Serum Tacrolimus Levels Research Articles

Catatonia as a manifestation of tacrolimus-induced neurotoxicity in organ transplant patients: a case series

Tacrolimus has been associated with severe neurotoxicity in organ transplant patients. Catatonia can be a rare manifestation of tacrolimus-induced neurotoxicity as we report two cases of catatonia in solid organ transplant patients on tacrolimus. Catatonic symptoms completely resolved in these patients after reducing the tacrolimus dosage or switching it to alternative immunosuppressants. Catatonia symptoms in organ transplant patients should alert clinicians to look for tacrolimus-induced neurotoxicity despite normal serum tacrolimus levels and neuroimaging findings.

Ação do tacrolimus na pancreatite aguda experimental induzida pela arginina

To determine whether tacrolimus administered to rats, in the presence of pancreatitis induced by L-Arginine, interferes with the serum levels of amylase and glucose and the histological pattern of the pancreatic parenchyma. Forty Wistar rats were divided into four groups with 10 rats each: control group (C), tacrolimus group (T), pancreatitis group (P) and pancreatitis-tacrolimus group (PT). We evaluated serum levels of amylase, glucose, and tacrolimus and made histological assessments of the pancreas. Induction of pancreatitis was made by inoculation of L-Arginine at a dose of 500 mg/100g body weight intraperitoneally, and tacrolimus treatment at a dose of 1ìg/kg subcutaneously for four days. Serum amylase was higher (p = 0.0000) in groups PT, P and T than in the control group. The PT group mean was higher (p = 0.0009) than in the T group, but did not differ (p = 0.6802) from the average of the P group. There was no difference between groups P and T (p = 0.2568). Neither in mean blood glucose between the groups (p = 0.4920); serum levels of tacrolimus were similar in PT and T groups (p = 0.7112). There were no histological changes in groups T and C and no hemorrhage in the pancreas of rats in groups P and PT. In group P, there was no edema in 30%, mild edema in 20% and in 50%, moderate; as for inflammatory infiltration, it was moderate in 80% and absent in 20%, and atrophy of the parenchyma was moderate in 60% and severe in 40%. In the PT group, there was edema, inflammatory infiltration or atrophy in the pancreas in all rats. Treatment with Tacrolimus induced an increase in serum amylase in normal mice, but did not affect blood glucose or the histological pattern of the pancreatic parenchyma. In the presence of pancreatitis induced by L-Arginine tacrolimus induced edema, inflammatory infiltration and more severe atrophy in the pancreatic parenchyma.

49 Emphysematous Pyelonephritis in Renal Allograft Successfully Treated with Medical Management

EMPHYSEMATOUS PYELONEPHRITIS IN RENAL ALLOGRAFT SUCCESSFULLY TREATED WITH MEDICAL MANAGEMENT Guillermo Carnero, Susmitha Dhanyamraju, Junu Bhattarai, Rajesh Govindasamy, Michael Schultz. Geisinger Medical Center, Danville, PA Emphysematous pyelonephritis (EPN) is rare and life-threatening necrotizing bacterial infection of the kidney caused by gas-forming organism, mostly in diabetic patients and often requires nephrectomy. We report the case of EPN in renal allograft successfully treated with medical therapy. A 51 year old woman with history of cadaveric kidney transplant 1.5 years back presents to the emergency department with fever, hypotension and vomiting. On admission she appeared acutely ill and dry on physical examination; she had no graft tenderness. She was noted to have diabetic keto-acidosis. Blood urea nitrogen and creatinine level of 67 mg/dl and 4.3 mg/dL respectively from baseline of 20 mg/dl and 1.2 mg/dl. Her white cell count was elevated with bandemia of 16% and her serum tacrolimus level was 5.2 ng/mL. Urine analysis showed numerous WBC and bacteria. Patient was treated with intravenous hydration, insulin infusion and broad spectrum antibiotics. Prograf and Cellcept were held and patient was started on stress dose steroid. Kidney transplant doppler ultrasound showed echogenic foci which likely represented a gas forming infection. CT scan without contrast showed an enlarged and heterogeneous attenuation in right lower quadrant transplant with several pockets of parenchymal gas most consistent with emphysematous pyelonephritis. Two nonobstructive renal calculi in the transplanted kidney were found. Blood and urine cultures grew pan sensitive Escherichia coli responding to intravenous Ceftriaxone. Her general condition improved and sepsis and ketoacidosis resolved. Her allograft function improved and her BUN and creatinine were 27 mg/dl and 1.4 mg/dL at discharge. This is a rare presentation of EPN in a renal allograft associated with calculi. No real consensus exists on the optimal treatment of EPN in kidney transplant recipients and some debate on need for nephrectomy. In conclusion, this case demonstrates successful non-operative therapy of EPN with aggressive medical management in a kidney transplant recipient who presents with urosepsis, shock and renal failure.

