tacrolimus and Tremor

Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.

Topics: Calcineurin Inhibitors; Cyclosporine; Everolimus; Humans; Immunosuppressive Agents; Prospective Studies; Retrospective Studies; Sirolimus; Tacrolimus; Tremor

To explore the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in patients with idiopathic membranous nephropathy (IMN).. A literature search was performed using Embase, Cochrane Library and PubMed from inception through May 31, 2021. All randomized controlled trials (RCTs) exploring the efficacy and safety of TAC combined with corticosteroids in IMN patients were included based on the inclusion and exclusion criteria. Data analyses were conducted using RevMan software (version 5.4).. Seven RCTs involving 520 patients were included in this meta-analysis. Compared with control treatment, TAC combined with corticosteroids could significantly increase the complete remission (CR) rate, total remission (TR) rate, and serum albumin levels, as well as decrease the proteinuria levels within 6-month treatment, but the advantage did not persist to 12-month treatment. After 18-month treatment, the effect of TAC combined with corticosteroids on increasing CR rate, TR rate, and serum albumin levels was significantly worse than control treatment. The mean time to remission in TAC combined corticosteroids group was significantly shorter than that in the control group. The relapse rate, no response rate, change in estimate of the glomerular filtration rate (eGFR), and overall incidence of adverse reactions showed no significant difference between TAC combined with corticosteroids group and control group. However, TAC combined with corticosteroids did have a higher risk of hand tremor, nephrotoxicity, and glucose intolerance than control treatment.. TAC combined with corticosteroids has a significant therapeutic effect for IMN patients within 1-year treatment, especially in the first 6 months. However, in the longer-term treatment, TAC combined with corticosteroids does not have an advantage. TAC combined with corticosteroids has a higher risk of hand tremor, nephrotoxicity, and glucose intolerance. More high-quality studies are needed to further verify the long-term efficacy and safety of TAC combined with glucocorticoids in IMN patients.

Topics: Adrenal Cortex Hormones; Drug Therapy, Combination; Glomerulonephritis, Membranous; Glucose Intolerance; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Serum Albumin; Tacrolimus; Treatment Outcome; Tremor

Topics: Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glucose; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Clearance Rate; Tacrolimus; Tremor

Topics: Blood Pressure; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus; Tremor

Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1-9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21,

Topics: Activities of Daily Living; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Organ Transplantation; Quality of Life; Tacrolimus; Transplant Recipients; Tremor

Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Area Under Curve; Delayed-Action Preparations; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome; Tremor; Young Adult

We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+ T lymphocytes expressing the activation molecule interleukin-2 receptor (p55 alpha chain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25+ CD4+ cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3 +/- 0.2 to 0.5 +/- 0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45R+ CD4+ cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25+ CD4+ cells and a reciprocal increase in CD45RA+ CD4+ cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration.

Topics: Administration, Oral; Adult; Aged; CD4-Positive T-Lymphocytes; Fatigue; Feeding and Eating Disorders; Female; Humans; Leukocyte Common Antigens; Male; Middle Aged; Multiple Sclerosis; Pilot Projects; Receptors, Interleukin-2; Tacrolimus; Tremor

Neurological complications were examined in a multicentre, randomized, parallel-group study of 545 patients undergoing primary liver transplantation to compare the efficacy and safety of FK 506- and cyclosporin A-based immunosuppressive regimens (CBIR). In an additional analysis, patients were divided into early and late randomized cohorts to detect the influence of protocol amendements that allowed for FK 506 dose reductions. Initial follow-up was for 6 months. Tremor, headache and insomnia were the most frequently reported adverse events involving the neurological system. Whereas these neurological symptoms were observed significantly more often in FK 506-treated patients (P < 0.05 vs. CsA for the overall population), this was no longer the case for the late FK 506 and CBIR cohorts. The risk of FK 506-treated patients developing tremor was related to the initial i.v. dose, the rate of administration of the i.v. dose and the daily dose (P < 0.01). Headache was significantly correlated with the FK 506 dose (P < 0.05), and insomnia was not related to any dosing variable. Major neurological symptoms, including psychosis, convulsion, coma, aphasia and intracranial haemorrhage, were reported with a low frequency (0.4-5.2%), and differences between both treatment groups were neither significant for the overall population nor for the early and late cohorts of FK 506 and CBIR. Data from the late cohorts showed no differences in the overall incidence of neurological adverse events between FK 506- and CBIR-treated patients.

