tacrolimus and Hypertension

Posterior reversible encephalopathy syndrome encompasses a spectrum of disorders with a constellation of clinical symptoms and neuroradiological features. It is commonly encountered in organ transplant where it poses a challenge in the diagnosis and treatment in the absence of strong evidence. The underlying pathophysiology of posterior reversible encephalopathy syndrome is the loss of cerebral autoregulation following elevated blood pressure and/or endothelial dysfunction. It is more likely to happen in patients treated with cyclosporine versus with tacrolimus. Posterior reversible encephalopathy syndrome manifests as headache, visual disturbances, seizure, and abnormal mentation. The characteristic radiological features are the result of posterior- circulation vasogenic edema secondary to blood-brain barrier disruption. Treatment varies based on the etiology of the condition. In addition to the symptomatic management of hypertension and seizure disorders, switching or replacing the calcineurin inhibitor with another immunosuppressant or decreasing the dose of the calcineurin inhibitor is the key in calcineurin inhibitor-associated posterior reversible encephalopathy syndrome. Here, we have reviewed the terminology, pathogenesis, clinical features, diagnosis, and treatment of posterior reversible encephalopathy syndrome with special reference to its presence in the posttransplant period.

Topics: Calcineurin Inhibitors; Humans; Hypertension; Magnetic Resonance Imaging; Organ Transplantation; Posterior Leukoencephalopathy Syndrome; Tacrolimus; Treatment Outcome

Biological processes are dynamically regulated by signaling networks composed of protein kinases and phosphatases. Calcineurin, or PP3, is a conserved phosphoserine/phosphothreonine-specific protein phosphatase and member of the PPP family of phosphatases. Calcineurin is unique, however, in its activation by Ca

Topics: Amino Acid Motifs; Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Computer Simulation; Cyclosporine; Gene Expression Regulation; Humans; Hypertension; Immune System; Immunosuppression Therapy; Immunosuppressive Agents; Isoenzymes; NFATC Transcription Factors; Nuclear Proteins; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Conformation; Protein Isoforms; Proteomics; Signal Transduction; Tacrolimus

The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).. The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.. In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.. CsA is an effective and safe agent in the therapy of patients with SRNS.

Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

Cyclosporine began to be used as one of the immunosuppressive agents in transplantation in the beginning of the 1980s, and in the treatment of nephrotic syndrome in the pediatric nephrology. Therapeutic area of cyclosporine is narrow and its side effects limit its usage. Preference for cyclosporine and tacrolimus as a calcineurin inhibitor is left for the choice of the department. There are still countries with preferred-cyclosporine use because of economic reasons. Cyclosporine is currently being used in the treatment of nephrotic syndrome, but due to its high relapse rates in a short-term use, and nephrotoxicity in long-term use, search for new drugs with fewer side effects keeps continuing. As long as its use is indispensable, it will be necessary to keep track of kidney function and blood level of this medication closely to protect the patients from toxicity.

Topics: Calcineurin Inhibitors; Child; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Nephrotic Syndrome; Recurrence; Tacrolimus

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

Topics: Albuminuria; Child; Cyclosporine; Diabetes Mellitus; Diabetic Retinopathy; Glucocorticoids; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Insulin; Liver Failure; Liver Transplantation; Metformin; Pediatrics; Risk Factors; Sirolimus; Tacrolimus

Focal segmental glomerulosclerosis (FSGS) is a pathologic condition that represents many disease entities. The goals of therapy are to cure the disease. When this is not possible, the secondary goals are to reduce proteinuria to avoid the complications of nephrotic syndrome and to delay progression of kidney disease. Proteinuria remission is one of the most important independent predictors of kidney survival. Children with FSGS who do not achieve partial or complete remission have a 50% risk of progression to ESRD within 5 years whereas those who enter complete remission have a 5-year kidney survival rate of 90%. Treatment of idiopathic FSGS commonly involves immune-based and nonimmunologic therapy options. This manuscript will review the current state of FSGS therapy for children.

Topics: Adrenal Cortex Hormones; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antihypertensive Agents; Child; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Obesity; Rituximab; Tacrolimus; Treatment Outcome; Vitamin D Deficiency

The therapeutic success of renal transplantation has been largely attributable to the development of effective and balanced immunosuppressive treatment regimens. This study provides a meta-analysis of a series of randomized controlled trials that compared the effects of tacrolimus and cyclosporine on metabolic syndrome (MetS) and cardiovascular risk factors after renal transplantation.. We searched various electronic databases and bibliographies, including MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE, for relevant studies published prior to October 2012.. Our meta-analysis included five randomized controlled trials that examined a total of 923 patients. The tacrolimus group and the cyclosporine group exhibited no significant differences in MetS incidence after renal transplantation; risk ratio (RR): 1.06, 95% confidence interval (CI): 0.73-1.55, P = 0.76. Cyclosporine treatment was associated with a higher incidence of hyperlipidemia (RR: 0.50, 95% CI: 0.39-0.64, P < 0.01). Although there were no statistically significant differences, cyclosporine treatment was associated with a higher incidence of hypertension (RR: 0.91, 95% CI: 0.83-1.00, P = 0.06) after renal transplantation compared to tacrolimus treatment, and tacrolimus treatment was associated with a higher incidence of diabetes after renal transplantation (RR: 1.79, 95% CI: 0.98-3.27, P = 0.06) compared to cyclosporine treatment.. Compared to tacrolimus treatment, cyclosporine treatment was associated with a higher incidence of hyperlipidemia. Future large-scale studies are expected to be conducted to further confirm our findings.

Topics: Calcineurin; Cardiovascular Diseases; Cyclosporine; Humans; Hyperlipidemias; Hypertension; Kidney Transplantation; Metabolic Syndrome; Randomized Controlled Trials as Topic; Tacrolimus

Tacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.. The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.. Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.. There are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.. FK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.

Topics: Humans; Hypertension; Immunosuppressive Agents; Organ Transplantation; Tacrolimus

Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects.. To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients.. We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013.. We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study.. Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance).. We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures.. Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).

Topics: Adult; Bronchiolitis Obliterans; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hypertension; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Middle Aged; Randomized Controlled Trials as Topic; Tacrolimus

Calcineurin inhibitors (CNIs), such as cyclosporin A and tacrolimus, are the cornerstone of maintenance immunosuppressive regimens in liver transplantation. CNIs prevent rejection by inhibition of calcineurin, via which lymphocyte proliferation and interleukin (IL)-2 production is prevented. Tacrolimus is now the first-choice immunosuppressant after liver transplantation, since it is associated with fewer episodes of rejection than cyclosporin A. In this review we will discuss interindividual differences, which influence tacrolimus metabolism. Because of these factors and the narrow therapeutic index of tacrolimus, monitoring of drug trough levels is necessary. Furthermore, we will discuss studies concerning conversion from the tacrolimus twice daily to tacrolimus once daily formulation in stable LT patients. Due to adverse effects of CNIs, such as chronic renal failure, hypertension, de novo malignancy and new-onset diabetes mellitus, CNI minimization strategies have been developed, which will be discussed too.

Topics: Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Drug Substitution; Graft Rejection; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Tacrolimus; TOR Serine-Threonine Kinases

We contacted and analyzed the data of 18 lung transplant recipients who had had children. The complications we detected included: hypertension (50%), diabetes mellitus (21%), preeclampsia (13%), infection (21%), rejection (30%), loss of graft function (23%) and a lower percentage of live births than in transplant recipients of other organs. Other aspects to keep in mind are: the potential risk for fetal alterations (caused by drugs used as prophylaxis against rejection crossing the placental barrier); greater risk for infection and alterations in drug levels due to changes in metabolism typical of pregnancy and postpartum period. We describe the two cases in Spain of female lung transplant recipients who have had children after transplantation. Although pregnancy in these cases can have a similar evolution as in non-transplanted women, doctors should recommend their transplanted patients to avoid becoming pregnant, while explaining the high risk of both fetal and maternal morbidity and mortality after transplantation.

Topics: Adult; Cardiomyopathies; Female; Graft Rejection; Heart Defects, Congenital; Heart-Lung Transplantation; Humans; Hypertension; Hypertension, Pulmonary; Immunosuppressive Agents; Infant, Newborn; Infant, Premature, Diseases; Lung Diseases, Interstitial; Lung Transplantation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy in Diabetics; Pregnancy Outcome; Pregnancy, High-Risk; Spain; Survivors; Tacrolimus

The use of calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients. The original oil-based formulation of cyclosporine has been superceded by a microemulsion formulation (Neoral), which has more predictable pharmacokinetics and allows more precise dose-tailoring. Cyclosporine microemulsion and tacrolimus (Prograf) have a similar efficacy in the prevention of acute rejection of heart transplants, but their use is accompanied by nephrotoxicity and by cardiovascular side effects. The efficacy of immunosuppression can be improved by adjunctive therapy, such as azathioprine, mycophenolate mofetil (MMF; Cellcept), corticosteroids, and induction therapy. One of the most important predictors of patient mortality at >5 years after heart transplantation is cardiac allograft vasculopathy (CAV)/late graft failure, which accounts for 31% of deaths. Neither cyclosporine nor tacrolimus have been shown to prevent the development of CAV. In terms of efficacy, MMF provides a modest advantage over azathioprine in preventing CAV, and the combination of cyclosporine plus MMF results in significantly lower mortality than cyclosporine plus azathioprine. Overall, CNIs have multiple cardiovascular side effects, such as hypertension, hyperlipidemia and new-onset diabetes after transplantation, although cyclosporine and tacrolimus have somewhat different cardiovascular side-effect profiles. The challenge in choosing the best immunosuppressive regimen is to balance efficacy and safety to optimize graft and patient survival over the course of many decades. Because cyclosporine and tacrolimus have similar efficacy against acute rejection the choice of CNI for heart transplant recipients should be based on the relative risk of cardiovascular and renal side effects.

Topics: Blood Glucose; Calcineurin Inhibitors; Cyclosporine; Heart Transplantation; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Survival Analysis; Survival Rate; Tacrolimus

Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.

Topics: Azathioprine; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Cyclosporine; Growth and Development; Hematologic Neoplasms; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Care; Sirolimus; Tacrolimus

Kidney transplantation has seen a remarkable improvement in allograft survival rates and patient survival rates, and an equally remarkable reduction in acute rejection rates. Most attribute these changes to the introduction and widespread use of calcineurin inhibitors as part of the standard immunosuppressive regimen. Cyclosporine and tacrolimus are ideal immunosuppressive agents, much more effective and safe than the previous agents used. Especially ironic, however, for those caring for kidney transplant patients has been the finding that these breakthrough agents are toxic to the kidney and can cause hypertension. We can protect the transplanted kidney from rejection, but still damage it paradoxically by the protecting agent. Moreover, the prevalence of hypertension in transplant clinics has increased (from 40%-50% to up to 90%-100%) as these newer agents have gained widespread use. We remain uncertain of the mechanism whereby these agents cause hypertension, and therefore remain uncertain of the ideal treatment; however, the search for a mechanism has taken us from the organ level to intracellular effects of the agents. The fact that both agents cause nephrotoxicity suggests that a renal mechanism is at the heart of the hypertension.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Tacrolimus

Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.

Topics: Adrenal Cortex Hormones; Animals; Cardiovascular System; Coronary Artery Disease; Cyclosporine; Diabetes Mellitus; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Sirolimus; Tacrolimus

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.

Topics: Adrenal Cortex Hormones; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors

In the last several years, a number of experiments have implicated a pivotal role of the calcium/calmodulin-calcineurin dependent pathway as a final common signaling mechanism by which diverse hypertrophic stimuli converge to mediate hypertrophic responses in cardiomyocytes. Calcineurin inhibitors, i.e. cyclosporine A (CsA) and FK506, can interrupt the pathway, thereby preventing cardiac hypertrophy. The data that convincingly support this novel hypothesis were derived either from in vitro studies in cultured cardiomyocytes or from in vivo studies in transgenic mice. However, when the hypothesis was tested in clinically relevant animal models of cardiac hypertrophy, controversial results and conclusions emerged. In conventional models of cardiac hypertrophy, two questions remain to be answered: (1) whether calcineurin is activated in hypertrophied cardiac muscle, and (2) whether calcineurin inhibitors prevent cardiac hypertrophy. In addition, clinical observations have revealed that calcineurin inhibitors appear to exert pro-hypertrophic effects in organ transplant recipients. The controversies suggest that current calcineurin inhibitors are blunt tools for testing the hypothesis in pressure-overload hypertrophy in vivo, because there are so many confounding effects that are associated with systemic administration of the drugs. As such, new genetic approaches may overcome some of the problems associated with pharmacological inhibitors. This invited review will focus on the controversies surrounding the ability of calcineurin inhibition to prevent conventional (pressure-overload) cardiac hypertrophy and the new genetic approaches to address the question.

Topics: A Kinase Anchor Proteins; Adaptor Proteins, Signal Transducing; Adrenergic beta-Agonists; Animals; Animals, Genetically Modified; Body Weight; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Cyclosporine; DNA-Binding Proteins; Exercise; Gene Transfer Techniques; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; Isoproterenol; Mice; Models, Animal; Muscle Proteins; Myocardium; Phosphoproteins; Rats; Tacrolimus

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.

Topics: Antihypertensive Agents; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Sirolimus; Tacrolimus

The high incidence of hypertension after renal transplantation contributes to the risk of cardiovascular morbidity and mortality in renal transplant recipients. Although cyclosporine has been influential in the improvement of transplant outcome, it has emerged as a major cause of hypertension after organ transplantation. The underlying pathophysiological mechanisms of cyclosporine-induced hypertension include enhanced sympathetic nervous system activity, renal vasoconstriction, and sodium/water retention. Hypertension is also significantly associated with reduced graft survival and thereby requires aggressive treatment intervention. Calcium channel blockers may offer some advantages over angiotensin-converting enzyme inhibitors for the treatment of hypertension in stable renal transplant recipients. Nevertheless, selection of the most appropriate antihypertensive agent should take into account the possibility of pharmacokinetic interactions with immunosuppressive agents. There is evidence to suggest that the use of tacrolimus-based immunosuppression induces less hypertension compared with cyclosporine. Not only do patients receiving tacrolimus tend to require less antihypertensive therapy, but converting patients from cyclosporine to tacrolimus has been shown to result in significant reductions in blood pressure. Thus, tacrolimus may be associated with an improved cardiovascular risk profile in renal transplant recipients.

Topics: Antihypertensive Agents; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Tacrolimus

Topics: Cyclosporins; Humans; Hypertension; Immunosuppressive Agents; Tacrolimus

Topics: Area Under Curve; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Organ Transplantation; Tacrolimus

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

Topics: Acute Disease; Bone Marrow Transplantation; Drug Interactions; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney; Multicenter Studies as Topic; Nervous System; Randomized Controlled Trials as Topic; Tacrolimus; Transplantation, Homologous

Topics: Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Tacrolimus; Transplantation Immunology

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.

Topics: Acute Kidney Injury; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Incidence; Infections; Male; Methylprednisolone; Middle Aged; Patient Compliance; Retrospective Studies; Seizures; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Nephrotoxicity from immunosuppressive drugs can complicate otherwise successful therapy. This paper reviews the clinical and pathophysiologic aspects of nephrotoxicity. The chronic progressive nephropathy is emphasized based on a recently developed animal model. Experimental and clinical data regarding FK506, new cyclosporine analogs, and Rapamycin are also discussed.

Topics: Animals; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Polyenes; Rats; Sirolimus; Tacrolimus

Topics: Cyclosporine; Follow-Up Studies; Humans; Hypertension; Immunosuppression Therapy; Liver Cirrhosis; Liver Transplantation; Renal Insufficiency; Tacrolimus; Time Factors

Acute and chronic nephrotoxicity frequently limits the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications. The clinical aspects, pathophysiology, and relevant pharmacology of current and future immunosuppressive drugs are reviewed in this paper. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented.

Topics: Acute Kidney Injury; Animals; Cyclosporins; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polyenes; Sirolimus; Tacrolimus

Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population.. Randomized noninferiority crossover trial (noninferiority margin, -2.8mmHg).. Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m. Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout).. Average daytime (9 am to 9 pm) ambulatory SBP.. Blood pressure and laboratory parameters.. 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, -4.2 [95% CI, -7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, -65 [95% CI, -108 to -35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P<0.05 for both). In contrast, chlorthalidone temporarily reduced kidney function and increased both serum uric acid and glycated hemoglobin levels.. Open-label design, short follow-up, per-protocol analysis.. Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chlorthalidone; Cross-Over Studies; Edema; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus; Treatment Outcome

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).