Tumefactive demyelination, an uncommon form of tacrolimus neurotoxicity

The immunosuppressant tacrolimus (FK 506) is widely used in transplantation medicine, although it has neurotoxic side effects. The neurotoxicity of tacrolimus to the CNS consists mainly of leukoencephalopathy with clinical and radiologic features similar to posterior reversible encephalopathy syndrome (PRES).1 The neurologic symptoms and signs of leukoencephalopathy usually develop within 3 months of commencing treatment with tacrolimus.1 We describe a patient who developed tumefactive inflammatory demyelinating lesions as an atypical manifestation of tacrolimus neurotoxicity. ### Case report. A 54-year-old woman with hepatocellular carcinoma underwent cadaver liver transplantation in May 2009. After transplantation, she was treated with tacrolimus 0.075 mg/kg and mycophenolate mofetil 250 mg BID. In September 2009, she developed slurred speech and right-side weakness 2 days before admission. Brain MRI scanned 2 days after symptoms onset showed 2 large mass-like lesions in the left corona radiata and frontal lobe. The lesions were hyperintense on T2-weighted images with an open ring pattern on gadolinium enhancement (figure,A). The serum tacrolimus level was 8.5 ng/mL (therapeutic range 5.0–15.0 ng/mL). The CSF analysis showed normal cell count, but elevated total protein level (103 mg/dL). Oligoclonal bands were absent and …

Managing the atazanavir–tacrolimus drug interaction in a renal transplant recipient

The management of the drug interaction between atazanavir and tacrolimus in a renal transplant recipient is described. A 53-year-old African-American man with human immunodeficiency virus (HIV) received a renal transplant and was treated in accordance with a corticosteroid-sparing immunosuppressive protocol and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. His highly active antiretroviral therapy included atazanavir 400 mg daily, abacavir 600 mg daily, and lamivudine 100 mg daily. Because of the potential for a significant interaction between tacrolimus and atazanavir, the tacrolimus dosage was to be based on serum tacrolimus concentrations. The patient was initially administered one dose of tacrolimus 0.5 mg on the morning of postoperative day 2. Evaluation of the tacrolimus profiles revealed that a higher dosage was necessary because serum tacrolimus levels decreased to subtherapeutic levels by 6 hours after dose administration. In an attempt to minimize tacrolimus toxicity and limit the duration of a subtherapeutic tacrolimus level, dosing was adjusted to 1 mg every 8 hours. After 48 hours of this regimen, peak serum tacrolimus levels were lower, and the drug concentrations remained at a relatively steady level throughout the dosing interval. One final dosage adjustment (1.5 mg every 12 hours) was performed to optimize serum tacrolimus levels and patient compliance. In a 53-year-old man with HIV infection who underwent renal transplantation, the drug interaction between atazanavir and tacrolimus was managed by modifying the tacrolimus dosage regimen after determining the patient's blood tacrolimus concentration profile.

