Hemofiltration was performed 6 times during the anuric phase of acute renal failure. One day later, the clinical status of the patient remained unchanged although blood parameters of inflammation declined (WCC 25.1 giga/L; CRP 232.1 mg/L). Liver function parameters were unchanged. We found a tacrolimus trough level of 75 ng/mL and discontinued tacrolimus treatment at once. Hemofiltration treatment was performed daily, but did not result in a significant decline in tacrolimus trough levels (Fig 1). Neurological examination revealed persistent disorientation concerning space, time, and person, somnolence, dysarthria, eye opening only to pain, inadequate motor reactions, and undirected withdrawal of upper and lower limbs to pain. CT scan of the brain did not show signs of cerebral hemorrhage, malignancy, edema, or cortical atrophy. Ammonia blood level was not measured as there was no conclusive evidence for ammonemia from the patient’s history (no tarry stools, no visible blood staining of stools). Drug screening and ethanol blood levels were not done because the patient’s relatives firmly denied that the patient abused drugs or alcohol. Tacrolimus trough levels remained high on April 29 (73 ng/mL). Catecholamine dosage was reduced to 2 to 4 g/min. Blood parameters of inflammation slowly declined.
As there was no improvement in the neurological status, we concluded that tacrolimus intoxication played a major role in the central nervous system dysfunction. On April 30, the patient developed an arrhythmia due to atrial fibrillation and was heparinized. On the night from April 30 to May 1, a massive gastrointestinal hemorrhage occurred with peranal outflow of bright red blood. Proctoscopic intervention showed internal hemorrhoids as the source of bleeding. The patient was transfused with 5 red cell concentrates, 4 fresh frozen plasmas, and 2 thrombocyte concentrates. Heparin was stopped. With that, blood loss was halted. On May 1, the tacrolimus trough level had dropped to 25 ng/mL (see Fig 1). The clinical status of the patient dramatically improved on May 1. She was still disoriented in space and time, but was no longer somnolent and showed adequate reactions when spoken to. Dysarthria had disappeared. Renal graft function improved and diuresis started again. Liver function improved, too, with falling liver enzymes in the blood. This development was paralleled by an improvement in inflammation parameters (see Table 1). The last hemofiltration was performed on May 2. On May 3, the patient was transferred from the intensive care unit to the renal transplant unit. On May 8, tacrolimus administration was restarted. DISCUSSION
Tacrolimus (Prograf; Astellas Pharma Inc. Deerfield, Ill, USA) is an immunosuppressive agent indicated for the prophylaxis of organ rejection in liver and kidney transplantation. Following oral application it is rapidly absorbed. In blood tacrolimus is mainly associated with erythrocytes and soluble plasma proteins. The unbound tacrolimus fraction is 1% to 2%. Tacrolimus is metabolized by the cytochrome P450 3A enzyme system subfamily in the liver and the intestine. Most of the metabolites are excreted via the bile into the feces.1 Several cases of intentional or accidental tacrolimus intoxications have been reported (tacrolimus trough levels reported: 27–197 ng/mL).2– 8 The clinical signs and symp-
524
RENNER, STAAK, BUR AM ORDE ET AL
Fig 1. Time course of tacrolimus trough levels and hemoglobin values. ⴱ ⫽ blood taken in the morning; ⴱⴱ ⫽ blood taken in the evening; ⴱⴱⴱ ⫽ blood taken at noon. Arrows indicate time and number of packed erythrocyte transfusions, each arrow representing 1 unit.
toms described were mainly related to the known neurotoxicity, nephrotoxicity, hepatotoxicity, and the immunosuppressive properties of tacrolimus: tonic-clonic seizures, tremor, myalgias, diplopia, cranial nerve palsy, paresthesias, nystagmus, muscular weakness, areflexia, tetraparesis, decrease of epicritic sensitivity, axonal neuropathy, dysmetria, coma, opportunistic infections (pneumonia, sepsis), renal (transplant) failure, nausea, headache, diabetes mellitus, and elevated liver enzymes. Signs of side effects with therapeutic trough levels were reported by Oliverio et al9 and Veroux et al.10 The descriptions of symptoms and especially the severity of clinical signs varied. Variable options of therapy have been proposed. In all reported cases, tacrolimus was temporarily withheld or the dosage significantly reduced. Close clinical observation of intoxicated patients is also recommended by all. Other management options proposed sought to hinder gastrointestinal absorption (gastric lavage, oral administration of activated charcoal to bind ingested tacrolimus) only within 1 hour following ingestion6 or enhanced tacrolimus metabolism by inducing the hepatic P450 CYP3A enzyme system (phenytoin 1.7 mg/kg7; thyroxin5; phenobarbital 5 mg/kg8).