Topics: Adult; Aged; Creatinine; Cyclosporine; Female; Gingival Hyperplasia; Humans; Hyperlipidemias; Hypertension; Hypertrichosis; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Prospective Studies; Tacrolimus

To investigate the efficacy and safety of an immunosuppressive regimen of steroid avoidance in combination with induction therapy and tacrolimus in liver transplant recipients.. Eighty-two adult liver transplant recipients were randomized into 2 groups: standard protocol group (n=41) in which steroids were withdrawn 3 months after the operation, and a 24-hour steroid avoidance group (n=41) in which steroids were eliminated within 24 hours. The incidence of acute rejections, infections (bacterial, fungal, and cytomegalovirus), and metabolic complications were analyzed between the groups.. The incidence of early posttransplant diabetes mellitus and the average dosage of insulin consumption among diabetic recipients were significantly higher in recipients in the standard protocol group than in the 24-hour avoidance group (P < .05). In addition, the incidence of hypertension and infection during the follow-up were also higher in patients of the standard protocol group (P < .05). The incidence of hypertension in the early posttransplant period, hyperlipemia, and acute rejection during the follow-up were comparable between the groups (P > .05).. Twenty-four hour steroid avoidance combined with induction therapy and tacrolimus maintenance is a safe and efficient immunosuppression strategy that can significantly reduce posttransplant infections and other complications owing to long-term use of steroids, without increasing the risk of acute rejection.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; China; Diabetes Mellitus; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Recombinant Fusion Proteins; Risk Factors; Steroids; Tacrolimus; Time Factors; Withholding Treatment

Steroids have had the main role in renal transplant for more than 4 decades. However, chronic use of steroids is associated with many comorbidities, owing to a lack of assessing cost-benefit of steroid avoidance in live-donor renal allotransplants. In this prospective, randomized, controlled study, we aimed to assess the cost-benefit of a steroid-free immunosuppression regimen among Egyptian live-donor renal transplants.. One hundred patients were randomly allocated to receive tacrolimus, mycophenolate mofetil, and steroids for only 3 days (n=50 patients; study group) or tacrolimus, mycophenolate mofetil, and steroids on a maintenance basis (n=50 patients; control group). All patients received basiliximab (Simulect) induction, with median follow-up of 12 months.. Both groups showed comparable graft and patient survivals, rejection episodes, and graft functioning. Posttransplant comorbidities were significantly more prevalent in the steroid-maintenance group. Hypertension was detected in 4% of steroid-free group versus 24% in the steroid-maintenance group (P = .0009). Posttransplant diabetes mellitus, serious infections, and hyperlipidemia were significantly more prevalent in the steroid-maintenance group (P < .05). Associated hospitalization costs were 2.2-fold higher in the steroid-maintenance group than they were in the steroid-free group. One year after transplant, the cost of managing posttransplant comorbidities was significantly higher in steroid-maintenance group, despite comparable costs of immunosuppression.. In low, immunologic risk recipients of live-donor renal transplants, using basiliximab induction and maintenance with tacrolimus, mycophenolate mofetil, steroid avoidance was associated with lower first annual total costs despite comparable immunosuppression costs, which was attributed to lower costs of associated morbidities.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Comorbidity; Contraindications; Cost-Benefit Analysis; Diabetes Mellitus; Female; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Steroids; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Young Adult

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

Topics: Adult; Diabetes Complications; Diarrhea; Dose-Response Relationship, Drug; Female; France; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Thrombocytopenia; Treatment Outcome

New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation.. To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM.. In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study.. At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001).. These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Topics: Adrenal Cortex Hormones; Alkaline Phosphatase; Bilirubin; Cholesterol; Creatinine; Cyclosporine; Diabetes Mellitus; Female; gamma-Glutamyltransferase; Graft Rejection; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Liver Transplantation; Logistic Models; Male; Middle Aged; Pilot Projects; Prospective Studies; Tacrolimus

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

Topics: Cardiovascular Diseases; Cyclosporine; Diabetes Complications; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus

Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation.. Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation.. 70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation.. Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects).. Main outcome was change in left ventricular mass index (LVMi) at month 18.. A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, -1.7 +/- 3.3 mm Hg; 95% confidence interval [CI], -4.8 to 8.2; P = 0.6 for SBP; 0.3 +/- 2.2 mm Hg; 95% CI, -4.8 to 4.1; P = 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 +/- 16.3 g/m(2.7); 95% CI, 4.2 to 16.1; P < 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P < 0.01; differences between cyclosporine and tacrolimus group, 13.3 +/- 3.9 g/m(2.7); 95% CI, 5.3 to 21.2; P < 0.01 in the ACE-inhibitor group; 3.7 +/- 4.2 g/m(2.7); 95% CI, -4.7 to 12.2; P = 0.4 in the control group).. Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis.. A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cyclosporine; Drug Interactions; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Transplantation; Linear Models; Lisinopril; Male; Middle Aged; Tacrolimus

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients.. The associations between tacrolimus trough concentrations (C(0)), non-trough concentrations (C(1), C(2), C(4), C(6/8)), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients.. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C(0), C(1), C(2), C(4), C(6/8) or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects.. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Topics: Adult; Area Under Curve; Female; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Models, Theoretical; Tacrolimus

Previous multicenter, randomized trials, lacking standardized post-transplant protocols, have compared tacrolimus (Tac) and cyclosporine (CyA, Sandimmune) and demonstrated similar outcomes with some different adverse effects. The microemulsion form of CyA (mCyA, Neoral) has replaced Sandimmune CyA as the more widely utilized CyA formulation. This is the first 5-year follow-up study of a large, single-center trial (n = 67) under a standardized post-transplant protocol comparing Tac and mCyA.. Sixty-seven heart transplant patients were randomized to Tac (n = 33) or mCyA (n = 34), both in combination with corticosteroids and azathioprine without cytolytic induction. Five-year end-points included survival, Grade > or = 3A or treated rejection, angiographic cardiac allograft vasculopathy (CAV; any lesion > or = 30% stenosis), renal dysfunction (creatinine > or = 2.0 mg/dl), use of two or more anti-hypertensive medications, percent diabetic and lipid levels.. Five-year survival, freedom from Grade > or = 3A or any treated rejection and angiographic CAV, mean cholesterol level and percent diabetic were similar between the two groups. The Tac group had a significantly lower 5-year mean triglyceride level (Tac 97 +/- 34 vs mCyA 175 +/- 103 mg/dl, p = 0.011) and average serum creatinine level (Tac 1.2 +/- 0.5 mg/dl vs mCyA 1.5 +/- 0.4 mg/dl, p = 0.044). There was a trend toward fewer patients requiring two or more anti-hypertensive drugs in the Tac group (Tac 33% vs mCyA 59%, p = 0.065).. Tac and mCyA appear to be comparable with regard to 5-year survival, freedom from rejection and CAV. However, compared with mCyA, Tac appears to reduce the adverse effect profile for hypertriglyceridemia and renal dysfunction and the need for hypertensive medications.

Topics: Adult; Antihypertensive Agents; Coronary Stenosis; Cyclosporine; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Diseases; Male; Middle Aged; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

Few studies used paired kidneys for comparison between tacrolimus and cyclosporine in renal transplantation. Most of the published data used whole blood trough levels for drug monitoring. However, the use of limited sampling strategy and abbreviated formula to estimate the 12-h area under concentration-time curve (AUC(0-12)) allowed better prediction of drug exposure. Sixty-six first cadaveric renal transplant recipients receiving paired kidneys were randomized to receive either tacrolimus-based (n = 33) or cyclosporine microemulsion (Neoral)-based therapies (n = 33). Abbreviated AUC(0-12) was used for drug monitoring and dose titration. Mean follow-up duration was 2.8 +/- 2 years. The patient and graft survival were comparable. Fewer incidence of acute rejection was observed in tacrolimus group (15% vs. 27.3%) though the difference was not significant (P = 0.23). The absolute value and the rate of decline of creatinine clearance were both significantly better in tacrolimus-treated patients. Prevalence of hypertension, post-transplant diabetes mellitus, infection, and malignancy were similar in both groups. Prevalence of hypercholesterolemia (11/33 vs. 4/33) and gum hypertrophy (6/33 vs. 1/33) was more common in cyclosporine-treated patients (P = 0.04 in both parameters). This was the first prospective, randomized study with paired kidney analysis showing the renal function was significantly better in tacrolimus-treated patients than in cyclosporine-treated patients.

Topics: Acute Disease; Adult; China; Cyclosporine; Emulsions; Female; Graft Rejection; Graft Survival; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Survival Rate; Tacrolimus

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Safety; Tacrolimus

Calcineurin inhibitor (CNI)-free regimens posttransplantation have been claimed to conserve graft function in addition to reduce the risk factors for cardiovascular and malignant disease in renal transplant recipients.. The primary aim of this prospective, open-label, randomized, parallel-group, single-center study was to compare the effect of complete CNI-avoidance posttransplant (daclizumab + mycophenolate mofetil + prednisolone: Dac-group, n=27) with the standard CNI-based immunosuppressive protocol at our transplant unit (cyclosporine A + mycophenolate mofetil + prednisolone: CsA-group, n=27) on renal function (glomerular filtration rate [GFR] determined as plasma clearance of 51Cr-EDTA) in a selected low immunogenic risk population (DR-matched, PRA-negative de novo cadaveric transplant recipients).. There were no significant difference in GFR at week 10 (P=0.61), but GFR was significantly (P=0.029) lower in the Dac-group (52+/-20 ml/min) at month 12 than in the CsA-group (69+/-29 ml/min). One-year patient and graft survival did not differ between the two groups. Overall acute rejection rate was 70.4% (19/27) in the Dac-group and 29.6% (8/27) in the CsA-group (P=0.006).. The strategy to select DR-matched, PRA-negative de novo cadaveric transplant recipients for a CNI-avoidance protocol was not successful. The incidence of acute rejection was unacceptable high even though anti-CD25 antibody induction as well as initial higher mycophenolate mofetil doses (3 g/day) were applied, and renal function was significantly lower in the CNI-avoidance patients at 1 year. Other strategies need to be examined for avoidance of CNI's in the early posttransplant period.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Diabetes Mellitus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Histocompatibility; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Tissue Donors; Urinary Tract Infections

Candesartan cilexetil is a possible treatment for hypertension in renal allograft recipients. Tacrolimus is widely used as an immunosuppressant following renal transplantation. The aim of this study was to evaluate the effect of multiple doses of candesartan cilexetil on the steady-state pharmacokinetics of tacrolimus.. Twelve patients received oral doses of tacrolimus twice daily for 12 days from study day -2 until day 10, single oral doses of candesartan cilexetil placebo on study days -2 to -1, single oral doses of 2 mg candesartan cilexetil once daily on study days 1 to 3, oral doses of 4 mg candesartan cilexetil once daily on study days 4 to 6, and oral doses of 16 mg candesartan cilexetil once daily on study days 7 to 9. Serial blood samples were collected on days -1, 6 and 9 and were analysed for tacrolimus using microparticle enzyme immunoassay.. Mean C(max,ss) and AUC(tau,ss) values for tacrolimus on day 6 (4 mg candesartan) and day 9 (16 mg candesartan cilexetil) were similar to those on day -1 (tacrolimus alone). Renal function did not change under treatment with candesartan cilexetil compared with baseline. The co-administration of multiple oral doses of cardesartan cilexetil with oral doses of tacrolimus was well tolerated.. Concomitant administration of multiple doses of candesartan cilexetil does not alter the steady-state pharmacokinetics of tacrolimus.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Benzimidazoles; Biological Availability; Biphenyl Compounds; Blood Pressure; Creatinine; Drug Administration Schedule; Drug Interactions; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Tacrolimus; Tetrazoles

The hyperlipidemic and hypertensive effects of ciclosporin constitute a cardiovascular risk. Cosmetic side-effects are known to reduce patients' quality of life. This was a 6-month, open, prospective, multicentre study in 296 adult kidney transplant patients to evaluate the conversion from ciclosporin to a tacrolimus-based regimen. Primary indications for conversion were hyperlipidemia (n =77), hypertension (n = 72), hypertrichosis (n = 32) and gingival hyperplasia (n = 115). At month 6, hyperlipidemia and hypertension were at least moderately improved in 59.1% and 63.5% of patients, and strongly or completely resolved in 29% and 25%. Gingival hyperplasia and hypertrichosis were strongly or completely resolved in 73% and 72% of patients. Mean total cholesterol was reduced from 255 to 218 mg/dl. Mean systolic blood pressure (SBP) was reduced from 152.9 to 137.5 mmHg and mean diastolic blood pressure (DBP) from 90.7 to 85.8 mmHg. Ciclosporin-related side-effects resolved or improved after conversion to tacrolimus.

Topics: Adult; Cyclosporine; Esthetics; Female; Gingival Hyperplasia; Humans; Hyperlipidemias; Hypertension; Hypertrichosis; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Retreatment; Tacrolimus; Treatment Outcome

Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation.. In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored.. Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy.. Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Topics: Acute Disease; Adult; Biopsy; Body Mass Index; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Kidney Transplantation; Lipids; Lymphocele; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Sirolimus; Steroids; Tacrolimus; Wound Healing

This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented.. Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events.. By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group.. Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Topics: Acute Disease; Adult; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

Calcineurin inhibitors (CIs) cause substantial long-term morbidity and mortality among orthotopic liver transplantation (OLT) patients. Our aim was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) among OLT patients with CI-related side effects.. Thirty three adult patients, including 29 men and 4 women of mean age 57 years, underwent OLT between 1986 and 2000 under treatment with CIs (28 cyclosporine and five tacrolimus). Mean follow-up after OLT was 59 months. Adverse effects were renal dysfunction in 26, hypertension in 23, and neurotoxicity in two. MMF was added gradually while simultaneously reducing the dosage of CI.. After a mean 15-months follow-up of MMF treatment, CIs had been withdrawn in 28 patients (85%). The mean time from the initiation of MMF and CI withdrawal was 5 months. During the first year of follow-up chronic renal dysfunction improved in 16 of 26 patients (61.6%) accompanied by a decreased serum creatinine and urea and an increase in creatinine clearance. Among 13/23 (56.5%) hypertensive patients, there was a significant decrease in blood pressure or the number of antihypertensive drugs (P<.05). One patient with neurotoxicity improved. Twenty-two patients (66%) displayed adverse events: five rejections (15%) including four acute episodes, controlled by CI re-introduction, and one chronic reaction. The most frequent adverse effects were herpes simplex infection in 10 patients (30%), asthenia in nine (27%), diarrhea in five (15%) and thrombocytopenia in four (12%). Nevertheless, only six patients (19%) required MMF dose reduction, namely, three patients with GI intolerance, two with repeated VHS infections, and one with anemia.. MMF monotherapy improves renal function and blood pressure levels in more than 50% of patients with chronic renal impairment and hypertension after OLT. Many of the side effects of MMF were mild; it was safe accompanied by a low incidence of rejection reactions.

Topics: Adult; Blood Pressure; Creatinine; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Reproducibility of Results; Tacrolimus; Time Factors

Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure.. We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Phi, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean+/-SEM. MSNA was significantly elevated in hemodialysis patients (43+/-4 bursts/min), RTX-CSA (44+/-5 bursts/min), RTX-FK (34+/-3 bursts/min), and RTX-Phi (44+/-5 bursts/min) as compared with CON (21+/-3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20+/-3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44+/-6 versus 43+/-5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney.. Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Hemodynamics; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Muscle, Skeletal; Nephrectomy; Renal Dialysis; Sympathetic Nervous System; Tacrolimus; Uremia

Topics: Blood Pressure; Creatinine; Cyclosporine; Drug Therapy, Combination; Humans; Hypertension; Incidence; Kidney Transplantation; Postoperative Complications; Tacrolimus

Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients.. Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened).. Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients.. Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

Topics: Adult; Aged; Black or African American; Black People; Body Weight; Creatinine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous; Treatment Outcome; White People

Topics: Azathioprine; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Triglycerides

Tacrolimus-based immunosuppression seems safe and effective in liver and kidney transplantation. To assess the safety and efficacy of tacrolimus (TAC)-based immunosuppression after cardiac transplantation as well as the relative impact of tacrolimus on immunosuppression-related side effects such as hypertension and hyperlipidemia, we conducted a prospective, randomized, open-label, multicenter study of otherwise identical tacrolimus- and cyclosporine-based immunosuppressive regimens in adult patients undergoing cardiac transplantation.. Eighty-five adult patients (pts) at six United States cardiac transplant centers, undergoing their first cardiac transplant procedure, were prospectively randomized to receive either TAC-based (n = 39) or cyclosporine (CYA)-based (n = 46) immunosuppression. All pts received a triple-drug protocol with 15 pts (18%) receiving peri-operative OKT3 to delay TAC/CYA due to pre-transplant renal dysfunction. Endomyocardial biopsies were performed at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 24, and 52. The study duration was 12 months.. Patients were mostly male (87%) Caucasian (90%) with a mean age of 54 years and primary diagnoses of coronary artery disease (55%) and idiopathic dilated cardiomyopathy (41%). There were no significant demographic differences between groups. Patient and allograft survival were not different in the two groups. The probability and overall incidence of each grade of rejection, whether treated or not, and the types of treatment required did not differ between the groups. At baseline and through 12 months of follow-up, chemistry and hematology values were similar between the groups except serum cholesterol was higher in the CYA group at 3, 6, and 12 months (239 vs 205 mg/dL, 246 vs 191 mg/dL, 212 vs 186 mg/dL, respectively, p < 0.001). Likewise, LDL-cholesterol, HDL-cholesterol and triglycerides were significantly higher in the CYA group. More CYA patients received therapy for hypercholesterolemia (71% vs 41% at 12 months, p = 0.01). There were no significant differences in renal function, hyperglycemia, hypomagnesemia, or hyperkalemia during the first 12 months. More CYA patients developed new-onset hypertension requiring pharmacologic treatment (71% vs 48%, p = 0.05). The incidence of infection was the same for the two groups (2.6 episodes/pt/12 month follow-up).. Tacrolimus-based immunosuppression seems effective for rejection prophylaxis during the first year after cardiac transplantation and is associated with less hypertension and hyperlipidemia and no difference in renal function, hyperglycemia or infection incidence when compared to cyclosporine-based immunosuppression.