Antibody-mediated rejection presenting as allograft hydronephrosis

An 18-year-old boy underwent living-donor renal transplantation. His mother was the donor. The patient was started on tacrolimus (0.1 mg/kg/d), prednisolone (20 mg/d) and azathioprine (2 mg/kg/d), after initial 3 days of I.V. methyl prednisolone (15 mg/kg/d), as immunosuppressive regimen. Six months after transplantation, he presented with fever that had occurred for two days. There was no history of dysuria, altered urine colour, pyuria or edema. Serum creatinine increased from 1.0 mg/dl to 1.9?2.8?3.7 mg/dl over the next 3 days. On the day of admission, serum tacrolimus levels, blood and urine cultures, and search for polyoma virus were ordered. A Doppler ultrasound of the renal allograft artery revealed a resistive index of 0.9 and hydronephrosis, which had not been present on any of the previous ultrasound exams. A CT scan of the abdomen, with an empty urinary bladder, confirmed hydronephrosis of the allograft, with possible pelvic ureteric junction obstruction (Fig. 1). Blood clots, a technically poor ureteral implantation and ureteral are common causes of obstruction in the early post operative phase, whereas periureteral fibrosis, lymphocele and calculi are possible causes in the late post-operative phase. On the same day, the renal transplant surgeon reviewed the operation protocol notes and confirmed that an antireflux procedure, the Lich reimplantation, had indeed been performed. The radionuclide micturition cystography did not reveal vesicoureteral reflux. Ureteric stenosis due to polyoma virus–associated nephropathy (PVAN) was provisionally diagnosed. However, it is known that PVAN typically induces stenosis in the distal rather than the proximal part of the ureter [1, 2]. On day two, the polyoma virus DNA was found to be negative in both urine and blood. Blood and urine cultures were also sterile. Serum tacrolimus levels were found to be 1.8 ng/l. Circulating donor-specific antibodies determination was unfortunately not available in our hospital. The allograft biopsy was done, under ultrasound guidance, and it revealed neutrophils in the capillaries and in the interstitium, diffuse acute tubular injury and C4d positivity in peritubular capillaries. PVAN may be differentiated from acute antibody-mediated rejection (AMR), but not from acute cellular rejection, by the presence of mononuclear and plasma cell infiltration. After renal transplantation, the ureter receives its entire blood supply from the ureteral branch of the renal artery [3]. Acute rejection involves both the kidney and the ureter, and the resulting edema and possible secondary ischaemia may also lead to ureteral obstruction [3]. In an animal model, Hricak et al. [4], found significant alterations in the ureteral dynamics during rejection, as shown by the progressive decrease in electrical activity of the ureteral muscle on electromyography and the reduced G. Swarnalatha R. Ram (&) B. H. Santosh Pai V. Ramesh K. V. Dakshinamurty Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad 082, India e-mail: ram_5_1999@yahoo.com

296 Macrophage migration in tolerance

Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.

Case Report: Drug Interaction Between Tacrolimus and Amiodarone With QT Prolongation