Most of the delineated cases of tacrolimus intoxication resolved without sequelae. To our knowledge, this is the first description of a profound reduction of tacrolimus blood concentrations by hemorrhage and transfusion of packed erythrocytes. One may ask why this patient who did not change her drug administration scheme developed tacrolimus intoxication. It is well known that inhibitors of the P450 CYP3A enzyme system, such as diltiazem11 or verapamil, inhibit hepatic degradation of tacrolimus leading to increased tacrolimus blood concentrations. Other drugs like erythromycin interfere with hepatic enzymal detoxification as competent concurrents and hence higher blood levels of tacrolimus. Metoclopramide was described to support enteral absorption in patients suffering from impaired gastric motility.12 However, the patient in our case received none of these drugs. Hochleitner and co-workers13 related increased tacrolimus trough levels (up to 60 ng/mL) with ongoing infectious gastroenteritis. They put forth a reduced presystemic metabolic degradation within bowel mucosa as explanation for the overproportional increase in intestinal absorption of tacrolimus leading to intoxication. In all of their 6 cases, the
TACROLIMUS INTOXICATION
increased trough levels declined with treatment discontinuation.13 We hypothesized that tacrolimus intoxication in our case resulted from a vicious circle where the preexisting liver dysfunction due to the hepatic cysts in the context of ADPKD exacerbated under the growing influence of septicemia led to the accumulation of tacrolimus which itself worsened both liver dysfunction and septicemia. Patients on tacrolimus therapy presenting with new neurological disorders (central or peripheral) should be checked for tacrolimus toxicity. In cases of pronounced liver function impairment in combination with subacute tacrolimus overdose, exchange blood transfusions offer an alternative therapeutic approach. Discontinuation of tacrolimus administration and close clinical surveillance are prerequisites for successful therapy. REFERNCES 1. Wallemacq PE, Reding R: FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects. Clin Chem 39:2219, 1993 2. Boukriche Y, Brugiere O, Castier Y, et al: Severe axonal polyneuropathy after a FK506 overdosage in a lung transplant recipient. Transplantation 72:1849, 2001
525 3. Curran CF, Blahunka PC, Lawrence ID: Acute overdoses of tacrolimus. Transplantation 62:1376, 1996 4. Filler G, Amendt P, von Bredow M, et al: Transient diabetes mellitus and peripheral insulin resistance following tacrolimus intoxication in a child after renal transplantation. Nephrol Dial Transplant 12:334, 1997 5. Haas M, Kletzmayer J, Staudinger T, et al: Hypothyroidism as a cause of tacrolimus intoxication and acute renal failure: a case report. Wien Klin Wochenschr 112:939, 2000 6. Mrvos R, Hodgman M, Krenzelok EP: Tacrolimus (FK506) overdose: a report of five cases. J Toxicol Clin Toxicol 35:395, 1997 7. Yeh CN, Hsieh CH, Hung CM, et al: Case report: acute overdoses of tacrolimus (FK506). Dig Dis Sci 44:1650, 1999 8. Quiros-Tejeira RE, Chang IF, Bristow LJ, et al: Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient. Pediatr Transplant 9:792, 2005 9. Oliverio PJ, Restrepo L, Mitchell SA, et al: Reversible tacrolimus-induced neurotoxicity isolated to the brain stem. Am J Neuroradiol 21:1251, 2000 10. Veroux P, Veroux M, Puliatti C, et al: Severe neurotoxicity in tacrolimus-treated living kidney transplantation in two cases. Urol Int 71:433, 2003 11. Hebert MF, Lam AY: Diltiazem increases tacrolimus concentrations. Ann Pharmacother 33:680, 1999 12. Prescott WA Jr, Callahan BL, Park JM: Tacrolimus toxicity associated with concomitant metoclopramide therapy. Pharmacotherapy 24:532, 2004 13. Hochleitner BW, Boesmueller C, Nehoda H, et al: Increased tacrolimus levels during diarrhea. Transplant Int 14:230, 2001