Topics: Cyclosporine; Drug Therapy, Combination; Europe; Graft Rejection; Headache; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Nervous System Diseases; Sleep Initiation and Maintenance Disorders; Survival Rate; Tacrolimus; Time Factors; Tremor

Topics: Cyclosporine; Drug Therapy, Combination; Graft Rejection; Headache; Humans; Immunosuppression Therapy; Liver Transplantation; Neurotoxins; Retrospective Studies; Seizures; Sleep Wake Disorders; Tacrolimus; Tremor

Tacrolimus is a potent immunosuppressant drug commonly used after solid organ transplant surgery. The use of this drug is frequently associated with the emergence of tremors. There is little information on the clinical and physiological characteristics of tacrolimus-induced tremors. Characterizing these tremors is essential as they can promote the development of specific therapies.. We describe four patients placed on tacrolimus immunosuppressant therapy following kidney transplant surgery and who developed tremors impacting their daily functional activities. We describe the clinical and physiological characteristics of the tremor and the response generated after a limb cooling test.. A postural and kinetic tremor mainly involving the distal hands was observed in our cohort. In the accelerometer-based assessment, the tremor amplitude was noted to be mild to moderate, and the frequency was 5-6 Hz. Cooling the forearm and the hand led to a temporary albeit significant reduction of tremor amplitude (p = 0.03). Limb cooling lowered the tremor frequency by 1 Hz in two patients with no change in the other two patients, and the statistical comparison was not significant (p > 0.05).. Limb cooling may be pursued as a therapeutic option for addressing tacrolimus-induced tremor, as the patients in our cohort benefitted from temporary tremor suppression.

Topics: Forearm; Humans; Immunosuppressive Agents; Tacrolimus; Tremor; Upper Extremity

Topics: Acute Disease; Adult; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Compounding; Drug Dosage Calculations; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus; Treatment Outcome; Tremor

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Topics: Animals; Axons; Cell Death; Cell Survival; Cuprizone; Cytoprotection; Demyelinating Diseases; eIF-2 Kinase; Encephalomyelitis, Autoimmune, Experimental; Enzyme Activation; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Signal Transduction; Tacrolimus; Tremor

Tacrolimus is an important immunosuppressant administered to patients following liver transplantation (LT), with a recommended trough concentration of 8 to 11 ng/mL to prevent allograft rejection. We retrospectively examined our data to identify the tacrolimus trough concentration that combined efficacy with minimal adverse effects.. The case records of LT recipients, who were nondiabetic, nonhypertensive, and with normal renal parameters prior to LT were retrospectively examined for acute cellular rejection (ACR) episodes and three major adverse effects of tacrolimus, i.e. neurotoxicity, nephrotoxicity, and new onset diabetes mellitus (NODM).. Thirty-two LT recipients fulfilled the criteria for the study. The mean (±SD) tacrolimus level for the 290 troughs (after 10 days) was 8.5 ± 3.8 ng/mL. At 10 days, 1 month, 3 months, and 6 months, the trough values were 7.3 ± 2.9, 9.7 ± 3.4, 7.9 ± 3.3, and 7.6 ± 2.6 ng/mL, respectively. The mean time taken for stabilization of the blood pressure and biochemical parameters was 7 ± 2 days. Overall, a trough window with the least adverse effect was 7 to 7.9 ng/mL. Neurotoxicity was least in the trough range 5 to <8 ng/mL. Symptoms included headache in four, tremors in three, seizure in one, confusion and psychosis in two, and combination in three. Nephrotoxicity was least in trough 8 to <11 ng/mL. One patient progressed to chronic kidney disease at 6 months. NODM was present in 11 % to 18 % across the various trough range, including the extremes (mean trough level, 8.4 ± 4.4 ng/dL). At 6 months, five recipients were on treatment for NODM. Three recipients developed ACR, two within the first month and one at 7 weeks. The trough levels were 8.5, 9, 15.2 ng/mL, respectively. All recovered with three pulse doses of methylprednisolone.. Tacrolimus concentration of 5 to <8 ng/mL was associated with least overall toxicity, neurotoxicity, and ACR.