Topics: Adult; Biopsy; Cardiomyopathy, Dilated; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Muromonab-CD3; Prospective Studies; Tacrolimus; Triglycerides

1. Disturbances of the blood pressure regulation, probably due to dysfunction of the autonomic nervous system, are well known complications in chronic renal failure. Haemodialysis and transplantation have been reported to ameliorate nerve dysfunction. 2. In this study, the function of the blood pressure control was investigated in kidney transplant recipients after longtime haemodialysis treated with ciclosporine A and tacrolimus and compared to healthy individuals. To investigate the influence of immunosuppression, the measurements were performed twice, at low and high whole blood concentrations of ciclosporine and tacrolimus. Besides ciclosporine, tacrolimus, azathioprine and prednisolone no other drugs were used in the group of kidney transplant recipients. 3. Kidney transplant recipients (KTR) treated with ciclosporine showed reduced blood pressure and heart rate responses to the cardiovascular stress tests (head-up tilt and cold pressure test) under basal conditions. Two hours after ciclosporine application, the differences in the responses to cardiovascular stress tests between KTR and controls were significantly more pronounced. 4. Patients with tacrolimus immunosuppression showed a similar blood pressure and heart rate response under basal conditions. Two hours after drug application, the blood pressure response following orthostatism and heart rate response to the cold pressure test were significantly higher in tacrolimus treated patients. 5. Our results indicate, that kidney transplant recipients still express an altered function of the blood pressure control. Furthermore, ciclosporine A and tacrolimus seem to contribute to dysfunction of the blood pressure regulation by their own. Tacrolimus immunosuppression does not seem to offer advantages concerning the function of the blood pressure control as compared to ciclosporine A.

Topics: Adult; Blood Pressure; Cardiovascular System; Cold Temperature; Cyclosporins; Exercise Test; Female; Heart Rate; Humans; Hypertension; Hypotension, Orthostatic; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus

Topics: Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Diabetes Mellitus, Type 1; Follow-Up Studies; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Prevalence; Tacrolimus

Hypertension frequently develops early after liver transplantation when cyclosporine-based immunosuppression is used. However, initial experience with tacrolimus has suggested that its use leads to a lower early incidence of hypertension. In this study, the blood pressure status of patients treated with cyclosporine (n = 131) and those treated with tacrolimus (n = 28) was compared 24 months after liver transplantation. At this time interval, the prevalence of hypertension in the cyclosporine and tacrolimus groups were 82% and 64%, respectively (P < .05). For those patients who were hypertensive by 24 months, onset was delayed in the tacrolimus group compared with the cyclosporine group: 40% versus 71% and 73% versus 93% at 1 and 12 months, respectively (P < .05). Within the cyclosporine group, patients with hypertension were heavier than those with normal blood pressure, 84.7 +/- 1.8 versus 73.4 +/- 4.0 kg, respectively (P < .05). Within the tacrolimus group, hypertensive patients had lower glomerular filtration rates and higher renal vascular resistances compared with normotensive patients, 74 +/- 12 versus 47 +/- 6 mL/min and 15,711 +/- 2,445 versus 28,830 +/- 4,310 dyne/s/cm5/m2, respectively (P < .05). There were no within-group differences for age, gender, pretransplant history of hypertension, family history of hypertension, graft function, or daily doses of prednisone, cyclosporine, or tacrolimus. These results indicate that, compared with cyclosporine, the onset of hypertension after liver transplantation is delayed and less prevalent with tacrolimus. Additionally, hypertension is associated with increased body weight in cyclosporine-treated patients and with more severe renal dysfunction in patients receiving tacrolimus. The relationships of these findings to the development of posttransplant hypertension requires further study.

Topics: Blood Pressure; Body Weight; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Vascular Resistance

Following primary liver transplantation, immunosuppressive efficacy of Neoral and Prograf was similar and superior to that of Sandimmune. Rejection incidence was statistically increased with Sandimmune therapy. Incidence of hypertension, posttransplant diabetes mellitus, and infectious complications was not statistically different. Although early compromise in renal function was associated with Sandimmune, Neoral, and Prograf immunosuppression, no progressive renal dysfunction was identified.

Topics: Adult; Analysis of Variance; Azathioprine; Communicable Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Function Tests; Liver Transplantation; Methylprednisolone Hemisuccinate; Postoperative Complications; Regression Analysis; Retrospective Studies; Tacrolimus

We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Cyclosporine; Disease-Free Survival; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Incidence; Male; Methotrexate; Middle Aged; Nuclear Family; Recurrence; Survival Analysis; Tacrolimus; Tissue Donors; Transplantation, Homologous; Treatment Outcome

To examine the possible drug interaction between nifedipine and tacrolimus in liver transplant recipients.. A retrospective study was done comparing two groups of liver transplant recipients. The starting time for comparison was the same after transplant. One group (n = 22) consisted of hypertensive patients who were treated with nifedipine; the other group (n = 28) did not receive nifedipine. The two groups were compared over 1 year. The effect of nifedipine on tacrolimus was measured in terms of tacrolimus whole blood trough concentrations, daily tacrolimus dosages, and cumulative tacrolimus dosages at 1, 3, 6, and 12 months. All patient charts were reviewed with regard to concurrent medication that could affect the metabolism of tacrolimus and eventually affect tacrolimus concentrations and dosages.. All required information was retrieved from medical records.. There was a statistically significant difference between daily dosage requirements of tacrolimus at 90 (p = 0.03), 180 (p = 0.004), and 365 (p = 0.0004) days between the nifedipine and no-nifedipine groups. The tacrolimus daily dosage in the nifedipine group was decreased by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage of the no-nifedipine group. Statistically significant differences in cumulative dosages of tacrolimus were observed at 180 (p = 0.02) and 365 (p = 0.003) days between the nifedipine and no-nifedipine groups, with cumulative dosage reduction of 25% and 31% by 6 and 12 months, respectively, in the nifedipine group compared with the no-nifedipine group.. Nifedipine decreased the daily and cumulative dosage requirement of tacrolimus. The interaction observed between nifedipine and tacrolimus is the first reported in humans and is clinically important. As a result of this drug interaction, it is recommended that blood concentrations of tacrolimus be monitored during coadministration of these drugs and that the tacrolimus dosage be adjusted accordingly.

Topics: Adult; Aged; Calcium Channel Blockers; Creatinine; Drug Interactions; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Nifedipine; Retrospective Studies; Tacrolimus

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Topics: Adult; Bone Marrow Transplantation; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Infections; Kidney Diseases; Life Tables; Liver Diseases; Male; Methotrexate; Middle Aged; Pilot Projects; Safety; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Tacrolimus (FK506) has recently become available clinically as an alternative to cyclosporine-based immunosuppression. This study reports the middle-term results of a prospective, randomized trial that compared FK506 with cyclosporine-based immunosuppression in heart transplant recipients.. Twenty-five consecutive patients were randomized at a 2:1 ratio into two groups, one of which received FK506 (15 patients), the other cyclosporine (10 patients). Both groups received similar concomitant immunosuppression. The patients were followed up for 12 months. The following outcome parameters were analyzed: survival, rejection and infection rate, lymphocyte subsets, new-onset diabetes, renal and hepatic function, hypertension, right-sided heart catheterization data, graft coronary artery disease, and neurologic side effects.. The mortality rate (two patients) in the FK506 group was 13% versus 0% in the cyclosporine group (p = NS). The two deaths were the consequences of early infections and higher doses of FK506. From the outset, the FK506 group presented a lower prevalence of acute rejection, a lower requirement for rejection treatments and a higher incidence of infections. Accordingly, we reduced overall immunosuppression for the last seven patients in the FK506 group; the decrease in FK506 and prednisone dosage led to a decrease in the early infection rate without an increase in the rejection rate. There was no difference between the two groups in diabetes incidence, renal and hepatic function, right-sided heart catheterization data, or coronary angiograms. Hypertension was less frequent and milder in the FK506 group.. This experience suggests that FK506 can be safely used in heart transplantation. It can decrease the frequency of rejection episodes. Low-dose administration allows a lower infection rate without an increase in rejection. With a protocol of delayed starting and low dosing, side effects such as renal toxicity, hypertension, and neurologic toxicity seem to be unlikely. Further studies are needed to establish the exact dosage and therapeutic levels of the drug.

Topics: Acute Disease; Bacterial Infections; Cardiac Catheterization; Coronary Disease; Cyclosporine; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney; Liver; Lymphocyte Subsets; Male; Middle Aged; Nervous System; Prevalence; Prospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications.. A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia.. The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months).. MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.

Topics: Acute Disease; Adult; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Mycophenolic Acid; Prednisone; Prospective Studies; Survival Analysis; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Azathioprine; Communicable Diseases; Coronary Disease; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Incidence; Muromonab-CD3; Prednisone; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous

Clinical aspects of FK-506 or cyclosporine immunosuppression regimens were evaluated in 48 consecutive pediatric renal transplant recipients. Tapering and discontinuation of prednisone was employed only in children receiving FK-506 who experienced minor or no rejection episodes during the 1st posttransplant month. At 1 year follow-up, 17 of 22 (77%) of all children with functioning allografts were receiving no prednisone (n = 13) or a mean dosage of 0.07 mg/kg per day (n = 4). During the 1st month, acute cellular rejection was more common in the FK-506 group (0.58 vs. 0.21 rejections per patient, P < 0.05) but allograft survival (92%) and renal function at 1 year posttransplant were identical in both groups. Compared with the cyclosporine regimen, FK-506 immunosuppression may be associated with a higher incidence of cytomegalovirus or reversible Epstein-Barr virus-induced lymphoproliferative disease. However, the FK-506 group had less hirsutism and gingival hypertrophy and required fewer antihypertensive medications independent of steroid use. Height standard deviation scores and weight-for-height index improved only in pre-adolescents receiving FK-506 but no prednisone (P < 0.02 and P < 0.05, respectively), but did not differ between children on FK-506 plus prednisone and those in the cyclosporine group. We conclude that the major advantages of FK-506 over cyclosporine immunosuppression are a reduced severity of hypertension and an improved cosmetic appearance which may improve long-term medical compliance. When used as monotherapy, FK-506 also shows promise in relieving the growth retardation associated with cyclosporine regimens that include prednisone.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Drug Evaluation; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Growth; Humans; Hypertension; Infant; Kidney; Kidney Transplantation; Male; Tacrolimus

Topics: Creatinine; Cyclosporine; Diuretics; Europe; Follow-Up Studies; Humans; Hypertension; Immunosuppression Therapy; Kidney; Liver Transplantation; Prospective Studies; Tacrolimus; Time Factors

We examined the occurrence of renal complications and hypertension in 540 primary liver recipients entered into the European liver trial comparing primary FK 506 to a cyclosporin A based immunosuppression regimen (CBIR). No difference in serious renal impairment or mean creatinine levels was observed with similar rates of "kidney failure" (FK 506 9.4% vs. CBIR 7.3%) and dialysis requirements (FK 506 12% vs. CBIR 11%). "Abnormal kidney function", a less serious parameter of renal impairment, was reported in 89 recipients (33%) in the FK 506 group versus 58 (21%) in the CBIR group (P < 0.01). Development of this complication was associated with elevated intravenous FK 506 dosing schedules, with the mean cumulative dose 43% higher than treated patients with unaffected kidney function. In a later cohort of patients where intravenous dosing was lower, no significant difference in renal complications was detectable. The 6-month prevalence rate of systemic arterial hypertension was noted to be lower in the FK 506-treated patients compared to the CBIR group [33 (17.2%) vs. 47 (25.7%)].

Topics: Adolescent; Adult; Aged; Azathioprine; Cohort Studies; Creatinine; Cyclosporine; Drug Therapy, Combination; Europe; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prednisolone; Renal Insufficiency; Tacrolimus

In a retrospective study, we analysed the FK 506 dosage used in primary liver graft recipients enrolled in the European FK 506 multicenter trial conducted from September 1990 to January 1992. In addition, a second cohort of patients treated more recently in a single centre was investigated. The impact of different dosing strategies on the clinical course of the patients was analysed with special emphasis on the incidence of rejection episodes and FK 506 side-effects. Among the patients enrolled in the European FK 506 multicenter trial, those patients enrolled during the "early" phase of the study received a higher oral FK 506 dose [mean oral dosage on day 7 = 0.19 mg/kg body weight (bw) per day, n = 134] compared to patients enrolled during the "late" period of the study (mean oral dosage on day 7 = 0.14 mg/kg bw per day, n = 133). This lower dosage was the result of several protocol amendments performed to reduce the incidence of FK 506 side-effects. Lowering of the FK 506 dosage was accompanied by a reduction in the long-term prevalence of side-effects such as diabetes (n. s.) or hypertension (P < 0.05), while patient survival and rejection frequency remained constant. Patients treated in centres with online FK 506 blood level monitoring experienced significantly less hypertension, less episodes of diabetes and less rejection episodes compared to patients treated in centres without. The clinical course of those patients enrolled in the multicentre trial was compared with the course of a cohort of liver-grafted patients treated with FK 506 more recently in a single centre. These patients had a further reduction in the FK 506 dosage (0.10 mg/kg bw per day p.o. or less according to whole blood levels, with no intravenous FK 506 administration). When compared to patients enrolled in the multicentre trial, these patients experienced less side-effects (nephrotoxicity, hypertension, serious early neurotoxicity) while adaequate immunosuppression was maintained.

Topics: Administration, Oral; Adult; Diabetes Mellitus; Dose-Response Relationship, Drug; Europe; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Infusions, Intravenous; Liver Transplantation; Male; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus

Long-term renal function was compared in 49 liver recipients [25 patients received cyclosporin (CyA) and 24 patients received FK 506] followed for a period of 1 year. Creatinine (CR) and glomerular filtration rate (GFR) pretransplantation (pre-Tx) and at 1, 3, 5, and 12 months post-Tx were recorded, as well as incidences of hyperkalemia, post-Tx hypertension, and insulin-dependent diabetes mellitus (IDDM) in the two groups. At 1 year post-Tx, the mean Cr had risen from baseline by 56% and 60% in the FK and CyA groups, respectively; the mean GFR had dropped by 32% in FK patients and by 27% in CyA patients. Acute nephrotoxicity occurred in 7/25 CyA patients (2/7 required dialysis) and 9/26 FK patients (7/9 required dialysis; 2/7 were switched to CyA). None remained on dialysis at 3 months. Renal insufficiency persisted at 1 year in 7/16 patients with early toxicity (CyA, 4; FK, 3) and in 3 of the remaining 36 pts (P < 0.001). Hyperkalemia occurred in 4/25 CyA, and in 12/24 FK patients (P < 0.025), post-Tx hypertension occurred in 15 CyA, and 7 FK patients (P < 0.05), and IDDM occurred in 4 CyA and 7 FK patients (P = ns). FK 506 and CyA, thus, exerted similar chronic renal effects. Although acute renal insufficiency improved upon dose reduction, renal impairment was permanent in some cases.

Topics: Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Postoperative Complications; Tacrolimus; Time Factors

Topics: Adult; Anti-Bacterial Agents; Diabetes Mellitus, Type 1; Female; Graft Rejection; Heart; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney; Male; Middle Aged; Opportunistic Infections; Prospective Studies; Survival Analysis; Tacrolimus

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Creatinine; Diabetes Mellitus, Type 1; Female; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Infant; Infant, Newborn; Kidney; Male; Middle Aged; Oliguria; Prospective Studies; Tacrolimus; Uremia

Topics: Adult; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Kidney Function Tests; Male; Middle Aged; Prospective Studies; Tacrolimus

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Infant; Infant, Newborn; Kidney Function Tests; Male; Monitoring, Immunologic; Tacrolimus

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Tacrolimus

Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the. Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states.. Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin,. α2δ-1 is essential for calcineurin inhibitor-induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor-induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor-induced neurogenic hypertension.

Topics: Animals; Aspartic Acid; Brain; Calcineurin Inhibitors; Gabapentin; Hypertension; Mice; Rats; Receptors, N-Methyl-D-Aspartate; Tacrolimus

Atherosclerotic renal artery stenosis is one of the risk factors for cardiovascular death and can lead to the ischemic nephropathy. In this report, we describe the successful management of ischemic nephropathy that developed in a kidney transplant recipient with graft artery stenosis. The 52-year-old male patient had diabetes and hypertension and was a nonsmoker with hypothyroidism on replacement therapy. He had a history of recurrent urinary tract infection due to vesicoureteric reflux before starting hemodialysis in July 2009. In November 2020, he received a deceased donor renal allograft and showed slow graft function. He received thymoglobulin as induction and steroid, tacrolimus, and mycophenolate mofetil as maintenance therapy. He was discharged with nadir creatinine around 130 μmol/L. His diabetes was controlled by intensive insulin regimen. Later, he presented with graft dysfunction with partially controlled hypertension and suspected graft artery stenosis by Doppler ultrasonography but no evidence of obstruction. His tacrolimus level was adequate, and his echocardiography was unremarkable. He received empirical pulse steroid. A graft biopsy showed severe acute tubular necrosis, suspicious T-cell-mediated rejection, and negative C4d and positive SV40 stain, suggesting BK nephropathy. His BK viremia (500 copies/mL) and viruria (885 billion copies/mL) improved after immunosuppression minimization, although he remained dependent on dialysis. A repeated Doppler ultrasonogram showed flattening of the systolic wave. Computed tomographic angiography revealed diffusely attenuated graft arteries. The patient received graft artery angioplasty and stenting of the 2 arteries. The patient showed good response, with same-day urine production and Doppler showing good systolic wave. His graft function started to improve, and he was discharged with stable graft function. His immunosuppressive regimen was subsequently tailored to steroid and low-dose tacrolimus. In conclusion, we found that ischemic nephropathy could be reversed if properly managed, even in presence of other comorbidities.