Both amiodarone (Cordarone; Wyeth, Philadelphia, PA) and tacrolimus (Prograf; Astellas, Markham, ON) are metabolized through the cytochrome (CYP) P450 3A metabolic pathway (1, 2). Amiodarone is known to be a potent inhibitor of CYP 3A4 and can increase serum concentrations of drugs that are substrates of this enzyme system (such as tacrolimus). Previous case reports recommend diligent serum tacrolimus concentration monitoring and prospective tacrolimus dose reductions when the two drugs are given in combination (3, 4). This case report provides further evidence to support the drug interaction between tacrolimus and amiodarone as well as evidence of QT prolongation seen in a renal transplant recipient on this drug combination. CASE REPORT A 65-year-old man underwent a living, nonrelated, renal transplant. His medical history was significant for end-stage renal disease secondary to diabetes, sleep apnea, obesity, and bilateral knee arthroscopy. In addition, he had known coronary artery disease and had undergone coronary artery bypass grafting 5 years before transplant. He had been started on amiodarone postoperatively for presumed atrial fibrillation and maintained on 200 mg daily, since then. Preoperatively, he was in sinus rhythm, and a stress test and echocardiogram were normal. QTc was 440 ms (2 days preoperatively). Posttransplant, he began taking tacrolimus 3 mg orally two times per day for immunosuppression in combination with corticosteroids and mycophenolate mofetil 1000 mg orally two times per day. His initial tacrolimus dose had been empirically reduced by approximately 50% because of an anticipated drug interaction with amiodarone. He was also receiving sulfamethoxazole/trimethoprim, metoprolol, nifedipine, simvastatin, insulin, lansoprazole, betahistine, calcium carbonate, and alfacalcidol. The doses of nifedipine and simvastatin, both of which can interact with tacrolimus, were unchanged during the transplant period. His serum tacrolimus levels are presented in Figure 1.FIGURE 1.: Serum tacrolimus concentrations and QTc.On postoperative day 1, his electrocardiogram revealed normal sinus rhythm, with no evidence of ischemia; however, his QTc was prolonged and equal to 535 ms. His troponins were negative. His magnesium, potassium, calcium, and liver enzymes levels were within the normal range. He was empirically treated with magnesium intravenously, and as the QTc was not improving, the amiodarone was discontinued on postoperative day 2. After withdrawal of the amiodarone, his QTc slowly fell over the next few days to 493 ms on postoperative day 5, when he was discharged with good kidney function (Fig. 1). His tacrolimus serum concentrations were maintained in the 12.3 to 14.9 ng/mL range and he was discharged on a dose of 1.5 mg two times per day orally (∼25% of the usual recommended starting dose). DISCUSSION Both amiodarone and tacrolimus have been implicated in prolonging the QT interval (5–8). Our patient's borderline prolongation of QTc preoperatively might be attributable to long-term amiodarone use. Both amiodarone and tacrolimus are substrates at CYP 3A for enzyme metabolism and could potentially be implicated in increasing the concentration of the other agent through competition for metabolism sites. Some studies suggest that the risk of QT prolongation and torsades de pointes with tacrolimus is concentration dependent (5) whereas others do not (6). Tacrolimus-induced QT prolongation is believed to be due to inhibition of the delayed rectifier K+ current (IK), inward rectifier K+ current (IKI), L-type Ca2+ current (ICaL), and prolongation of the action potential duration although other pharmacological mechanisms have been postulated (5, 6). QT prolongation is common with amiodarone but with a low incidence of proarrhythmic events (<1%) (9). Torsades de pointes may be provoked in patients on amiodarone, usually in conjunction with electrolyte imbalances, increased amiodarone doses, or in combination with other drugs that prolong the QT interval (9). The amiodarone-induced inhibition of tacrolimus metabolism resulted in markedly lower doses of tacrolimus than would usually be expected to achieve desired therapeutic serum concentrations. In our patient, despite adjustment and reduction in tacrolimus dose, the patient still had an elevated tacrolimus level. Even more concerning was that the amiodarone-tacrolimus interaction led to a sudden and marked prolongation of the QT interval when tacrolimus was commenced and improved when the amiodarone was discontinued. This is a significant interaction because a large percentage of patients with end-stage renal disease have left ventricular hypertrophy (10) and subsequently are at higher risk of atrial fibrillation especially in the posttransplant operative period. Amiodarone is a commonly used agent for atrial fibrillation and given the importance of the amiodarone-tacrolimus interaction, we suggest that patients who are on, or require, amiodarone while on tacrolimus be closely monitored through serial electrocardiograms or on telemetry. Otherwise, consideration should be given to use an alternative agent. Cathy I. Burger1 Catherine M. Clase2 Azim S. Gangji2 1Department of Pharmacy St. Joseph's Healthcare Hamilton, ON 2Department of Medicine McMaster University Department of Nephrology and Transplant St. Joseph's Healthcare Hamilton, ON

PTH-102 Renal dysfunction is an early morbid event in intestinal transplantation

<h3>Introduction</h3> Renal dysfunction (RD) following intestinal transplantation (SBTx) contributes to significant morbidity and is associated with reduced patient survival. RD has been shown to occur within the first two postoperative years, but renal function in the early postoperative period is poorly described. <h3>Methods</h3> The study was performed in a single centre on patients who had a minimum survival of 6 months following small bowel/multivisceral transplantation. A total of 20 transplants were performed during the study period and 11 were eligible for this study. The data collected were recipient demographics, pre-transplant renal function, donor demographics, immunosuppressive therapy. Renal function (measured by serum creatinine and e-GFR), serum Tacrolimus levels were at 7, 14 and 21 days, 6, 12, 18 and 24 months and 3 years. In addition, number of admissions, acute rejection episodes, need for modulation of immunosuppressants and function of the allografts. The data were retrieved from a prospectively collected database. <h3>Results</h3> 8/11 patients had deterioration in the renal function with mean serum creatinines at Day 14, 21 of 172.4 and 161.2 μmol and at 3 and 6 months 163.1 and 143.9 μmol, respectively. The serum Tacrolimus levels were well controlled between 8.27 and 9.17 μg/l throughout the study period. The RD was treated by 3/8 patients being converted to m-TOR inhibitors and in the other 5/8 patients reduced Tacrolimus levels were used. The renal function for patients converted to MTOR inhibitors improved. The mean number of admissions in the first year after the transplant was 3.66 and 4.13 during 3 years. There was an association between the number of readmissions and renal dysfunction suggesting that these patients had a poorer outcome as previously observed by others. However, we did not find an association between RD and Tacrolimus levels which other have reported. <h3>Conclusion</h3> In our cohort, the renal dysfunction was noted in 73% (8/11) of patients and it occured within the first month of the SBTx. The association with readmission suggests it is related to impaired outcome, its cause remains speculative.