Topics: Adolescent; Adult; Aged; Confusion; Dose-Response Relationship, Drug; Drug Monitoring; Female; Graft Rejection; Headache; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Psychotic Disorders; Renal Insufficiency, Chronic; Retrospective Studies; Seizures; Tacrolimus; Tremor; Young Adult

Neurologic complications are a significant cause of morbidity in children after liver transplant. In this study, we sought to evaluate the neurologic complications in children after liver transplant.. All children aged younger than 18 years old who had undergone liver transplant between June 2004 and June 2007 were included in this prospective study. There were 30 boys (62.5%) and 18 girls (37.5%) (mean age, 9.6 -/+ 4.3 years; mean duration of follow-up, 21.6 -/+ 9.4 months). The most common indications for liver transplant were biliary atresia (n=12, 25%), Wilson disease (n=7, 14.6%), tyrosinemia (n=7, 14.6%), progressive familial intrahepatic cholestasis (n=6, 12.5%), and autoimmune cirrhosis (n=5, 10.4%).. Immunosuppressive medication consisted tacrolimus (n=44, 91.7%) or cyclosporine (n=4, 8.3%) combined with mycophenolate mofetil (n=33, 68.7%) and prednisolone (n=18, 37.5%). The most-common neurologic complications were tremor (n=8, 16.7%), convulsions (n=6, 12.5%), insomnia (n=6, 12.5%), headache (n=5, 10.4%), muscle cramps (n=5, 10.4%), paresthesia (n=3, 6.2%), and weakness (n=3, 6.2%).. We conclude that the most-common neurologic complication after liver transplant in children in contrast to other studies is tremor, same as adult patients. This may be due to higher rate of use of tacrolimus in our patients.

Topics: Adolescent; Autoimmune Diseases; Child; Child, Preschool; Cholestasis, Intrahepatic; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Transplantation; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome; Tremor

To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA).. Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids.. 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints.. This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Pressure; Creatinine; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Long-Term Care; Male; Middle Aged; Tacrolimus; Treatment Outcome; Tremor

To assess tremor characteristics and severity in patients with severe liver disease without hepatic encephalopathy and following orthotopic liver transplantation (LTX) and immunosuppression (IS) with cyclosporin A (CsA) or tacrolimus (FK 506).. A total of 35 consecutive patients were included into the prospective study and serum levels of CsA (n = 29) or FK 506 (n = 6) were monitored following LTX. Tremor characteristics and severity were assessed by two-blinded raters before and following LTX. In addition, accelerometric recordings were taken before and after LTX, and compared with 16 normal controls without tremor and without clinical signs of hepatic encephalopathy or liver disease. Accelerometry was performed while sitting in a comfortable chair with the forearms supported and included rest and postural condition with and without weight load (500 g) on each hand. Kolmogorov-Smirnov test, paired t-test and t-test for independent samples were used for statistical analysis.. The clinical rating revealed no rest but a mild postural hand tremor before LTX with a significant increase following LTX (p < 0.001). After LTX the mean score of postural tremor was significantly (p < 0.05) higher in patients with plasma levels of >850 ng CsA/ml compared with patients with lower levels. Patients and normal controls showed comparable mean peak frequencies of rest and postural hand tremor. The mean amplitude of postural hand tremor was significantly higher in patients before and after LTX compared with controls. In the majority of patients (89%) and controls (88%), the dominant tremor frequency decreased significantly (>1.5 Hz) when applying a weight load on each hand.. The present study is the first to describe hand tremor characteristics in patients with severe liver disease without clinical signs of hepatic encephalopathy and in patients following LTX and IS. Compared with normal controls the patients showed a significant postural hand tremor prior and post-LTX and an increase of mean tremor amplitude following LTX and CsA/FK 506 treatment. The decrease of the dominant tremor frequency with weight load and an increase of tremor amplitude with higher plasma levels of CsA are both indicative of an enhanced physiological or toxic tremor.

