Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea

Eades, Shannan K.; Boineau, Frank G.; Christensen, Michael L.

doi:10.1034/j.1399-3046.2000.00086.x

Cited by 44 publications

(40 citation statements)

References 7 publications

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“…In another very recent report on the case of a pediatric renal transplant patient with a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis, the authors speculate that the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time [3].…”

Section: Discussionmentioning

confidence: 99%

Increased tacrolimus levels during diarrhea

Hochleitner¹,

Bösmüller²,

Nehoda³

et al. 2001

Transplant International

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While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

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Section: Discussionmentioning

confidence: 99%

Increased tacrolimus levels during diarrhea

Hochleitner¹,

Bösmüller²,

Nehoda³

et al. 2001

Transplant International

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“…Elevation of serum tacrolimus levels in the setting of gastroenteritis is now well-recognized. [13][14][15][16] Although PI in the newborn period is a well-recognized entity often associated with necrotizing enterocolitis, the propensity for younger children outside of the neonatal period to develop PI is not well-described. 17 The most likely causes for this include differences noted in bowel and associated lymphoid tissue, as well as the tendency for younger children to have more episodes of infectious gastroenteritis.…”

Section: Discussionmentioning

confidence: 99%

Pneumatosis Intestinalis After Pediatric Thoracic Organ Transplantation

et al. 2002

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ABSTRACT. Objective. To review and describe pneumatosis intestinalis (PI) in children who have undergone thoracic organ transplantation and evaluate potential risk factors.Methods. We retrospectively reviewed abdominal radiographs obtained from June 1992 through September 2000 in all pediatric (age <21 years) thoracic organ recipients who survived at least 1 week after transplantation. In this group, a case was defined as an episode of radiographically confirmed PI; those without PI were assigned as controls. Variables analyzed included demographic data, gastroenteritis history (stool cultures or symptoms of gastroenteritis), and transplant-related factors (ie, graft type, rejection history, immunosuppression regimen). Significance was defined as P < .05.Results. Over this 8-year period, PI occurred in 8 (7%) of 116 patients (0.86% annual risk). No child had >1 diagnosed episode of PI. Of these 8 cases, 7 presented with 1 or more abdominal symptoms. Three of these children had rotavirus antigen isolated in their stool, 2 others were noted to have stool positive for Clostridium difficile toxin, and in the other 3, no pathogen was identified. All cases were treated with a regimen of intravenous antibiotics and total parenteral nutrition. There were no deaths; however, 1 patient developed an Aspergillus pulmonary infection during his course of antibiotic therapy, and another underwent an exploratory laparotomy without bowel resection. Significant risk factors included black race (unadjusted odds ratio: 16), younger age at presentation (age <5 years; unadjusted odds ratio: 9), higher steroid dose (steroid dose >0.5 mg/kg/d; unadjusted odds ratio: 7), and a higher tacrolimus level at presentation (tacrolimus level >1; unadjusted odds ratio: 6). PI did not occur with a steroid dose <0.4 mg/kg/d. Variables not associated with increased risk for developing PI included gender, graft type, total white blood cell count, recent antibiotic use, concurrent use of an antimetabolite, cytomegaloviral infection, past use of extracorporeal membrane oxygenation, and graft rejection history.Conclusions. Significant risk factors for the development of PI in our pediatric thoracic organ transplantation population included black race, younger age, higher daily steroid dosing, and a high tacrolimus level at presentation. In the children diagnosed with PI, there were no related deaths, significant gastrointestinal sequelae, or complications. These findings suggest that in this population, PI will often have a benign course when treated aggressively, and that steroid dosing should be reduced to <0.5 mg/kg/d whenever possible. Pediatrics 2002;109(5). URL: http://www.pediatrics.org/cgi/content/ full/109/5/e78; pediatric heart transplantation, pediatric lung transplantation, pediatric heart-lung transplantation, pneumatosis intestinalis, steroids.

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“…Intestinal epithelial cells may be destroyed during enterocolitis, particularly in the case of rotavirus replication [8], reducing the global enzymatic activity of the CYP3A system and P-gp in enterocytes, thereby increasing the levels of tacrolimus [9]. The delay before normalisation of the tacrolimus blood level may thus reflect the time required for enterocyte regeneration and recovery of CYP3A enzymatic activity and P-gp function after gastrointestinal injury [10].…”

Section: Discussionmentioning

confidence: 99%

“…The shortened intestinal transit time during diarrhoea may also contribute to the elevated tacrolimus levels by increasing absorption [11]. The CYP3A system is highly expressed in the duodenum and then progressively declines to the colon [9][10][11]. If higher concentrations of tacrolimus reach the colon, in which CYP3A system activity is lower, this may theoretically contribute to elevated blood levels [8].…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction and pharmacogenetics

et al. 2010

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Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.

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Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea

Cited by 44 publications

References 7 publications

Increased tacrolimus levels during diarrhea

Increased tacrolimus levels during diarrhea

Pneumatosis Intestinalis After Pediatric Thoracic Organ Transplantation

Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction and pharmacogenetics

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