Topics: BK Virus; Constriction, Pathologic; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Renal Artery Obstruction; Tacrolimus; Treatment Outcome

Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor-induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone.. We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN.. Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment-induced hypertension in conscious rats.. Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor-induced hypertension.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Blood Pressure; Calcineurin; Calcineurin Inhibitors; Hypertension; Hypothalamus; N-Methylaspartate; Paraventricular Hypothalamic Nucleus; Rats; Receptors, N-Methyl-D-Aspartate; Sympathetic Nervous System; Tacrolimus

BACKGROUND The interaction of viral infection may be associated with increased morbidity after renal transplantation. This study aimed to identify the incidence and risk factors of viruria infections in renal transplant recipients. MATERIAL AND METHODS In this longitudinal study, 502 episodes recorded in 81 kidney transplant patients from 1/2019 to 12/2021 in a hospital in Vietnam were included. BK, JC polyomaviruses, CMV, EBV, and HSV were detected. Multivariable Cox regression analysis was performed to evaluate risk factors for the viruria infection. RESULTS Fifty-six patients (69.1%) had viruria co-infection. The incidence of JC, CMV, and BK infection was the most common viruria, with 67.9%, 61.7%, and 56.8%, respectively. Cox regression revealed that the risk factors for JC were single infection, dose of MMF (HR 1.002), corticoid (HR 1.02), hypertension (HR 1.65), and hematuria (HR 2.03); risk factors for CMV infection were male sex (HR 1.92) and eGFR (HR 0.98); risk factors for BK single infection were hypertension (HR 1.67), proteinuria (HR 3.80), higher tacrolimus trough level (HR 1.17), and dose of MMF (HR 1.002). Hypertension (HR 1.68), fasting plasma glucose (HR 1.13), proteinuria (HR 6.01), tacrolimus trough level (HR 1.12), and dose of MMF (HR 1.004) were independent risk factors for the viruria co-infection. CONCLUSIONS Kidney function was associated with the incidence of viruria. Higher tacrolimus trough level and dose of MMF were associated with higher risk of BK, JC, and co-infection.

Topics: BK Virus; Blood Glucose; Coinfection; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Humans; Hypertension; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Polyomavirus; Polyomavirus Infections; Proteinuria; Risk Factors; Tacrolimus

Tacrolimus (TAC, also called FK506), a common immunosuppressive drug used to prevent allograft rejection in transplant patients, is well known to alter the functions of blood vessels. In this study, we sought to determine whether chronic treatment of TAC could inhibit the activity of big-conductance Ca

Topics: Animals; Calcium; Cerebral Arteries; Hypertension; Immunosuppressive Agents; Mice; Muscle, Smooth; Norepinephrine; Potassium Channels, Calcium-Activated; Tacrolimus; Vasoconstriction

Kidney transplant (KT) recipients are at an increased risk for severe COVID-19 because of their immunosuppressed state. A 42-year-old KT patient was diagnosed with COVID-19 three months after KT. Despite lymphopenia and several risk factors, he had a mild disease course. Nasopharyngeal real-time reverse transcriptase polymerase chain reaction for SARS-CoV-2 became negative 48 days after detection. SARS-CoV-2 IgG antibodies became negative after day 40. TTV DNA load increased with the onset COVID-19 and reduced after its resolution. This is the first report where TTV DNA load was measured during the course of COVID-19.

Topics: Adult; Antibodies, Viral; Comorbidity; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Serological Testing; Diabetes Mellitus; DNA Virus Infections; DNA, Viral; Glucocorticoids; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Lymphopenia; Male; Mycophenolic Acid; Obesity; Prednisolone; SARS-CoV-2; Severity of Illness Index; Tacrolimus; Torque teno virus; Viral Load

Cases of concurrent immunoglobulin A nephropathy (IgAN) and IgG4-related tubulointerstitial nephritis (IgG4-TIN) are rare and previous case reports have lacked important data. KDIGO suggests a treatment with systemic glucocorticoids in IgAN patients. Glucocorticoids are recommended as the first-line therapy for IgG4-TIN. The use of tacrolimus as a long-term maintenance treatment has not been described. We report the case of a man who developed IgAN and IgG4-TIN without abnormalities in extra-renal tissue, without renal function abnormalities or impairment as well, and was treated by tacrolimus as a long-term maintenance during 45 months follow-up.. A 56-year-old Chinese man first presented to our hospital with the chief complaint of foamy urine for 1 year and hematuria for 3 months, with a medical history of hypertension. Testing revealed a notable increase in serum IgG4 level without abnormalities in renal function or imaging, or in dysfunction other organs. Renal biopsy showed mesangial extracellular matrix proliferation, increased mesangial cell numbers and infiltration of plasma cells. Immunofluorescence showed mesangial positivity for IgA and C3. Immunohistochemistry staining showed widespread IgG4 and increased CD38 and CD138 expression. Electron microscopy showed immune complexes located on the tubular basement membrane. He was diagnosed with IgAN and IgG4-TIN. He received glucocorticoids, leflunomide and tacrolimus to induce remission. He was given tacrolimus as long-term maintenance treatment. When tacrolimus was temporarily withdrawn, proteinuria recurred. After resuming tacrolimus therapy, he again entered complete remission. After 45 months of therapy, he remains in complete remission and the serum IgG4 level is normal.. The finding of concurrent IgAN and IgG4-TIN without abnormalities in renal function, imaging or extra-renal tissue is rare and their coexistence may be coincidental. Long-term treatment with tacrolimus proved effective and he has remained in remission during 45 months follow-up.

Topics: Duration of Therapy; Glomerulonephritis, IGA; Humans; Hypertension; Immunoglobulin G; Immunoglobulin G4-Related Disease; Immunosuppressive Agents; Kidney; Kidney Function Tests; Male; Middle Aged; Tacrolimus; Treatment Outcome

High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated.. This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant.. At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected.. BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).

Topics: Adolescent; Age Factors; Blood Pressure Determination; Child; Child, Preschool; Cyclosporine; Europe; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Prevalence; Registries; Retrospective Studies; Sex Factors; Tacrolimus; Time Factors; Transplant Recipients

Diltiazem is a calcium-channel blocker commonly used for the treatment of hypertension. Common adverse effects include dizziness, headache, and edema. Fewer than 20 cases of diltiazem-associated photodistributed hyperpigmentation have been reported in the literature. Here, we present the case of a 71-year-old woman with new-onset facial hyperpigmentation 6 months after initiating treatment with diltiazem.

Topics: Aged; Biopsy; Calcium Channel Blockers; Dermatologic Agents; Diltiazem; Female; Humans; Hyperpigmentation; Hypertension; Ointments; Photosensitivity Disorders; Skin; Tacrolimus; Treatment Outcome; Withholding Treatment

Transplantation is not only the best method for treating end-stage failure of many organs but also the way to improve the quality of life of patients. For women of childbearing age, an organ transplant often brings a restoration of regular reproductive functions, which means, among other things, the possibility of having biological offspring.. The aim of the study was to analyze the medical records and assess the impact of a liver transplant on the course of pregnancy and labor.. The research was carried out from March to May 2019 in the Nephrology and Transplant Clinic Medical University of Warsaw. The study group consisted of 19 women after liver transplantation. Medical records were analyzed, and laboratory test results routinely performed on patients were also used for the study.. The mean age of conception of the patients following transplantation was 30 ± 4 years old. In the analyzed period, 6 patients gave birth to 2 children each, and 8 patients to 1 child each. Only 3 patients experienced premature birth. Twelve patients gave birth by caesarean delivery. Fourteen patients took tacrolimus.. Pregnancy is possible in patients following a liver transplant and does not appear to have a damaging effect on liver functionality. There is an increased risk of pre-eclampsia, intensified hypertension, and premature birth among patients following a transplant, which is why it is essential for these patients to remain under the care of a specialistic therapeutic team.

Topics: Adult; Female; Humans; Hypertension; Liver Transplantation; Postoperative Complications; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Quality of Life; Tacrolimus; Treatment Outcome

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3

Topics: Adaptor Proteins, Signal Transducing; Angiotensin II; Animals; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Cullin Proteins; Gene Expression Regulation; Germ-Line Mutation; Humans; Hyperkalemia; Hypertension; Kidney; Kidney Tubules, Distal; Mice; Microfilament Proteins; Multiprotein Complexes; Phosphorylation; Protein Serine-Threonine Kinases; Renal Insufficiency; T-Lymphocytes; Tacrolimus; Ubiquitination

Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Pseudohypoaldosteronism; Severity of Illness Index; Tacrolimus

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

Arterial hypertension represents a common complication of immunosuppressive therapy after liver transplantation (LT). The aim of the study is to evaluate the prevalence and risk factors associated with hypertension after LT. From a cohort of 323 cirrhotic patients who underwent LT from 2008 to 2012, 270 patients were retrospectively evaluated, whereas 53 (16.4%) patients deceased. Hypertension was defined as blood pressure ≥140/90 mm Hg in at least two visits and/or the need for antihypertensive therapy. The prevalence of hypertension was 15% before LT and significantly increased up to 53% after LT (P < .001). Mean follow-up was 43 ± 19 months. In normotensive (NT) subjects at baseline, 35.9% developed sustained hypertension after LT, whereas 15.2% developed transient hypertension within the first month after LT, and then returned NT. The development of sustained hypertension after LT was related to the mammalian target of rapamycin inhibitor treatment (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.26-13.48; P = .02), alcoholic cirrhosis before LT (OR, 3.38; 95% CI, 1.44-8.09; P = .005), and new-onset hepatic steatosis after LT (OR, 2.13; 95% CI, 1.10-4.11; P = .02). Tacrolimus, the etiology and severity of liver disease, and other immunosuppressive regimens were not related to the development of hypertension after LT. In our cohort, the prevalence of arterial hypertension has increased up to 53% after LT, and metabolic comorbidities and immunosuppressive treatment with mammalian target of rapamycin inhibitors are the risk factors for the development of hypertension after LT.

Topics: End Stage Liver Disease; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Tacrolimus; Treatment Outcome

Over the years, survival after liver transplantation has increased and metabolic complications are becoming more common, contributing to patients' morbidity and mortality. The objectives of this study were to describe a population of patients with hepatic transplantation and diabetes mellitus (DM), evaluate the frequency of metabolic complications, and assess the impact of a multidisciplinary team on DM management.. This was a retrospective study involving interview and medical record analysis of 46 consecutive patients followed at the diabetes mellitus and liver transplantation unit of a tertiary university hospital, all evaluated by a multidisciplinary team.. Of all patients, 76.1% were men, with a median age 60 years old (interquartile range: 56 to 65 years) and liver transplantation time of 5 years (interquartile range: 0.6-9 years). Hypertension, hypercholesterolemia, hypertriglyceridemia, alcoholism, and smoking were present in 47.8%, 34.8%, 23.9%, 34.8%, and 30.4% of the patients, respectively. The most frequent immunosuppressant in use was tacrolimus (71.1%). Regarding nutritional status, 37.9% of patients were classified as overweight according to body mass index, and 41.2% were considered overweight according to the triceps skin fold. The median glycosylated hemoglobin and weight before and after intervention of the multidisciplinary team in all 46 patients were, respectively, 7.6% (5.7% to 8.8%) versus 6.5% (5.7% to 7.7%); P = .022 and 70.5 kg (64.7 to 82.0 kg) versus 71.6 kg (65.0 to 85.0 kg); P = .18.. Hypertension and dyslipidemia were common in transplanted patients with DM. Intervention of the multidisciplinary team resulted in a significant improvement in glycosylated hemoglobin without significant weight gain.

Topics: Aged; Body Mass Index; Body Weight; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Nutritional Status; Patient Care Team; Postoperative Complications; Postoperative Period; Retrospective Studies; Risk Factors; Tacrolimus

This study aims to verify the new-onset diabetes after kidney transplant (NODAT) incidence in recipients within 1 year after kidney transplantation from a single center in Southern Brazil and to assess the associated conditions.. A retrospective study of 258 post-renal transplant patients was performed. Demographic (gender, age, ethnic background) and clinical (origin of graft, associated infections, body mass index (BMI) at transplant time and 6 and 12 months after, causes of renal failure, and comorbidities) data were analyzed. All patients were on tacrolimus, mycophenolate mofetil, and prednisone treatment. Patients with and without NODAT were compared.. A NODAT incidence of 31.2% was noted 1 year post transplantation. In the univariate analysis, patients with NODAT were older (p = 0.001), mostly had African-American ethnic background (p = 0.02), and had renal failure secondary to high blood pressure (HBP) (p = 0.001). The group of patients with NODAT also had more incidence of post-transplant HBP (p = 0.01), heart failure (p = 0.02), and dyslipidemia (p = 0.001). Logistic regression showed that African-American ethnic background, post-transplant HBP, and dyslipidemia were independently associated with NODAT.. This study shows a NODAT incidence that is greater in patients with African-American ethnic background and that is associated with HBP and dyslipidemia.

Topics: Adult; Brazil; Diabetes Mellitus; Dyslipidemias; Female; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Transplantation; Logistic Models; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Statistics, Nonparametric; Tacrolimus

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus, Type 1; Dyslipidemias; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prevalence; Prospective Studies; Risk Factors; Severity of Illness Index; Spain; Survival Analysis; Tacrolimus; Transplant Recipients

Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension.

Topics: Animals; Gene Deletion; Hypertension; Immunosuppressive Agents; Kidney; Male; Mice; Tacrolimus; Tacrolimus Binding Protein 1A

Topics: Administration, Topical; Bariatric Surgery; Drug Administration Schedule; Female; Femoral Neuropathy; Follow-Up Studies; Humans; Hypertension; Middle Aged; Nerve Compression Syndromes; Obesity, Morbid; Pain; Postoperative Period; Pruritus; Tacrolimus; Treatment Outcome

Application of cyclosporine-A (CsA) or tacrolimus is associated with numerous side effects. One of the main reasons for restricting usage of CsA is hypertension. In tacrolimus treated subjects the frequency of these phenomena is significantly lower. The known molecular mechanism of action of tacrolimus and cyclosporine-A seems to be the same, thus we decided to compare modulatory effect of drugs on vascular smooth muscle contractility.. Experiments were performed on isolated and perfused tail artery of Wistar rats. Contraction force was measured by increased degree of perfusion pressure with a constant flow rate.. Concentration-response curves for agonist in the presence CsA were significantly shifted to the left with increase in maximal responses. This effect was due to increased calcium influx from extracellular calcium stores whereas there were no significant changes in calcium influx in the presence of tacrolimus; concentration-response curve was comparable to controls.. Our results strongly support the idea that main difference between effects on smooth muscle contractility of calcineurin-dependent immunosuppressants: CsA and tacrolimus is related to the different level of extracellular calcium influx to the cytoplasm. The elucidation of these mechanisms may permit the identification of new therapeutic strategies against CsA-induced hypertension.

Topics: Animals; Calcium; Cyclosporine; Dose-Response Relationship, Drug; Hypertension; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Rats, Wistar; Tacrolimus; Vasoconstriction

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Cardiovascular diseases are among the most frequent causes of patient death after liver transplantation. The aim of this retrospective clinical study was to estimate the prevalence of arterial hypertension among patients after successful liver transplantation and the role of immunosuppressive drugs in the pathogenesis of hypertension in these patients.. A total of 88 patients (age 47 .5 ±  12.1 years; 33 women and 55 men) who had undergone successful liver transplantation and completed 24 months follow-up were studied. The results are presented as means with standard deviations.. At 1, 12, and 24 months after liver transplantation, the prevalences of hypertension were 44.3%, 54.5%, and 62.5%, respectively. Systolic and diastolic blood pressure in these months were 124.1 ± 14.8, 132.8 ± 19.1, and 135.2 ± 17.3 mm Hg and 83.3 ± 12.0, 87.3 ± 11.1, and 87.9 ± 11.1 mm Hg, respectively. The estimated glomerular filtration rates were 77.8 ± 32.3, 80.3 ± 30.8, and 78.8 ± 29.1 mL/min/1.73 m(2), respectively. Arterial hypertension was significantly more frequent in patients treated with cyclosporine A than in those treated with tacrolimus (P = .004) or everolimus (P = .005). In patients treated with tacrolimus, a positive correlation was found between tacrolimus blood concentration and systolic blood pressure (R = 0.34; P = .01) and a negative correlation was found between estimated glomerular filtration rate and systolic blood pressure (R = -0.28; P = .02).. Based on study findings, the following conclusions were drawn: arterial hypertension occurs in more than 50% of patients after liver transplantation (significantly higher frequency than in the general population); calcineurin inhibitors may participate in the pathogenesis of arterial hypertension in patients after successful liver transplantation; and the clinical importance of these findings and the influence on cardiovascular outcome of the liver transplant recipients need further investigation.