Topics: Adult; Aged; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Tremor

1. Tacrolimus, a potent immunosuppressant, induces impaired renal function and neurological complications. We investigated the influence of dosing time on the neurotoxicity, nephrotoxicity, and immunosuppressive effect of tacrolimus in rats. 2. The repeated injection of tacrolimus in the light phase (8:00) produced a significantly greater increase than that in the dark phase (20:00) in the duration of harmine-induced tremors and in the blood urea nitrogen (BUN) concentration in rats. An immunosuppressive effect of tacrolimus on the xenotransplantation of mouse-to-rat skin grafts was apparent in the dark phase but not in the light phase. 3. The dosing time-dependent pharmacokinetic results were not observed when tacrolimus concentrations in rat whole blood were measured after a single or repeated injection in the light or dark phase. 4. These findings suggest that treatment in the active phase of the diurnal cycle ameliorates neurotoxicity and nephrotoxicity while maintaining the immunosuppressive effect of tacrolimus. The present findings have important implications for therapeutic approaches to avoid tacrolimus-induced neurotoxicity and nephrotoxicity.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Darkness; Graft Survival; Harmine; Kidney; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Wistar; Skin Transplantation; Tacrolimus; Transplantation, Heterologous; Tremor

Topics: Animals; Hemolytic-Uremic Syndrome; Immunosuppressive Agents; Insulin; Islets of Langerhans; Kidney; Macaca mulatta; Pancreas; Tacrolimus; Tremor

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Anti-Bacterial Agents; Antifungal Agents; Biopsy, Needle; Clarithromycin; Creatinine; Diltiazem; Drug Interactions; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Infusions, Intravenous; Itraconazole; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Time Factors; Transplantation, Homologous; Tremor; Ultrasonography; Vasodilator Agents

The presence of severe and mild neurotoxicity in our pediatric renal transplant recipients treated with tacrolimus was determined by chart review (severe neurotoxicity) and patient survey (mild neurotoxicity). 14 patients were studied (mean age 15 yr, 5 month, +/- 4.4 yr). 1 patient experienced seizures, felt to be related to malignant hypertension. No other episode of severe neurotoxicity was documented. Most patients (12/14) reported at least one mild neurologic symptom, and half stated their symptoms were present at least 'most of the time'. The most frequent complaints were myalgias (7/14, 50%) and tremors (7/14, 50%) followed by fatigue (5/14, 38%). Severe neurotoxicity may be relatively infrequent in pediatric renal transplant patients treated with tacrolimus. Milder neurologic complaints may be commonly seen in this population, but in general are not severe enough to cause discontinuation of tacrolimus.

Topics: Adolescent; Adult; Child; Evaluation Studies as Topic; Eye; Fatigue; Follow-Up Studies; Headache; Humans; Hyperesthesia; Hypertension, Malignant; Immunosuppressive Agents; Kidney Transplantation; Muscle, Skeletal; Pain; Peripheral Nervous System Diseases; Retrospective Studies; Seizures; Sleep Initiation and Maintenance Disorders; Tacrolimus; Tremor