Combined topical dexamethasone/tacrolimus therapy for management of oral chronic GVHD

Chronic GVHD (cGVHD) frequently affects the oral cavity. The purpose of this study was to estimate the efficacy of combined topical dexamethasone (DEX) and tacrolimus (TAC) solutions in the management of oral cGVHD. The records of 14 patients with oral cGVHD treated with combined topical DEX/TAC were reviewed retrospectively. Pre-to-post treatment changes in subjective and objective measures were evaluated at a median follow-up of 60 days. Serum TAC levels were examined. Marginal objective improvement was detected at follow-up. The median pre-to-post treatment differences were 0.5 (range, -1 to 1) for erythema score, and 0.5 (range, 0 to 2) for lichenoid score, (P=0.06, 0.07 and 0.02, respectively). Subjective improvement was noted in three of four measures at the follow-up visit. The median differences in pain, sensitivity and dryness scores were 1 (range -1 to 6), 1 (range -3 to 5) and 2.5 (range, -5 to 5), respectively (0-10 scale, P<0.05). Four patients (37%) showed increased serum TAC levels; however, all remained within therapeutic range. In conclusion, combined topical DEX/TAC therapy appears to be effective in reducing symptoms attributable to oral cGVHD. Our data has shown minimal evidence of systemic TAC absorption.

Improved Adherence and Outcomes for Pediatric Liver Transplant Recipients by Using Text Messaging

The goal was to improve immunosuppressant adherence for pediatric patients with orthotopic liver transplants by using text messaging (TM). A prospective study of sending TM reminders to the primary medication administrator (patient or caregiver) for pediatric transplant recipients was performed. Patient records were reviewed, comparing the year before and the year of the study. The SD of serum tacrolimus levels was used as an indicator of adherence. Forty-one patients provided consent. The median age was 15 years (range: 1-27 years), and the median age at the time of transplantation was 2 years (range: 4 months to 23 years). Fourteen patients (34%) were male. In 29 of 41 cases, the medications were self-administered by the patient. The mean duration of study was 13 +/- 1.5 months. Twenty-two patients were receiving 1 immunosuppressant, 14 were receiving 2, and 5 were receiving 3. Thirteen patients (37%) stopped the study after 4 months. The mean tacrolimus level SD decreased from 3.46 microg/L before the study to 1.37 microg/L (P < .005). The number of immunosuppressants taken and patient self/caregiver medication administration did not significantly affect the results. The number of acute cellular rejection episodes decreased from 12 to 2 during the study. Risk factors for rejection were older age (17.67 vs 13.28 years) and administration of >1 immunosuppressant. We observed significant improvement in medication adherence and a reduction in rejection episodes with TM reminders for pediatric recipients of liver transplants.

Akinetic Mutism Induced by Tacrolimus

Akinetic mutism is an uncommon clinical syndrome characterized by the inability to produce voluntary movements or speech without loss of awareness. Cerebrovascular diseases are the most frequent etiology. It has been reported in cyclosporine-related neurotoxicity, but it is exceptional as the presenting form of tacrolimus intoxication. We report the case of a 66-year-old man who underwent an orthotopic liver transplantation and was treated with intravenous methylprednisolone and tacrolimus. He had an uneventful postoperative course until the third day after surgery, when he developed acute onset mutism, akinesia, and waxy rigidity of passive limb movements. His arterial blood pressure and temperature were normal. Blood analysis and a magnetic resonance image of the brain showed no acute abnormalities. Serum levels of tacrolimus were 20.8 ng/mL, so it was substituted by cyclosporine and mycophenolate mofetil with progressive and complete recovery of akinetic mutism during the following days. Akinetic mutism is an exceptional manifestation of tacrolimus neurotoxicity, but early recognition of the syndrome and withdrawal of the drug are important to avoid persistent cerebral lesions.