Topics: Adult; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; End Stage Liver Disease; Everolimus; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus

The evolution of metabolic and cardiovascular disease (CVD) complications after liver transplantation (LT) is poorly characterized. We aim to illustrate the prevalence of obesity and metabolic syndrome (MS), define the cumulative incidence of CVD, and characterize risk factors associated with these comorbidities after LT. A retrospective review of 455 consecutive LT recipients from 1999 to 2004 with an 8- to 12-year follow-up was performed. Obesity increased from 23.8% (4 months) to 40.8% (3 years) after LT. Increase in body mass index predicted MS at 1 year after LT (odds ratio, 1.1; P < 0.001, per point). CVD developed in 10.6%, 20.7%, and 30.3% of recipients within 1, 5, and 8 years, respectively. Age, diabetes, hypertension, glomerular filtration rate < 60 mL/minute, prior CVD, ejection fraction < 60%, left ventricular hypertrophy, and serum troponin (TN) > 0.07 ng/mL were associated with CVD on univariate analysis. Age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.06; P = 0.019), diabetes (HR, 1.78; 95% CI, 1.09-2.92; P = 0.022), prior history of CVD (HR, 2.46; 95% CI, 1.45-4.16; P < 0.001), and serum TN > 0.07 ng/mL (HR, 1.98; 95% CI, 1.23-3.18; P = 0.005) were independently associated with CVD in the long term. Smoking history (ever), sex, hyperlipidemia, and serum ferritin levels were not predictive of CVD. Tacrolimus use versus noncalcineurin-based immunosuppression (HR, 0.26; 95% CI, 0.14-0.49; P < 0.001) was associated with reduced risk of CVD but not versus cyclosporine (HR, 0.67; 95% CI, 0.30-1.49; P = 0.322). CVD is common after LT. Independent of MS, more data are needed to identify nonconventional risk factors and biomarkers like serum TN. Curbing weight gain in the early months after transplant may impact MS and subsequent CVD in the long term.

Topics: Adult; Biomarkers; Body Mass Index; Cardiovascular Diseases; Comorbidity; Cyclosporine; Diabetes Complications; End Stage Liver Disease; Female; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Obesity; Odds Ratio; Prevalence; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tacrolimus

We evaluated the clinical efficacy of tailoring tacrolimus dosage to cytochrome P450 (CYP) 3A5 genotype in liver transplant patients. One hundred patients who received tacrolimus-based therapy were included in the retrospective study in which the relationship between the tacrolimus blood trough concentration/dosage ratio and the CYP3A5 genotype of both donors and recipients was determined. Subsequently, 106 patients were continuously enrolled in a prospective study and followed-up for 6 months; the relationship between tacrolimus dosage and CYP3A5 genotype was also determined. Rates of acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, and hyperglycemia were compared between the groups. During the 6 months following liver transplantation, the mean tacrolimus concentration/dosage ratio among patients who did not have the CYP3A5*1 genotype and who received a transplant from a donor with the same genotype (24/100, 24% of patients) was higher than that among patients who did have the CYP3A5*1 genotype and/or had a donor with the same genotype (76/100, 76% of patients). In the second part of the study, the tacrolimus dosage was tailored to CYP3A5 genotype and 24 patients (22.64%) received a lower dose. There was an obvious decrease in acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, hyperglycemia, and Pneumocystis carinii infection among the latter group. A lower tacrolimus dose was suitable for about 25% of the liver transplant patients, as these patients did not have the CYP3A5*1 genotype and received a transplant from a donor with the same genotype. Tailoring the tacrolimus dosage according to the CYP3A5 genotype could reduce rejection and adverse effects.

Topics: Adult; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Gene Frequency; Genotype; Graft Rejection; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Outcome Assessment, Health Care; Polymorphism, Genetic; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

Tacrolimus is a calcineurin inhibitor primarily metabolized by CYP3A4 and secondarily by CYP3A5. Several drugs can modify tacrolimus blood levels as calcium channel blockers (CCBs). Interaction with nicardipine was reported in some cases. A man with a history of malignant arterial hypertension treated with nicardipine, underwent kidney transplantation. After transplantation, he was treated with tacrolimus, mycophenolate mofetil and corticoids. Therapeutic drug monitoring of tacrolimus was done regularly showing a mean trough concentration (C0) of 24.39 ng/mL with some concentrations reaching 52 ng/mL. After changing nicardipine by prazosine, the first tacrolimus C0 after stopping nicardipine was 3.2 ng/mL. Increase of tacrolimus trough concentrations is due to the inhibition of CYP3A4. Very high levels of tacrolimus suggest the non expression of CYP3A5. Thus, because of the possible lack of the secondary pathway, therapeutic drug monitoring of tacrolimus is highly recommended at the introduction of CCBs and also at its stopping.

Topics: Antihypertensive Agents; Biotransformation; Calcium Channel Blockers; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Drug Substitution; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Nicardipine; Polypharmacy; Prazosin; Tacrolimus

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. Hypertension is a widely accepted risk factor for its outcome.. We analyzed 169 heart transplant recipients. The diagnosis of hypertension was made on the basis of information gathered at 3 consecutive visits. Complete blood count, urea, serum lipids, fasting glucose, creatinine, and N-terminal pro-B-type natriuretic peptide were also studied.. In the orthotopic heart transplantation (OHT) population, 11% had diabetes and 68% had chronic kidney disease. Hypertension was diagnosed and treated in 68% of the OHT patients. Hypertensive patients were significantly older, with a lower estimated glomerular filtration rate and higher serum creatinine and erythrocyte count. Thirty-three percent of patients did not achieve target blood pressure despite optimal medical treatment. Patients treated with tacrolimus had similar systolic blood pressure compared with those treated with cyclosporine (with a tendency to have lower values). Patients treated with mammalian target of rapamycin inhibitors had similar systolic and diastolic blood pressures compared with those treated without these inhibitors. In the group of patients given steroids, systolic and diastolic blood pressures were significantly lower than in the group not treated with steroids. In addition, steroid-treated patients had a significantly lower estimated glomerular filtration rate, hemoglobin, and erythrocyte count and higher serum creatinine, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. Chronic kidney disease was also more prevalent in this group. Blood pressure was not related to the kidney function.. Despite polytherapy, optimal blood pressure control was not achieved in the majority of patients. OHT patients have a high prevalence of hypertension, which should be treated adequately. More efforts should be made to optimize blood pressure control, particularly when other comorbidities are present. Blood pressure was not related to patient kidney function.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Comorbidity; Creatinine; Cyclosporine; Erythrocyte Count; Female; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prevalence; Renal Insufficiency, Chronic; Risk Factors; Tacrolimus

Tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) is a potential complication of allogeneic stem cell transplant (SCT). Due to the paucity of information on the management of PRES in SCT patients receiving tacrolimus, more information is needed on trends associated with the incidence of PRES and to characterize its management. A retrospective review was conducted of patients receiving tacrolimus for prevention of graft versus host disease (GVHD) after allogeneic SCT who developed PRES from September 2008 to July 2011. Nineteen patients were identified. Altered mental status, seizures, and visual abnormalities were experienced by 78.9%, 52.6%, and 31.5% of the patients, respectively, at time of PRES onset. Compared with baseline, patients with PRES were likely to have an increase in mean arterial pressure (P < 0.0001) and serum creatinine. Elevated tacrolimus levels and hypomagnesemia were not observed with PRES onset. Tacrolimus was managed in three general strategy groups: not held, held then continued, and switched to another agent. Survival was defined as survival to discharge from PRES hospitalization. When tacrolimus was not held, held then continued, or switched to another agent, 40% (2 of 5), 40% (4/10), and 50% (2/4) survived to discharge, respectively. PRES was associated with high blood pressure and adequate blood pressure control should be part of its management. No management strategy pertaining to tacrolimus usage appeared more beneficial over another.

Topics: Adult; Aged; Blood Pressure; Disease Management; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Immunosuppressive Agents; Leukemia; Male; Middle Aged; Posterior Leukoencephalopathy Syndrome; Retrospective Studies; Survival Analysis; Tacrolimus; Transplantation, Homologous

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Bacterial Agents; Breast Diseases; Colchicine; Diabetes Mellitus, Type 2; Drug Resistance; Female; Granuloma; Humans; Hypertension; Immunosuppressive Agents; Isotretinoin; Male; Pyoderma Gangrenosum; Remission Induction; Tacrolimus

Topics: Antihypertensive Agents; Cyclophosphamide; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Fatigue; Glomerulosclerosis, Focal Segmental; Gynecomastia; Humans; Hypertension; Male; Mastodynia; Middle Aged; Muscle Weakness; Mycophenolic Acid; Prednisone; Proteinuria; Tacrolimus

Topics: Blood Pressure; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Sensitivity and Specificity; Signal Transduction; Sodium Chloride Symporters; Tacrolimus

Topics: Amlodipine; Antihypertensive Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child, Preschool; Cytochrome P-450 CYP3A; Drug Interactions; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Pharmacogenetics; Tacrolimus; Treatment Outcome

Arteriolar hyalinosis in kidney transplants is considered the histopathologic hallmark of chronic calcineurin inhibitor (CNI) toxicity. However, the lesion is not specific. We assessed prevalence, progression, and clinical significance of arteriolar lesions in 1239 renal transplant sequential protocol biopsy samples and 408 biopsy for cause samples in 526 patients. Associations between arteriolar lesions and presumed risk factors, concomitant histopathologic lesions, demographic factors, and graft function were evaluated. The frequency of arteriolar lesions was stable during the first 2 years after transplantation, and increased thereafter (14.8% at 6 months versus 48.6% at >2 years; P < 0.0001). We were unable to find associations with diabetes, hypertension, or CNI therapy. However, patients with early arteriolar lesions received grafts from older donors (mean ± SD age, 54.4 ± 13.4 years versus 43.1 ± 16.6 years; P < 0.0001), and had inferior graft function (estimated glomerular filtration rate 55 ± 21 mL/min versus 63 ± 24 mL/min at 6 weeks, 53 ± 19 mL/min versus 60 ± 23 mL/min at 1 year, and 49 ± 19 mL/min versus 59 ± 22 mL/min at 2 years; P < 0.05). Evaluation of late biopsy samples from patients not receiving CNI therapy revealed a high prevalence of AH without clear-cut identifiable underlying cause. Reproducibility of arteriolar lesions was at best moderate (κ ≤ 0.62). Sampling error in sequential biopsy samples was frequent. In conclusion, in samples from sequential protocol biopsies and biopsies for cause in individual patients, arteriolar lesions in renal transplants not only increase over time without being specific for CNI toxicity but are affected by sampling error and limited reproducibility.

Topics: Adult; Age Factors; Aged; Arterioles; Biopsy; Cyclosporine; Diabetes Mellitus; Disease Progression; Female; Glomerular Filtration Rate; Humans; Hyalin; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Observer Variation; Reproducibility of Results; Retrospective Studies; Tacrolimus; Tissue Donors

Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5.. We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases.. Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others).. CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.

Topics: Adolescent; Antihypertensive Agents; Child; Cytochrome P-450 CYP3A; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Nicardipine; Risk; Tacrolimus; Young Adult

Tacrolimus (Tac) in combination with mycophenolate mofetil is widely used after heart transplantation (HT). Everolimus (EVR), a new potent proliferation signal inhibitor can be used with a carcineurin inhibitor to reduce the occurrence of rejection. The purpose of this study was to evaluate the efficacy and safety of Tac combined with EVR in de novo HT.. From January 2009 to April 2011, 33/62 patients who underwent HT were prescribed Tac and EVR as de novo immunosuppression. The main exclusion criteria were poor kidney function (serum creatinine > 2.8 mg/dL), panel-reactive antibodies > 25%, donors > 60 years old, or cold ischemia time > 6 hours. All patients received Tac (C0 blood level 5-10 ng/mL during the first 6 months, then 3-5 ng/mL), EVR (C0 target 3-8 ng/mL), and corticosteroids. After transplantation, routine examinations included echocardiogram and protocol endomyocardial biopsy.. There was no operative mortality. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%. One patient who had undergone coronary artery bypass grafting previously and received intra-aortic balloon pumping and extracorporeal membrane oxygenator-assisted cardiopulmonary resuscitation before HT died of Aspergillus septicemia 58 days after HT. No biopsy-proven acute rejection > grade 2R or acute rejection associated with hemodynamic compromise was observed. Hyperlipemia was noted in 16 cases (48.5%), hypertension in 11 (33.3% 5%), and diabetes mellitus in 12 (36.4%). No other severe adverse events were noted.. Concentration-controlled EVR (C0 target 3-8 ng/mL) in combination with Tac achieved good efficacy and safety. The 1- and 3-year actuarial survivals were 95.74% ± 3.49%.

Topics: Adolescent; Adult; Aged; Child; Diabetes Mellitus; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Sirolimus; Survival Analysis; Tacrolimus; Taiwan; Time Factors; Treatment Outcome; Young Adult

Follicular carcinoma of the thyroid is a relatively rare malignancy in childhood even in paediatric solid organ transplant recipients. The risk of developing de novo malignancies after liver transplantation is higher compared to the general population. We report an 18-yr-old girl who had successfully undergone liver transplantation five yr earlier for neonatal sclerosing cholangitis complicated by the development of dysplastic nodules. Baseline immunosuppression was with tacrolimus and prednisolone. Mycophenolate mofetil was later added in view of steroid-resistant episodes of graft rejection. She subsequently suffered from marked obesity and essential hypertension needing antihypertensive medication. Five yr after liver transplantation, she presented with a right-sided thyroid swelling that was rapidly progressive with no associated lymphadenopathy and normal systemic examination. Ultrasound of her neck revealed a solid lesion in the right lobe of the thyroid gland with ill-defined margins, and a diagnostic right thyroid lobectomy confirmed the diagnosis of follicular carcinoma with focal capsular and vascular invasion. She underwent total thyroidectomy and currently remains well on thyroxine supplements. Our report highlights the need for high level of suspicion and prompt investigation into any abnormal lesion in the long-term follow-up of solid organ transplant recipients.

Topics: Adenocarcinoma, Follicular; Adolescent; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Obesity; Prednisolone; Tacrolimus; Thyroid Neoplasms; Treatment Outcome

Posterior reversible encephalopathy syndrome (PRES) is a condition characterized by reversible symptoms including headache, visual disturbances, focal neurological deficits, altered mentation, and seizures. It has been associated with circumstances that may affect the cerebrovascular system, such as hypertension, eclampsia, and immunosuppression with calcineurin inhibitors. The underlying etiology of PRES has remained unclear; however, cerebrovascular autoregulatory dysfunction, hyperperfusion, and endothelial activation have been implicated.. We describe a case of a young patient with lung transplant, who presented with headache, acute binocular blindness, and seizure immediately after infusion of saline through a peripherally inserted central catheter line, which inadvertently terminated cephalad in the left internal jugular vein, near the jugular foramen. Subsequent brain magnetic resonance imaging revealed vasogenic edematous lesions in a pattern consistent with PRES--a diagnosis supported by his constellation of symptoms, history of lung transplantation on tacrolimus immunosuppression, and relative hypertension.. This is the first reported case describing the development of PRES after the insertion of a peripherally inserted central catheter line. The development of PRES in a typical high-risk patient immediately after cerebral venous outflow obstruction implicates the role of the cerebral venous system and provides potential insight into the mechanism of this disorder that remains of unclear pathogenesis.

Topics: Adult; Blindness; Brain; Catheterization, Central Venous; Headache; Humans; Hypertension; Immunosuppression Therapy; Lung Transplantation; Magnetic Resonance Imaging; Male; Posterior Leukoencephalopathy Syndrome; Seizures; Tacrolimus; Treatment Outcome

The cytochrome P450 3A5 (CYP3A5) enzyme has been implicated to determine blood pressure (BP) in humans. Different results have been reported concerning CYP3A5 gene polymorphisms and posttransplantation hypertension in kidney recipients. Our objective was to investigate whether CYP3A5 1/3 polymorphism was associated with ambulatory BP among a population of renal transplant recipients receiving the calcineurin inhibitor tacrolimus for immunosuppression.. Sixty primary kidney transplant recipients undergoing treatment with tacrolimus were genotyped for the CYP3A5 1/3 polymorphism. We analysed the association of the CYP3A5 alleles with ambulatory systolic and diastolic BP measured at 6 and 24 months posttransplantation.. We observed that 23.3% of the patients were CYP3A5 1 carriers and 76.7% were homozygous for CYP3A5 3. CYP3A5 1 carriers showed higher adjusted systolic BP and diastolic BP at 6 and 24 months posttransplantation, and they were prescribed more antihypertensive drugs compared with non CYP3A5 1 carrier patients, albeit not significant. No significant differences were found comparing the distribution of the hypertension classes.. We did not observe a significant association of CYP3A5 1/3 polymorphism with posttransplantation hypertension, although there were some differences in BP associated with the presence of the CYP3A5 1 allele.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcineurin Inhibitors; Cytochrome P-450 CYP3A; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Tacrolimus; Time Factors; Treatment Outcome

Maintenance therapy with calcineurin inhibitors (CNIs) increases cardiovascular risk. Use of the m-TOR inhibitors everolimus or sirolimus to minimize CNI exposure is usually undertaken to preserve renal function following kidney transplantation, but may also improve cardiovascular risk status. Recent studies of early conversion from CNI to m-TOR inhibitors have shown a numerical improvement in the incidence of hypertension, but results are not clear-cut. Dyslipidaemia, in contrast, is more frequent under m-TORs than with CNI-based immunosuppression. New-onset diabetes is rare (≤ 5%) using modern m-TOR regimens, for example, everolimus and reduced-exposure CNI. Renal function improvement with m-TOR inhibitor regimens versus CNIs would also be expected to improve cardiovascular risk. Moreover, m-TOR-based CNI-minimization regimens are not associated with proteinuria, a known cardiovascular risk factor, with the possible exception of late conversion in patients with poor renal function. Interestingly, m-TOR inhibitors may also exert cardioprotective effects. Animal data suggest that m-TORs may restrict the pathogenesis of atherosclerosis, consistent with preliminary clinical data that conversion from CNIs to everolimus can stabilize markers for arterial stiffness. In conclusion, use of m-TORs has the potential to lessen the toll of cardiovascular disease following kidney transplantation - an opportunity that merits further exploration.