Tacrolimus: review of pharmacokinetics, pharmacodynamics, and pharmacogenetics to facilitate practitioners' understanding and offer strategies for educating patients and promoting adherence

Kidney transplantation requires lifelong immunosuppression with agents that prevent allograft rejection. Immunosuppressive regimens typically include a steroid, an immune modulator (eg, azathioprine, mycophenolate mofetil, or mycophenolate sodium), and a calcineurin inhibitor, either cyclosporine or tacrolimus. Tacrolimus is metabolized by cytochrome P450 3A4 in both the liver and small intestine. Drugs that are substrates of cytochrome P450 3A4, as well as inhibitors and inducers of cytochrome P450 3A4, can cause significant interactions with tacrolimus. A review of the pharmacodynamics and pharmacokinetics of tacrolimus is important to enhance practitioners' understanding when using tacrolimus after kidney transplantation. It is also important to educate patients and their families about tacrolimus. Patients' adherence to this medication regimen is pivotal for allograft survival. A consistent and comprehensive approach to education and discharge teaching is a key component of adherence and the attainment of therapeutic drug levels. At Shands Jacksonville Transplant Center, discharge education and teaching tools aid the transplant professionals and facilitate patients' adherence. This in turn supports the goals of maintaining therapeutic serum levels of tacrolimus and improving renal allograft survival.

Tacrolimus: Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics to Facilitate Practitioners' Understanding and Offer Strategies for Educating Patients and Promoting Adherence

Kidney transplantation requires lifelong immunosuppression with agents that prevent allograft rejection. Immunosuppressive regimens typically include a steroid, an immune modulator (eg, azathioprine, mycophenolate mofetil, or mycophenolate sodium), and a calcineurin inhibitor, either cyclosporine or tacrolimus. Tacrolimus is metabolized by cytochrome P450 3A4 in both the liver and small intestine. Drugs that are substrates of cytochrome P450 3A4, as well as inhibitors and inducers of cytochrome P450 3A4, can cause significant interactions with tacrolimus. A review of the pharmacodynamics and pharmacokinetics of tacrolimus is important to enhance practitioners' understanding when using tacrolimus after kidney transplantation. It is also important to educate patients and their families about tacrolimus. Patients' adherence to this medication regimen is pivotal for allograft survival. A consistent and comprehensive approach to education and discharge teaching is a key component of adherence and the attainment of therapeutic drug levels. At Shands Jacksonville Transplant Center, discharge education and teaching tools aid the transplant professionals and facilitate patients' adherence. This in turn supports the goals of maintaining therapeutic serum levels of tacrolimus and improving renal allograft survival.

Effect of rotavirus on serum tacrolimus level in pediatric liver transplant recipients

Pediatrics InternationalVolume 50, Issue 4 p. 592-593 Effect of rotavirus on serum tacrolimus level in pediatric liver transplant recipients Gokhan Tumgor, Corresponding Author Gokhan Tumgor 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeyGokhan Tumgor, MD, Department of Pediatric Gastroenterology/Hepatology/Nutrition, Ege University School of Medicine, 35100 Izmir, Turkey. Email: [email protected]Search for more papers by this author 1,2 Cigdem Arikan, Cigdem Arikan 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 1,2 Unal Aydin, Unal Aydin 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 2 Murat Kilic, Murat Kilic 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 2 Sema Aydogdu, Sema Aydogdu 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 1,2 Gokhan Tumgor, Corresponding Author Gokhan Tumgor 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeyGokhan Tumgor, MD, Department of Pediatric Gastroenterology/Hepatology/Nutrition, Ege University School of Medicine, 35100 Izmir, Turkey. Email: [email protected]Search for more papers by this author 1,2 Cigdem Arikan, Cigdem Arikan 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 1,2 Unal Aydin, Unal Aydin 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 2 Murat Kilic, Murat Kilic 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 2 Sema Aydogdu, Sema Aydogdu 1Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine and 2Ege University Organ Transplantation and Research Center, Izmir, TurkeySearch for more papers by this author 1,2 First published: 25 August 2008 https://doi.org/10.1111/j.1442-200X.2008.02697.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume50, Issue4August 2008Pages 592-593 RelatedInformation

Onset of bronchiolitis obliterans organizing pneumonia in a liver transplant recipient under peg-interferon and ribavirin treatment

A 63-year-old man underwent orthotopic liver transplantation (OLT) on January 26, 2005 for hepatocellular carcinoma (HCC) on HCV related cirrhosis (HCV genotype 2a/2c). The patient was HBsAb, HBcAb and HBeAb positive (HBsAb = 316 mU/ml) and anti-cytomegalovirus (CMV) negative. HBV DNA (bDNA) in the serum was negative, HCV viremia (PCR) was 0.86 MEq/ml 1 month before OLT. The donor was HBcAb and anti-CMV positive. The autoimmunitary pattern was completely negative. Therapy at the discharge after transplantation was based on steroid, tacrolimus, valganciclovir and lamivudine. Steroid and lamivudine therapy were continued for 5 and 3 months respectively. His history was also significant for insulin dependent diabetes, arisen under immunosuppressive therapy. One month after OLT, the patient was submitted to liver biopsy because of an increase in transaminases (AST = 97 U/l, ALT = 159 U/l, normal range 0–40 U/l): no signs of rejection were observed but only a mild periportal necrosis with inflammation. HCV antigen, evaluated with immunohistochemical reaction, was present in more than 50% of hepatocytes. A further increase in transaminases occurred 3 months later (AST = 66 U/l, ALT = 137 U/l), thus the patient underwent a second liver biopsy: this time histological analysis demonstrated clearly a mild active chronic hepatitis HCV related (Knodell score 8, Ishak 14) and no evidence of rejection again. HCV RNA level was 4.35 mEq/ml. Therapy with pegylated interferon alpha 2a and ribavirin (Pegasys 180 mcg once a week plus ribavirin 600 mg/die) was started in July 2005. Liver enzymes rapidly normalized and HCV RNA became negative within a month. Eight weeks after starting this treatment, the patient complained of very intense asthenia and fever; physical examination revealed wheezing and crackles in left pulmonary base, chest x-ray demonstrated a suspicious inflammatory infiltrate in left inferior lobe. Treatment with oral ciprofloxacin and IM piperacillin + tazobactam, was commenced, but 3 days later, he was admitted to our ward for fever persistence. Peg-INF and RIBA were stopped when the patient was hospitalized. On admission he looked pale, lightly dyspnoic; he complained of severe asthenia. No other significative finding was present at physical examination beside the pulmonary one. Temperature was 39 C (102.2 F). Laboratory tests showed a white blood cell count of 6.72 9 10/ll (range 4.00–9.00 9 10/ll), 85% neutrophils, hemoglobin 7.5 g/ dl (range 12–15), ESR 71 mm/h (range 0–36), C-reactive protein 3.96 mg/dl (\0.8), LDH 567 U/l (range 230–460), AST 61 U/l, ALT 34 U/l, c-GT 247 U/l (range 0–50). Arterial blood gas analysis (room air) revealed pH = 7.46, PaCO2 = 34.6 mmHg, PaO2 = 112 mmHg. Tacrolimus serum level was 9.0 ng/ml. The anemia, ascribed to bone marrow depression and emolysis, induced by antiviral therapy, was treated with 2 U packed red blood cells. Because of the presence of various immunodepressant conditions (tacrolimus and interferon treatment, diabetes) an infective cause appeared to be the most likely explanation of fever and pulmonary infiltrates. Serologic tests for bacterial, viral and fungal agents (Legionella, Chlamydia, Mycoplasma pneumoniae, HIV, Parvovirus, EBV, Herpes SimplexVirus, Leishmania, Aspergillus, Cryptococcus) were negative. Only CMV antigenemia pp65 was positive (4 cells/ll). Quantitative C. Crespi (&) S. Gualandi F. Piscaglia L. Bolondi Dipartimento Malattie dell’Apparato Digerente e Medicina Interna, UO Medicina Bolondi, Azienda Ospedaliera Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy e-mail: cristina.crespi@aosp.bo.it

Repigmentation of pretibial vitiligo with calcineurin inhibitors under occlusion

Treatment of vitiligo is a challenge, especially in children. Recently, topical calcineurin inhibitors have been introduced in the management of vitiligo, but significant repigmentation is not achieved except on the face. Large pretibial lesions of a 15-year-old female with progressive vitiligo were treated twice daily over six months with 0.1% tacrolimus ointment on the right and 1% pimecrolimus cream on the left side without effect. Additional overnight occlusion with polyurethane and hydrocolloid foils during the following 18 months led to substantial repigmentation on both sides (tacrolimus-treated side, 88% repigmented area; pimecrolimus-treated side, 73%). Tacrolimus serum levels measured at four different time points did not exceed 1.8 ng/ml. This case report on a direct comparison of topical tacrolimus and pimecrolimus in vitiligo shows that on the shins considerable improvement could be induced with both agents only by additional long-term occlusion and that tacrolimus was somewhat more effective than pimecrolimus.