Topics: Animals; Blood Pressure; Calcineurin Inhibitors; Cardiovascular Diseases; Diabetes Mellitus; Everolimus; Glomerular Filtration Rate; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Risk; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

TAC is commonly prescribed in KTX recipients, though overexposure can be nephrotoxic. CIVN, used to treat post-KTX hypertension, may inhibit TAC metabolism resulting in overexposure and potential toxicity. We present two case reports and analysis of 2068 KTXs from the PHIS to characterize post-KTX intravenous anti-hypertensive use and to determine whether CIVN in TAC-treated patients would predict "immunosuppressive drug causing adverse effects in therapeutic use" (E-code E9331). CIVN was ordered in 11% of KTXs and prescribing increased from 6.2% in 2003 to 10.3% in 2008 (p=0.003, Mantel-Haenszel chi-square test). AEI were reported in 7.1% of TAC-treated patients with CIVN orders compared to 3% of those without (p=0.003, chi-square test). In univariate analysis using GEEs, AEI were twofold more likely in patients with CIVN orders than patients without (AOR 2.1, 95% CI 1.03-4.17) and threefold more likely than patients with orders for other continuous intravenous anti-hypertensives (AOR 3.2, 95% CI 1.09-9.08). In multivariate analysis, only CIVN significantly predicted AEI (AOR 2.8, 95% CI 1.29-6.04). Thus, until clinical studies to fully characterize this interaction are completed, CIVN should be used with caution in TAC-treated individuals.

Topics: Adolescent; Adult; Antihypertensive Agents; Child; Child, Preschool; Databases, Factual; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Nicardipine; Tacrolimus

The present studies examined the role and mechanism of action of infiltrating T lymphocytes in the kidney during salt-sensitive hypertension. Infiltrating T lymphocytes in the Dahl salt-sensitive (SS) kidney significantly increased from 7.2 ± 1.8 × 10(5) cells/2 kidneys to 18.2 ± 3.9 × 10(5) cells/2 kidneys (n = 6/group) when dietary NaCl was increased from 0.4 to 4.0%. Furthermore, the expression of immunoreactive p67(phox), gp91(phox), and p47(phox) subunits of NADPH oxidase was increased in T cells isolated from the kidneys of rats fed 4.0% NaCl. The urinary excretion of thiobarbituric acid-reactive substances (TBARS; an index of oxidative stress) also increased from 367 ± 49 to 688 ± 92 nmol/day (n = 8/group) when NaCl intake was increased in Dahl SS rats. Studies were then performed on rats treated with a daily injection of vehicle (5% dextrose) or tacrolimus (0.25 mg·kg(-1)·day(-1) ip), a calcineurin inhibitor that suppresses immune function, during the period of high-NaCl intake (n = 5/group). In contrast to the immune cell infiltration, increased NADPH oxidase expression, and elevated urine TBARS excretion in vehicle-treated Dahl SS fed high salt, these parameters were unaltered as NaCl intake was increased in Dahl SS rats administered tacrolimus. Moreover, tacrolimus treatment blunted high-salt mean arterial blood pressure and albumin excretion rate (152 ± 3 mmHg and 20 ± 9 mg/day, respectively) compared with values in dextrose-treated Dahl SS rats (171 ± 8 mmHg and 74 ± 28 mg/day). These experiments indicate that blockade of infiltrating immune cells is associated with decreased oxidative stress, an attenuation of hypertension, and a reduction of renal damage in Dahl SS rats fed high salt.

Topics: Albuminuria; Animals; Antioxidants; Cell Movement; Cyclic N-Oxides; Disease Models, Animal; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Spin Labels; T-Lymphocytes; Tacrolimus

The main objectives of this study were to estimate the prevalence of and the risk factors for the adverse effects of tacrolimus-based immunosuppression in patients who obtained renal transplant from living donors.. A multicenter cross-sectional observational study in 154 kidney transplant patients who received grafts from living donors.. Large proportion of patients had hypertension (83%) and hyperlipidemia (53%); 27% had posttransplant diabetes mellitus. Patients had on average two chronic diseases. Tremor was present in 40%, neurologic toxicity in 45%, and anemia in 51.5% of patients. The average number of adverse effects was 3.52 ± 1.57. In multivariate analysis some adverse effects were related to tacrolimus concentration, duration of treatment, number of medications or medical problems. In linear regression analysis correlation was found, among the others, between diastolic blood pressure and tacrolimus concentration, and inverse correlation between erythrocyte count and duration of treatment.. There is a significant prevalence of tacrolimus adverse effects and supratherapeutic TAC blood concentrations in Jordanian renal transplant patients in spite of using low TAC doses and overall adequate renal function.

Topics: Adolescent; Adult; Cross-Sectional Studies; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Kidney Transplantation; Living Donors; Male; Middle Aged; Prevalence; Tacrolimus; Young Adult

Limited data exist for the use of alemtuzumab (AL) induction in liver transplantation (LT) recipients. We compared the outcomes of hepatitis C virus-negative LT recipients who received AL induction followed by tacrolimus and mycophenolate mofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipients were compared to 85 non-AL-induced recipients with similar characteristics. Two-year patient survival (80% versus 88.2%, P = 0.0665) and graft survival (76.4% versus 82.4%, P = 0.1792) were not significantly different between the AL and non-AL groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creatinine levels: 1.3 ± 0.3 versus 1.4 ± 0.6 mg/dL), and immunosuppressant monotherapy (29.1% versus 44.3%), were not significantly different between the AL and non-AL groups, respectively (P > 0.05). The number of rejection episodes (12 versus 42, P = 0.02) and the number of patients with new-onset hypertension (3 versus 15, P = 0.03) were lower in the AL group, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P = 0.03), primarily because of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hypertension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients is called into question.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Chi-Square Distribution; Chicago; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Risk Factors; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

Tacrolimus has proven to be a potent immunosuppressive agent in orthotopic liver transplantation (OLT). The aim of this study is to examine its long-term efficacy and safety.. One thousand consecutive primary OLTs performed between August 1989 and December 1992 and maintained under tacrolimus-based immunosuppression were followed up until January 2009. Patient and graft survivals with corresponding causes of death and retransplantation, maintenance immunosuppression, and adverse effects were examined. The study population includes 600 males and 400 females comprising 166 children, 630 adults, and 204 seniors. The mean follow-up was 17.83 (range, 16.1-19.50) years. The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively. At the last follow-up, 442 patients were alive; 133 (77.1%) children, 265 (34.5%) adults, and 44 (16.1%) seniors (P=0.0001). After the first post-OLT year, cardiopulmonary events, recurrence of primary disease, and malignancy were the main causes of death. Overall, 183 recipients underwent retransplants; mainly for primary nonfunction, hepatic artery thrombosis, and recurrent primary disease, 180 required dialysis, and 45 underwent kidney transplant. A total of 97.7% of the survivors were on tacrolimus and 26.2% were also receiving adjunctive immunosuppressants at the last follow-up.. The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively, with significantly better survival among children. Age-related complications, recurrence of primary disease, and malignancy were the major causes of late graft loss. Graft loss related to immunologic reasons was rare. The prevention of recurrent disease and newer immunosuppressive regimen will further improve these results.

Topics: Adolescent; Adult; Aged; Child; Diabetes Mellitus; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Reoperation; Tacrolimus; Young Adult

Advagraf, a prolonged release formulation of tacrolimus, is administered once daily in the morning. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses.. We analyzed 50 consecutive recipients of a first liver transplantation with 6 months follow-up. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus and arterial hypertension de novo.. The incidence of biopsy proven acute rejection episodes was 10% (n = 5), none 7 of which were steroid resistant and all resolved favorably. The rate of diabetes mellitus de novo was 22% (n = 11), 7 of whom required insulin. Hypertension developed in 9 patients (18%), all of whom were treated with a single drug. The mean serum creatinine level was 1.08 ± 0.25 mg/dL, with 3 patients (6%) displaying a value ≥ 1.5 mg/dL. Patient and graft survivals were 100%.. Advagraf is an effective immunosuppressant in liver transplantation with a low incidence of biopsy-confirmed acute rejection episodes. The good results for patient and graft survival with few side effects make it a useful drug for de novo liver transplantation.

Topics: Creatinine; Diabetes Mellitus; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Tacrolimus

Topics: Animals; Blood Cells; Cytokines; Endothelial Cells; Hypertension; Immunosuppressive Agents; Mice; Mice, Knockout; Receptors, Transforming Growth Factor beta; Smad2 Protein; Smad3 Protein; T-Lymphocytes, Regulatory; Tacrolimus; Tacrolimus Binding Protein 1A; Th17 Cells

Patients treated with the immunosuppressive drug tacrolimus (FK506), which binds FK506 binding protein 12 (FKBP12) and then inhibits the calcium-dependent phosphatase calcineurin, exhibit decreased regulatory T cells, endothelial dysfunction, and hypertension; however, the mechanisms and whether altered T-cell polarization play a role are unknown. Tacrolimus treatment of mice for 1 week dose-dependently decreased splenic CD4(+)/FoxP3(+) (regulatory T cells), increased splenic CD4(+)/IL-17(+) (T-helper 17) cells, and caused endothelial dysfunction and hypertension. To determine the mechanisms, we crossed floxed FKBP12 mice with Tie2-Cre mice to generate offspring lacking FKBP12 in endothelial and hematopoietic cells only (FKBP12EC knockout [KO]). Given the role of FKBP12 in inhibiting transforming growth factor-β receptor activation, Tie2-Cre-mediated deletion of FKBP12 increased transforming growth factor-β receptor activation and SMAD2/3 signaling. FKBP12EC KO mice exhibited increased vascular expression of genes and proteins related to endothelial cell activation and inflammation. Serum levels of the proinflammatory cytokines IL-2, IL-6, interferon-γ, IL-17a, IL-21, and IL-23 were increased significantly, suggesting a T-helper 17 cell-mediated inflammatory state. Flow cytometry studies confirmed this, because splenic levels of CD4(+)/IL-17(+) cells were increased significantly, whereas CD4(+)/FoxP3(+) cells were decreased in FKBP12EC KO mice. Furthermore, spleens from FKBP12EC KO mice showed increased signal transducer and activator of transcription 3 activation, involved in T-helper 17 cell induction, and decreased signal transducer and activator of transcription 5 activation, involved in regulatory T-cell induction. FKBP12EC KO mice also exhibited endothelial dysfunction and hypertension. These data suggest that tacrolimus, through its activation of transforming growth factor-β receptors in endothelial and hematopoietic cells, may cause endothelial dysfunction and hypertension by activating endothelial cells, reducing regulatory T cells, and increasing T-helper 17 cell polarization and inflammation.

Topics: Animals; Aorta; Blood Cells; Cytokines; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hypertension; Immunoblotting; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Transforming Growth Factor beta; Smad2 Protein; Smad3 Protein; T-Lymphocytes, Regulatory; Tacrolimus; Tacrolimus Binding Protein 1A; Th17 Cells; Vasodilation

Unilateral and bilateral hand transplantations have been performed worldwide with good mid-term functional results. An above-elbow bilateral transplantation was performed in a 29-year-old male patient from a fully HLA-mismatched donor. Alemtuzumab induction and steroid-free maintenance immunosuppression with tacrolimus and mycophenolate was used. Due to acute rejection, steroids were introduced at 6 months. Three acute rejection episodes occurred, one treated with alemtuzumab. New-onset diabetes after transplant, dyslipemia and worsening of previous high blood pressure required treatment. At 26 months post-transplantation, the patient has excellent elbow active movement, active flexion and extension of the thumb and fingers, useful sensation and a gainful job. Based on the functional results of the case reported, bilateral trans-humeral transplantation could be a viable treatment for selected bilateral above-elbow amputees.

Topics: Adult; Alemtuzumab; Amputation, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Arm; Diabetes Complications; Hand Transplantation; HLA Antigens; Humans; Hypertension; Immunosuppressive Agents; Male; Mycophenolic Acid; Steroids; Tacrolimus; Transplantation; Transplantation, Homologous

Abstract Renal cytochrome P450 3A5 (CYP3A5) has been associated with blood pressure (BP) control in humans. We investigated whether CYP3A5 polymorphisms are associated with post- transplant hypertension in a selected population of kidney recipients receiving calcineurin inhibitors. Ninety-two kidney transplant recipients receiving cyclosporine (CyA) or tacrolimus (Tac) were genotyped for CYP3A5 polymorphisms, and the association between the CYP3A5 alleles (*1,*3) and hypertension on post-operative day (POD) 6 and POD 180 was verified, with multiple regression being used to identify the putative co-variates that may predict the extent and severity of hypertension in transplant recipients at different post-transplant times. The CYP3A5*1 carriers had higher systolic (SBP) and diastolic blood pressure (DBP) in both the immediate and delayed post-transplant period when adjusted for anti-hypertensive medication (POD 6: SBP = 161 ± 23 vs. 140 ± 23 mmHg; DBP = 120 ± 15 vs. 87 ± 14 mmHg, p < 0.05. POD 180: SBP = 136 ± 16 vs. 129 ± 14 mmHg; DBP = 89 ± 15 vs. 80 ± 15 mmHg, p < 0.05). The severity of hypertension between the CYP3A5*1 carriers and noncarriers on POD 6 was documented by the significantly different distribution of hypertension classes, but this was not confirmed on POD 180. The CYP3A5 genotype was the only independent variable affecting mean arterial pressure. The results of this study show that CYP3A5 polymorphisms are associated with the severity and degree of hypertension in kidney transplant recipients receiving calcineurin inhibitors regardless of the time of recording. However, the role of concomitant medications such as steroids with strong CYP3A5 inducing activity, should be taken into account.

Topics: Adolescent; Adult; Alleles; Blood Pressure; Calcineurin Inhibitors; Child; Child, Preschool; Cyclosporine; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Hypertension; Kidney Transplantation; Male; Polymorphism, Genetic; Severity of Illness Index; Tacrolimus; Young Adult

Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, including hyperkalemia, hypercalciuria and acidosis, often complicate their use. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.

Topics: Analysis of Variance; Animals; Bendroflumethiazide; Calcineurin Inhibitors; Calcium; Cell Line; Chlorides; Creatinine; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Humans; Hydrochlorothiazide; Hypertension; Immunoblotting; Immunohistochemistry; Kidney; Mice; Mice, Knockout; Sodium Chloride Symporters; Tacrolimus

Hypertension is an important cardiovascular risk factor that influences patient survival. This study sought to evaluate hypertension incidence and circadian rhythms of blood pressure (BP) among liver transplant recipients during the first posttransplant month. We also compared hypertension incidence according to clinical and automated blood pressure monitoring methods. BP was determined by clinical blood pressure monitoring (CBPM) methods and by automated blood pressure monitoring (ABPM) using the SpaceLabs device. We also assessed blood biochemistry, particularly kidney function parameters and immunosuppressive drug blood trough levels, among 32 white subjects (10 women and 22 men) of average age 47.58±14.19 years. The leading cause for transplantation was liver insufficiency due to viral hepatitis B and/or C infection (43.75%). The majority (93.75%) of patients was prescribed immunosuppressive treatment with tacrolimus. Although we observed hypertension in 28 patients (87.5%) by ABPM measurements and in 25 (78.12%) using CBPM method, the difference did not reach statistical significance. However, BP control was inadequate in 28 patients (87.5%) by ABPM assessment versus 3 (9.38%) according to CBPM readings (P=.025). The BP circadian rhythm was altered in 30 patients (93.75%) including 15 with higher nighttime BP readings. There was no correlation between tacrolimus blood levels and BP values or with kidney function as assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We concluded that prevalence of arterial hypertension among liver transplant recipients within 1 month after transplantation is high. The majority of the patients show disturbed circadian rhythms in the early period after liver transplantation with loss or even reversal of the normal nocturnal decrease in BP. Owing to the fact that ABPM enables more adequate daily assessment of BP values, it is an optimal method to adjust antihypertensive therapy to optimal levels.