Decrease in Serum Tacrolimus Level and Rise in Serum Creatinine Under Late Addition of Cinacalcet in a Renal Transplant Recipient With Hyperparathyroidism: A Case Report

Cinacalcet is a calcimimetic drug that has been approved for treatment of secondary and tertiary hyperparathyroidism in patients with renal failure requiring renal replacement therapy. A few cases of successful treatment in renal transplant patients immunosuppressed with cyclosporine have been reported. Herein we have reported the case of a 48-year-old renal transplant recipient presenting with secondary hypercalcemic hyperparathyroidism (parathyroid hormone [PTH] 896 pg/mL; total calcium, up to 3.3 mmol/L) under immunosuppressive therapy with tacrolimus. Owing to substantial comorbidity and a high operative risk, we decided to initiate a therapeutic trial with cinacalcet. Using a daily dose of 30 mg of Cinacalcet, normal calcium levels and a mild fall in PTH levels (decline of 62 pg/mL) were achieved within the first week of treatment. At this point, we also observed a marked decrease in tacrolimus levels (from 6.3 to 2.6 mg/dL) without any change in concomitant medications. Thus, we adapted the tacrolimus dosage. Concurrent with cinacalcet therapy, there was a rise in serum creatinine levels (from 3.9 to 4.9 mg/dL before discontinuation of cinacalcet), which was not reversible after termination of 3 weeks of treatment with cinacalcet, but continued. Cinacalcet and tacrolimus are both metabolized via cytochrome P 450. The documented decrease in tacrolimus serum levels, suggested a drug–drug interaction between tacrolimus and cinacalcet. The irreversible deterioration in renal function may be attributed to nephrotoxic properties of cinacalcet, but may also indicate an acceleration of the natural course of chronic allograft nephropathy.

Biochemical evaluation of glycemic levels of long-term tacrolimus therapy in rats

One of the more serious complications following transplantation is the development of post-transplantation diabetes mellitus (PTDM), which has a major impact on the quality of life, with effects ranging from the control of glycemia times to increased susceptibility to infections and cardiovascular complications. It has been suggested that immunosuppressive therapy, mainly tacrolimus therapy, may be an important factor in the development of PTDM. There is a lack of studies that explore the effects of long-term tacrolimus on PTDM in animal protocols. The objective of this study was therefore to evaluate the effects of long-term therapy with tacrolimus in rats. One group was treated with tacrolimus, injected subcutaneously, in a daily dose of 1 mg/kg of body weight. The chosen dose was sufficient to achieve therapeutic tacrolimus serum levels. The experimental periods were 60, 120, 180 and 240 days. One group was used as control and received daily subcutaneous injections of saline solution during all periods. A tendency towards increased glycemia levels during the initial periods (60 and 120 days) was observed. However, at 180 and 240 days, the glycemia levels were not statistically different from that of the control group of the same period. It may thus be concluded that the deleterious effects of tacrolimus therapy on glycemia may be a time-related side effect.

Toxic serum levels of tacrolimus after topical administration in an infant with severe cutaneous graft-versus-host disease

Previous reports have been published of increased cutaneous absorption of tacrolimus in children with concomitant conditions associated with a skin-barrier dysfunction. Our case is the first report on toxic levels of tacrolimus after topical administration in a child with severe cutaneous acute GVHD. An 11-month-old boy who underwent unrelated umbilical cord blood stem cell transplantation for a SCID received topical tacrolimus for severe cutaneous GVHD. After only two applications restricted to the upper extremities, tacrolimus serum levels reached 23.4 ng/ml. Serum levels rapidly decreased following discontinuation of the topical tacrolimus. No adverse effects related to tacrolimus toxic levels were observed. This case report suggests that significant topical tacrolimus absorption may occur in some children with concomitant conditions displaying skin-barrier dysfunction. Drug monitoring of tacrolimus should be considered in children with extensive skin lesions treated with topical tacrolimus to adjust appropriately dosage.