Topics: Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

The aim of this paper was to report the case of type 2 diabetes and significant insulin resistance that improved dramatically after removal of a pheochromocytoma in a liver transplant recipient , and to provide a review of the relevant literature. We describe the clinical presentation, diagnostic results and management of the patient. In addition, we performed a PubMed search for related English language articles, to provide an overview of the pertinent literature. A 53 year old woman with a history of an orthotopic liver transplantation and insulin-requiring type 2 diabetes was admitted to the hospital with fever, diaphoresis, tachycardia and hypertension. A pheochromocytoma was diagnosed and removed. The patient subsequently developed hypoglycemia and required no further insulin therapy. Pheochromocytomas have been described to lead to hyperglycemia and diabetes, due to the suppression of insulin release and increased insulin resistance. Furthermore, a review of the literature revealed only 3 other reported cases of pheochromocytomas in organ transplant recipients. None of these pheochromocytomas were believed to have occurred de novo after transplantation. This is the first report of a pheochromocytoma in a liver transplant recipient and possibly the first case of a de novo pheochromocytoma in any organ transplant recipient. Moreover, this case showcases pheochromocytomas as a rare cause of diabetes mellitus.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Diabetes Mellitus, Type 2; Female; Glipizide; Glucocorticoids; Humans; Hypertension; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Liver Diseases, Alcoholic; Liver Transplantation; Middle Aged; Pheochromocytoma; Postoperative Complications; Remission Induction; Tachycardia; Tacrolimus

The calcineurin inhibitors-cyclosporine and tacrolimus-are the mainstay of immunosuppressive therapy in solid organ transplantation. These drugs produce severe adverse drug effects (ADEs) such as nephrotoxicity, posttransplantation diabetes mellitus, and hypertension. Accumulated evidence suggests that the development of type 2 diabetes, hypertension, and renal failure may be associated with specific DNA genotypes. In this review, the genes involved with the development of these disease processes are compared with those implicated in calcineurin inhibitor-induced ADEs. The renin-angiotensin system genes, cytokine-encoding genes, and plasminogen activator inhibitor type 1 genes have been implicated in calcineurin inhibitor-induced nephrotoxicity, as well as in development of renal failure. A number of genes are implicated in contributing to diabetes, and these include the vitamin D receptor gene, VDR; hepatocyte nuclear factor genes, HNF; transcription factor 7-like 2 gene, TCF7L2; angiotensin-converting enzyme gene, ACE; cytokines; peroxisome proliferator-activated receptor gamma gene, PPARG; and others. Studies have suggested that the VDR, PPARG, HNF1A, and adenosine 5'-triphosphate-binding cassette ABCC8 (which encodes the sulfonylurea receptor) genes are associated with calcineurin inhibitor-induced diabetes. The genes encoding for the angiotensin-converting enzyme, endothelial constitutive nitric oxide synthase, and cytochrome P450 3A isoenzyme have been involved in the development of hypertension and in calcineurin inhibitor-induced hypertension. The genetic study of disease states can be the stepping stones for thoroughly understanding the genetic basis of ADEs. Gene polymorphisms are implicated in the development of diseases and corresponding disease-like ADEs. The disease-associated genes provide candidate genes for exploring ADEs and may provide genomic biomarkers for assessing the risk for developing severe calcineurin inhibitor-related ADEs as well as for developing preventive strategies.

Topics: Biomarkers, Pharmacological; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 2; Drug Discovery; Genotype; Humans; Hypertension; Immunosuppressive Agents; Polymorphism, Genetic; Precision Medicine; Renal Insufficiency; Risk Factors; Tacrolimus

Tacrolimus is an immunosuppressive medication in the class of calcineurin inhibitors that acts by inhibiting T-cell and interleukin-2 activity, and is commonly used after allogeneic organ transplant. We present a patient who used tacrolimus after cadaveric kidney transplant and experienced blurry vision. Ocular examination and patient's course subsequently revealed aqueous tear deficiency as a dose-dependent adverse effect of oral tacrolimus.

Topics: Dry Eye Syndromes; Glomerulonephritis, IGA; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lacrimal Apparatus Diseases; Male; Middle Aged; Ophthalmic Solutions; Tacrolimus; Vision Disorders; Visual Acuity

Topics: Acute Disease; Antibodies, Monoclonal; Antilymphocyte Serum; Calcineurin Inhibitors; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Pancreas Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Tacrolimus

We studied the effect of acute and sustained cyclosporine and tacrolimus on muscle sympathetic nerve activity (MSNA) in groups of healthy male volunteers.. Acute cyclosporine in normal dose (2.5 mg/kg) increased MSNA from 11 +/- 6 to 19 +/- 8 bursts/min (P < 0.05). Acute cyclosporine in high dose (10 mg/kg) increased MSNA from 13 +/- 6 to 25 +/- 4 bursts/min (P < 0.05) and increased heart rate and mean arterial pressure (heart rate from 64 +/- 8 to 74 +/- 6 b.p.m., MAP from 92 +/- 10 to 105 +/- 8 mmHg; both P < 0.05). Sustained cyclosporine (2.5 mg/kg b.i.d. for 2 weeks) suppressed MSNA from 14 +/- 6 to 8 +/- 7 bursts/min (P < 0.05). Blood pressure increased from 89 +/- 6 to 98 +/- 6 mmHg (P < 0.05). Body weight increased and plasma renin activity was suppressed. Acute tacrolimus in regular dose (0.05 mg/kg) and high dose (0.20 mg/kg) had no effect on MSNA and blood pressure. Sustained tacrolimus (0.05 mg/kg b.i.d. for 2 weeks) had no effect on blood pressure, body weight and plasma renin activity, but decreased MSNA from 14 +/- 6 to 8 +/- 5 bursts/min (P < 0.05).. Sympathetic overactivity plays a role in the acute hypertensive action of cyclosporine. Cyclosporine given during 2 weeks increases blood pressure and suppresses MSNA, possibly by volume retention. Tacrolimus, in the presently applied dosages, does not cause hypertension or sympathetic overactivity. However, sustained tacrolimus also suppresses sympathetic activity, the reason of which is unclear.

Topics: Blood Pressure; Body Weight; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Heart Rate; Humans; Hypertension; Immunosuppressive Agents; Male; Renin; Sympathetic Nervous System; Tacrolimus

Topics: Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Sympathetic Nervous System; Tacrolimus

Hypertension develops in many patients receiving the immunosuppressive drug tacrolimus (FK506). One possible mechanism for hypertension is a reduction in vasodilatory nitric oxide. We found that tacrolimus and a calcineurin autoinhibitory peptide significantly decreased vascular calcineurin activity; however, only tacrolimus altered intracellular calcium release in mouse aortic endothelial cells. In mouse aortas, incubation with tacrolimus increased protein kinase C activity and basal endothelial nitric oxide synthase phosphorylation at threonine 495 but reduced basal and agonist-induced endothelial nitric oxide synthase phosphorylation at serine 1177, a mechanism known to inhibit synthase activity. While this decreased nitric oxide production and endothelial function, the calcineurin autoinhibitory peptide had no such effects. Inhibition of ryanodine receptor opening or protein kinase C blocked the effects of tacrolimus. Since it is known that the FK506 binding protein (FKBP12/12.6) interacts with the ryanodine receptor to regulate calcium release, we propose this as the mechanism by which tacrolimus alters intracellular calcium and endothelial nitric oxide synthase rather than by its effect on calcineurin. Our study shows that prevention of the tacrolimus-induced intracellular calcium leak may attenuate endothelial dysfunction and the consequent hypertension.

Topics: Adaptor Proteins, Signal Transducing; Animals; Aorta; Calcineurin; Calcium; Endothelial Cells; Hypertension; Intracellular Signaling Peptides and Proteins; Mice; Nitric Oxide Synthase Type III; Phosphoproteins; Phosphorylation; Protein Kinase C; Ryanodine Receptor Calcium Release Channel; Tacrolimus; Tacrolimus Binding Proteins

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Tacrolimus and Cyclosporine A (CyA) are cornerstones in immunosuppressive therapy. Cyclosporine side eff ects include hypertension and hypercholesterolemia both of which may increase the risk of cardiovascular mortality, gingival hyperplasia and hirsutism are known to reduce quality of life. The aim of this prospective study was to evaluate changes in cardiovascular risk profile and cosmetic side eff ects after conversion from CyA to tacrolimus.. 25 stable kidney transplant recipients (9 male, 16 female) were converted from a CyA to a tacrolimus--based regimen. Mean age was 45.7 +/- 13.5 years. Time to switch following transplantation was 4.7+/-1.7 years. Reasons for conversion were multiple: arterial hypertension (9), hypertrichosis (3), gingival hyperplasia (3), hyperlipidemia (14).. 19/25 patients completed the one year study period. One patient died, two returned to hemodialysis, two were switched back to CyA and one patient was lost to follow-up. There were statistically significant changes (p = < 0.05) in systolic and diastolic pressure and antihypertensive medication could be reduced in 13 patients. The dose of lipid-lowering agents could be reduced in the majority of the recipients and a complete withdrawal was achieved in 7 patients. Hypertrichosis and gingival hyperplasia resolved in all patients. Further, there was a significant improvement (p = <0.05) in urea and serum creatinine levels. Adverse events were consistent with the established safety profile for tacrolimus.. Conversion to a tacrolimus-based regimen led to an improvement in the cardiovascular risk profile. Further, cosmetic side eff ects which may lead to non-compliance, resolved after the switch.

Topics: Adult; Cardiovascular Diseases; Cyclosporine; Female; Gingival Hyperplasia; Humans; Hyperlipidemias; Hypertension; Hypertrichosis; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Risk Factors; Tacrolimus

To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.. A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.. Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.. Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Topics: Acute Kidney Injury; Anticholesteremic Agents; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Rhabdomyolysis; Simvastatin; Tacrolimus

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; France; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Linear Models; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Retrospective Studies; Risk Assessment; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

BACKGROUND.: Sirolimus (SRL) is an important component of clinical immunosuppression in renal transplantation, but few international studies have examined how this agent is used in routine practice. METHODS.: Within a large prospective pharmacoepidemiological study, 718 de novo renal graft recipients treated with SRL in 65 centers in 10 countries were monitored for up to 5 years posttransplant to compare the principal outcomes and adverse effects by treatment regimen. RESULTS.: Principal treatment regimens were SRL without a calcineurin inhibitor (33%), SRL+cyclosporine A (CsA) (33%), and SRL+tacrolimus (TAC) (34%); 18% of subjects discontinued SRL, 124/718 (17%) developed biopsy-confirmed acute rejection (BCAR), 64/718 (9%) lost their graft, and 50/718 (7%) died during follow-up. Calculated creatinine clearance was 66+/-26 mL/min at 2 years. The most common adverse events were hypertension, hyperlipidemia, anemia, urinary tract infections, and diabetes. BCAR was significantly lower in subjects receiving SRL+TAC (hazard ratio [HR] 0.46, P=0.009) but not significantly lower in those receiving SRL+CsA (HR 0.62, P=0.102) compared with SRL without a calcineurin inhibitor. Graft loss or death did not significantly differ between treatment groups but were associated, respectively, with deceased donor grafts (HR 3.33, P<0.001) and increased age (HR 1.04, P<0.001). No improvement was observed in patients receiving mycophenolate mofetil in any treatment combination (HR 0.80, P=0.438 for BCAR; HR 0.93, P=0.849 for graft loss; and HR 0.75, P=0.531 for death). CONCLUSIONS.: SRL is most commonly used in combination with mycophenolate mofetil, CsA, or TAC. BCAR was least common in subjects receiving SRL+TAC, but other outcomes seemed comparable between the treatment regimens in routine practice.

Topics: Algorithms; Anemia; Cohort Studies; Creatinine; Drug Therapy, Combination; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Observer Variation; Prospective Studies; Sirolimus; Tacrolimus; Urinary Tract Infections

FK506 Binding Protein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca2+ release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca2+ levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca2+ leak in endothelial cells and whether this affects endothelial function and blood pressure regulation.. Rapamycin or FK506 concentration-dependently caused a Ca2+ leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 micromol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6-/- mice after displacement of FKBP12 with 1 micromol/L rapamycin or FK506. In hypertensive FKBP12.6-/- mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca2+ leak with ryanodine normalized NO production and endothelium-dependent dilation.. Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca2+ leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.

Topics: Animals; Calcium Channels; Calcium Signaling; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Gene Deletion; Hypertension; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nitric Oxide; Ryanodine Receptor Calcium Release Channel; Sensitivity and Specificity; Sirolimus; Tacrolimus; Tacrolimus Binding Protein 1A; Vasoconstriction; Vasodilation

To evaluate the outcome of pediatric patients who underwent liver transplantation between Oct. 2002 and May 2005 in the Pediatric Hospital.. Eight cases aged from 4 to 67 months who underwent liver transplantation were analyzed retrospectively. Four of the patients were boys and 4 girls, whose body weight at the time of liver transplantation was 6-19 kg. The underlying diseases were biliary atresia, congenital cholestasis, drug-induced cholestatic cirrhosis and cryptogenic cirrhosis. These patients had been followed up for blood routine examinations, liver and renal function, serum electrolytes and blood concentration of tacrolimus for 16 to 43 months after liver transplantation. Results of serological studies for viral etiology, liver biopsy, growth and mental development were also recorded.. One-year survival rate was 75.0% with the longest survival time being 43 months after transplantation. One patient died from renal failure due to postoperative bleeding 24 hours after the surgery and another case died of variceal hemorrhage 8 months after transplantation. Posttransplantation complications included acute cellular rejection, viral infection and hypoalbuminemia. Viral infections included cytomegalovirus infection in 3 cases, Epstein-Barr virus infection in 1 and hepatitis B virus infection in 1. Surgical complications of portal vein thrombosis and stenosis of inferior vena cava and hepatic vein occurred in 2 cases respectively. Side effects of tacrolimus including hypertension, renal damage, liver damage and diarrhea were observed. Significant growth-retardation was not often seen. A self-reported high quality of life was common.. Close follow-up and management of patients after liver transplantation may significantly increase the survival rate and improve quality of life in children with end-stage liver diseases.

Topics: Biliary Atresia; Child; Child, Preschool; Constriction, Pathologic; Female; Graft Rejection; Hepatitis B; Herpesvirus 4, Human; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Pediatrics; Postoperative Complications; Survival Rate; Tacrolimus; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

Lipid abnormalities including increased total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) have been frequently reported in renal transplantation and could be involved in the high frequency of cardiovascular diseases in this population.. Two hundred ninety-five patients were transplanted between January 1995 and October 2000 in our center. Two hundred two patients were included in this study. Seventy-six patients received tacrolimus (Tac), and 126 patients cyclosporine (CsA). Lipid parameters were assessed the day of transplantation and 1 year posttransplantation.. Serum lipids were similar between the two groups at D0. At M12, TC and LDL-C were significantly higher in the CsA group (6.14 +/- 1.37 vs 5.28 +/- 1.32 mmol/L; P < .05 and 3.98 +/- 1.05 vs 3.26 +/- 1.03 mmol/L; P < .05 CsA vs Tac, respectively). TG were comparable in both groups (1.86 +/- 1.07 vs 1.62 +/- 0.92 mmol/L; P = .55; CsA vs Tac). Incidence of de novo hypercholesterolemia was significantly higher in the CsA group (28 vs 8%) whereas incidence of hyperTG was similar in both groups. Prevalence of LDL-C was significantly higher in the CsA group (65% vs 31%; P < .001), whereas there was no difference in high density lipoprotein (HDL)-C levels.. Mean serum lipid levels and incidence and prevalence of hyperTC, especially LDL-C, was significantly higher in patients receiving CsA when compared with Tac. TG and HDL-C levels were similar. Although the study was retrospective, our results confirm that CsA increases lipid levels, whereas Tac does not.. Lipid disorders are frequently observed in renal transplant recipients. CsA, but not Tac, significantly increases incidence and prevalence of high TC and LDL-C.

Topics: Adult; Body Mass Index; Cholesterol; Cyclosporine; Dyslipidemias; Hemoglobins; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Tacrolimus; Triglycerides

At present, there is some controversy about the impact of diabetes mellitus on heart transplant patients. The effect of the disease on mortality and on other complications, such as infection or rejection, is unclear. The objective of this study was to investigate these factors in our heart transplant patients.. We studied 365 consecutive patients who underwent heart transplantation between November 1987 and May 2003. We divided them in three groups according to whether they had pretransplantation diabetes (group 1), de novo diabetes (group 2), or no diabetes (group 3). Baseline variables and the development of complications were recorded, and findings were analyzed using Student's t test, chi squared test, and Kaplan-Meier survival analysis.. There was no difference in the 1-year or 5-year survival rate between the groups (P=.24 and P=.32, respectively). Patients with pretransplantation and de novo diabetes were older (54.6 years vs 54.9 years vs 50.6 years, P=.04), had a higher prevalence of hypertension (48% vs 36% vs 23%, P=.001), and had more frequently been treated with tacrolimus (10% vs 12% vs 4%, P=.04) or steroids (92% vs 86% vs 70%, P=.001). The incidence of rejection during follow-up was greater in these two groups (64% vs 70% vs 45%, P=.001).. Neither pretransplantation diabetes nor de novo diabetes had a negative impact on survival in our heart transplant patients. The disease's presence was associated with treatment with steroids and tacrolimus. In these patients it would be preferable to individualize immunosuppressive therapy.

Topics: Adrenal Cortex Hormones; Age Factors; Chi-Square Distribution; Data Interpretation, Statistical; Diabetes Complications; Diabetes Mellitus; Female; Follow-Up Studies; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Postoperative Complications; Prevalence; Risk Factors; Survival Analysis; Tacrolimus; Time Factors

The aims of this study were to investigate the role of endothelin-1 in FK506-induced hypertension and vascular dysfunction of rats treated with the drug for 8 (short-term) or 30 (long-term) days and to measure malondialdehyde levels in the kidneys. Kidney and mesentery of rats were perfused. In the short-term treated groups, there was no significant change in systolic blood pressure. The response to noradrenaline only in renal vascular beds was significantly increased by FK506 and this increase was prevented by Bosentan. FK506 had no significant effect on sodium nitroprusside-induced vasodilation in comparison with solvent in both vascular beds. Bosentan failed to prevent these responses. In the long-term treated groups, at the end of the treatment with FK506, there was a significant increase in blood pressure, but no change in the response to noradrenaline in either kidneys or mesentery. The increase in blood pressure was prevented by bosentan treatment. FK506 increased malondialdehyde levels in the kidneys of the rats from only the long-term treated groups. Bosentan did not change this increase. Our results indicated that endothelin-1 plays a key role in the FK506-induced change in vascular reactivity to noradrenaline in renal vascular beds and drug-induced hypertension in the rats. There was no relationship between oxidative stress and FK506-induced hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension; Immunosuppressive Agents; Kidney; Male; Malondialdehyde; Mesentery; Nitroprusside; Norepinephrine; Oxidative Stress; Rats; Rats, Wistar; Receptor, Endothelin A; Sulfonamides; Tacrolimus; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.

Topics: Adult; Aged; Biopsy; Diabetes Mellitus; Female; Glomerulonephritis, IGA; Graft Survival; Hepatitis; Humans; Hydroxyethyl Starch Derivatives; Hypertension; Immunosuppressive Agents; Interferon-alpha; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Insufficiency; Risk; Tacrolimus; Time Factors

Dietary salt is an important contributor to hypertension in the general population. While its role in cyclosporine-induced hypertension is minimal, its role in tacrolimus-based immunosuppression has not been defined. We measured the 24-hour urine sodium excretion as an estimate of intake in a group of stable renal transplant recipients on tacrolimus (N = 143) who had serum creatinine fluctuations <20% during the preceding 3 months. Average clinic-measured blood pressure (BP) from before and after the 24-hour urine collection was computed. Patients with recent changes in antihypertensive medications were excluded. Average systolic BP was 126 +/- 14 and diastolic BP 76 +/- 7 mm Hg. Urine sodium was 162.6 +/- 70 mmol/d (range 50 to 351), and the sodium/creatinine ratio was 15.4 +/- 6.4. There was no correlation between urine sodium excretion and either systolic or diastolic BP (R = 0.07 and R = 0.05, P = NS) or the sodium/creatinine and systolic/diastolic BP (R = 0.13, R = 0.11, P = NS). By multiple linear regression only weight and urine protein were independently associated with both systolic BP (P < .0001 for each) and diastolic BP (P < .05 for each). In conclusion, there is no appreciable influence of dietary salt intake on BP under tacrolimus-based immunosuppression. Restricting dietary salt intake in these patients cannot be recommended at the current time.

Topics: Analysis of Variance; Blood Pressure; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Proteinuria; Sodium; Sodium Chloride, Dietary; Tacrolimus

This study was designed to test the hypothesis that heterotopic heart transplant (HHT) patients have lower blood pressure than orthotopic cardiac transplant (OCT) patients because their native heart is involved in blood pressure homeostasis.. Hypertension occurs more frequently after OCT than after liver or lung transplantation, suggesting that transplantation of the heart itself contributes to post-transplant hypertension.. Blood pressure and related measurements in 233 OCT and 38 HHT patients were studied retrospectively post-transplant.. Systolic blood pressure (SBP) was persistently lower among HHT patients (means 121 vs. 137, 126 vs. 137, 125 vs. 139, and 128 vs. 143 mm Hg at month 3 and years 1, 3, and 5 respectively, p < 0.005). Left ventricular and aortic systolic pressures were also lower (130 vs. 143 mm Hg, p = 0.01 and 129 vs. 142 mm Hg, p = 0.01). Multivariable analysis with age, gender, body mass index, creatinine, steroids, cyclosporine, use of antihypertensive medication, donor left ventricular ejection fraction, donor weight, and type of transplant as covariables showed HHT to be independently associated with a lower SBP at each time point (beta-coefficients -16.2, -12.1, -13.3, and -14.2 mm Hg, p < 0.01). The adjusted hazard ratio for the development of systolic hypertension among HHT compared with OCT patients was 0.59 (95% confidence interval 0.39 to 0.91, p = 0.017).. Heterotopic heart transplant patients had lower SBP than OCT patients, consistent with the hypothesis that the native heart continues to contribute to blood pressure homeostasis.

Topics: Adolescent; Adult; Aged; Aorta; Blood Pressure; Female; Heart Transplantation; Heart Ventricles; Humans; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Retrospective Studies; Risk Reduction Behavior; Systole; Tacrolimus; Time Factors; Transplantation, Heterotopic; Treatment Outcome

Topics: Adult; Brain Edema; Cerebral Hemorrhage; Fatal Outcome; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertension; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Myelin Sheath; Postoperative Complications; Seizures; Tacrolimus

Calcium channel blockers are widely used in the treatment of post-transplant hypertension but have the potential for drug interaction with calcineurin inhibitors. Renal allograft outcomes when diltiazem is used with cyclosporine have been reported, but similar data with tacrolimus are not available.. We performed a retrospective analysis of all our renal transplant recipients from March 1997 to March 2002 who were given tacrolimus, mycophenolate mofetil and prednisone. Patients were divided into two groups based on whether diltiazem was started in the first postoperative week. Outcome measures included renal function up to 2 years post-transplant, blood pressure (BP) control, tacrolimus exposure, and costs related to tacrolimus monitoring.. Sixty-four patients constituted the diltiazem group and 32 the control group. Their baseline characteristics were similar. The mean average daily dose of diltiazem used was 213.95 mg/day. There was no difference in renal function, graft survival, or patient survival over 2 years. BP control was similar although the diltiazem group required more medication. Diltiazem was discontinued in four patients due to side-effects. There was no difference in tacrolimus-related side-effects between the two groups. There was also no difference in tacrolimus exposure, cost related to tacrolimus monitoring, or combined costs when the expense of diltiazem was added.. Diltiazem use is acceptably safe and efficacious in renal transplant recipients treated with tacrolimus-based immunosuppressive therapy. It can be considered as a first-line antihypertensive in these patients and is cost neutral for tacrolimus use.

Topics: Adult; Blood Pressure; Calcium Channel Blockers; Diltiazem; Female; Health Care Costs; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus

Calcineurin inhibitors (CIs) contribute to cardiovascular risk (CR) in renal transplant (RT) patients. However, the CR profile in RT patients without preexistent diabetes is not well known. We compared CR factors in 191 nondiabetic RT recipients with functioning grafts beyond 1 year, receivingly either CsA (Neoral; n=100) or tacrolimus (Tac; n= 91). Clinical data and pretransplant CR profiles were similar in both groups. There were no differences in acute rejection episodes and graft survival rates during follow-up. The overall proportions of posttransplant diabetes (9% versus 6%), and of hypertension (73% vs 63%) were similar in both groups. Hyperlipidemia was more frequent in the CsA group (58% vs 31%; P=.0001). The cholesterol levels in the CsA group showed at 3 months (232+/-47 vs 202+/-42 m/dL; P=.0001), 6 months (232+/-49 vs 205+/-41 mg/dL; P=.0001), and 12 months (217+/-50 vs 202+/-40 mg/dL; P=.028), despite receiving a greater proportion of lipid-lowering drugs (49% vs 15%; P=.0001). Logistic regression analysis showed that CsA was an independent predictor of posttransplant hyperlipidemia (OR: 5.8, CI 95%; 3.3-10.7; P=.0001) as were age, female gender, pretransplant dyslipidemia, and body mass index (BMI). Interestingly, an interaction was observed between pretransplant BMI and CIs: Among pretransplant normal weight patients (BMI <25 kg/m2), CsA produced a greater incidence of hyperlipidemia than tacrolimus (58% vs 23%; P=.0001) while not among patients who were overweight (BMI >25 kg/m2: pretransplant 58% vs 42%; P=.341). In conclusion, CsA confers a higher risk of hyperlipidemia after RT in nondiabetic patients, particularly those with normal pretransplant weight.

Topics: Adult; Body Mass Index; Cardiovascular Diseases; Cholesterol; Cyclosporine; Diabetes Mellitus; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Renal Replacement Therapy; Risk Factors; Tacrolimus

Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience.. All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart.. Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression.. The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Topics: Abnormalities, Multiple; Adolescent; Adult; Anti-Inflammatory Agents; Birth Weight; Diabetes Mellitus, Type 1; Female; Fludrocortisone; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant, Newborn; Kidney; Liver; Liver Diseases; Liver Transplantation; Pre-Eclampsia; Prednisone; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy Outcome; Prospective Studies; Survival Rate; Tacrolimus; Transplantation, Homologous

This multicenter study was retrospectively evaluated for the predictive factors affecting the long-term graft survival of a kidney transplant from a non-heart-beating donor (NHBD).. A total of 706 patients received transplants from NHBD in 11 centers between 1986 and 2000 and the results were entered into the analysis. The patients were treated with cyclosporine- or tacrolimus-based immunosuppressive therapy. Graft survival was calculated by the Kaplan-Meier method. Factors selected for univariate analysis were donor age, and acute early and acute late rejection. Hypertension (HT), hyperlipidemia (HL), and diabetes mellitus were also analyzed in 638 recipients whose graft survived for more than 1 yr.. In the cases using NHBD, graft survival for 1, 5, and 10 yr was 87, 69, and 53%, respectively. Donor age of over 55 yr, acute early and late rejection, post-transplant HT and diabetes at the first post-operative year were shown to be significantly harmful on long-term graft survival. For longer graft survival in NHBD kidney transplantations, reducing acute rejection, and controlling blood pressure and sugar are crucial.

Topics: Age Factors; Cadaver; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Tissue Donors

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcineurin; Cardiomegaly; Echocardiography; Fibrosis; Gene Expression Regulation; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Stress, Mechanical; Tacrolimus; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Adolescent; Adult; Aged; Body Weight; Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Transplantation, Homologous

Topics: Adult; Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Follow-Up Studies; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Liver Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Cardiovascular Diseases; Creatinine; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Retrospective Studies; Risk Factors; Sex Characteristics; Tacrolimus

Cyclosporin A is a lipogenic immunosuppressor that can induce posttransplant hyperlipidaemia. Oxidation of low-density lipoprotein (LDL) has been recognized as a major atherogenic factor. Tacrolimus seems to be less lipogenic with an apparently better cardiovascular profile than CsA.. We have studied the lipidic profile and the oxidation of HDL and LDL in 20 renal transplant patients, 12 male and 8 female, mean age 45 +/- 10 year, who where switched from CsA to tacrolimus due to CsA adverse effects. LDL were determined by ultracentrifugation. Oxidation study before and 6 months after conversion to tacrolimus was performed by adding CuSO4.. After conversion, systolic blood pressure (BP) decreased from 154 +/- 21 to 133 +/- 21 mm Hg (p = 0.008), diastolic BP from 97 +/- 13 to 77 +/- 15 mm Hg (p = 0.016), total cholesterol from 6.08 +/- 0.9 to 5.68 +/- 1.1 mmol/l (p = 0.02), LDL-chol from 3.29 +/- 1.01 to 2.96 +/- 0.3 mmol/l (p = 0.04) and apo-B lipoprotein from 1.42 +/- 0.28 to 1.15 +/- 0.34 mg/dl (p = 0.003). The oxidation of LDL improved after conversion: the initial dienic compounds decreased from 95 +/- 20 to 63 +/- 12 umol/g and the final DC from 207 +/- 56 to 107 +/- 35 umol/g. Lag-phase increased from 33 +/- 21 to 45 +/- 17 min (p < 0.05).. Tacrolimus has improved hyperlipidaemia in our cyclosporin previously treated patients and increased the resistance to oxidation of high and low-density lipoproteins.

Topics: Adult; Antihypertensive Agents; Apolipoproteins B; Arteriosclerosis; Azathioprine; Cholesterol; Cyclosporine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Prednisone; Retrospective Studies; Tacrolimus; Triglycerides

Topics: Adrenal Cortex Hormones; Autopsy; Cardiomegaly; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

Prevalence of arterial hypertension suddenly rose in patients after renal transplantation since cyclosporine A was introduced. Arterial hypertension is now diagnosed in 67-90% of patients after renal transplantation. It has not only negative effect on cardiovascular system but also shortens survival of renal graft. Ambulatory blood pressure monitoring (ABPM) enables evaluation of diumal profile of BP and efficacy of treatment. This diagnostic tool is very useful in the management of these patients. Nocturnal hypertension was 2.5 times more frequent than daytime elevation of BP in the group of 58 consecutive renal transplant patients treated with calcineurin inhibitors who were assessed by ABPM at our department. Lack of nocturnal dip of BP was observed in most of the patients. Conversion from calcineurin inhibitors (cyclosporine A, tacrolimus) to sirolimus or mycophenolate mofetil may improve BP profile in this group of patients.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Poland; Sirolimus; Tacrolimus

With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed.. The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation.. Eighty-seven sequential patients (CSA: n = 50, mean age 48 years, M/F 32/18; and FK-506: n = 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were >/=18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx.. At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P < 0.05), HTN (62% versus 38%, P < 0.05), HLIP (14% versus 5%, P = 0.08), and cardiovascular disease (18% versus 0%, P < 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group.. Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease.

Topics: Cardiovascular Diseases; Cyclosporine; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart.. Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks (n=7), rats treated with calcineurin inhibitor from 8 weeks (n=6), and untreated rats (n=7).. Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed.. Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Calcineurin Inhibitors; Collagen Type I; Collagen Type III; Diastole; Fibrosis; Heart Ventricles; Hydroxyproline; Hypertension; Male; Myocardium; Rats; Rats, Inbred Dahl; RNA, Messenger; Tacrolimus; Tetrazoles; Ventricular Dysfunction, Left

Premature cardiovascular disease is the leading cause of death in renal transplant recipients and classical risk factors significantly underestimate the risk. The increased effect of arterial wave reflections on central arteries has recently been shown to be an important independent predictor of cardiovascular mortality in chronic hemodialysis patients. The aim of this study was to assess the contribution of several classical and potential non-classical cardiovascular risk factors on aortic pressure augmentation by the reflected arterial wave in stable renal transplant recipients.. Using the non-invasive technique of pulse wave analysis aortic augmentation was investigated in 250 stable renal transplant recipients. Peripheral pulse waveforms were recorded from the radial artery. Central aortic waveforms were then generated and the aortic augmentation index calculated.. In multivariate analysis, female sex (regression coefficient 7.5 +/- 1.7%; P < 0.001), heart rate (-4.8 +/- 0.5% per 10 beats/min; P < 0.001), mean arterial pressure (4.2 +/- 0.6% per 10 mm Hg; P < 0.001), the persistence of an arteriovenous fistula (4.1 +/- 1.3%; P < 0.005), total time on renal replacement therapy (3.8 +/- 0.9% per 10 years; P < 0.001), height (-3.1 +/- 0.8% per 10 cm; P < 0.001), immunosuppression with cyclosporine (2.8 +/- 1.3%; P < 0.005) and age (2.5 +/- 0.5% per 10 years; P < 0.001) were all important correlates of aortic augmentation index.. Our findings suggest, to our knowledge for the first time, that both the presence of a functioning arteriovenous fistula and immunosuppressive treatment with cyclosporine are associated with an increased aortic augmentation index in renal transplant recipients and could, therefore, be potential reversible contributors to the high cardiovascular risk profile in these patients.

Topics: Adult; Aged; Aorta; Arteriovenous Shunt, Surgical; Blood Pressure; Cyclosporine; Female; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Tacrolimus

It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.. In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg every second day) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg every second day but not with 0.01 mg/kg every second day of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Hypertension; Male; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Tacrolimus

In a living renal transplantation, the recipients are administered an immunosuppressive agent preoperatively. The drug exhibits a high incidence of side effects of special note. We examined the side effects of tacrolimus to evaluate the postoperative management of living renal transplantation. Hypertension, hyperglycemia, tachycardia and chest pain were found as the side effects. The blood concentration should be measured frequently to maintain the effective blood concentration and to prevent the side effect.

Topics: Adult; Aged; Female; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Monitoring, Physiologic; Perioperative Care; Tacrolimus

Tacrolimus is a potent immunosuppressive agent that provides higher freedom from acute and chronic rejection than cyclosporine after liver transplantation (LTx). Initially, a steroid-free state was observed in about 70% of patients at 1 year; this did not change over the next 5 years. The present study identifies the various reasons why the remaining 30% of adult patients still require steroids even after 5 years after successful LTx.. Eight hundred thirty-four consecutive patients who underwent LTx between August 1989 and December 1992 were included in this study. Four hundred ninety-nine patients were alive in January 1999 and were available for this study. The dose of steroid and the reason for steroid use were retrospectively determined from the clinical records.. Three hundred sixty-five patients (73.1%) were off steroid, whereas 134 patients (26.9%) were receiving prednisone (mean dose was 6.4+/-3.7 mg/day) at the time of the study. Four hundred and eight-four patients (97%) were off prednisone at some time after LTx; however, in 119 (23.8%) patients, steroids were reintroduced. Fifteen patients (3%) continued to receive prednisone; eight receive prednisone due to reluctance of the local physician to withdraw the medication; in five patients, the prednisone was not withdrawn because these patients were on cyclosporine; in the remaining two patients, repeated attempts to withdraw steroid resulted in a rise in liver function test. In the 49 (36.6%) of 119 patients in whom the steroid was reintroduced, it was restarted secondary to pathologically proven or clinically suspected rejection (group I). In five patients steroid was reintroduced for abnormal liver function after being off immunosuppression for treatment of a posttransplantation lymphoproliferative disorder. Six patients were noncompliant with their immunosuppressive medication, and the steroid was reintroduced to control rejection. Steroids were reintroduced in 30 patients (22.4%) for recurrence of original disease: primary biliary cirrhosis (n= 19), sclerosing cholangitis (n=6), and autoimmune hepatitis (n=5) (group II). In 24 patients (20.2%), steroids were reintroduced to lower the dose of tacrolimus secondary to nephrotoxicity. Six of these patients received kidney transplantation (group III). In 16 patients (13.4%) the steroid was reintroduced for concomitant medical problems, consisting of ulcerative/Crohn's colitis (n=6), adrenal insufficiency (n=5), hematological disorders (n=3), dermatitis (n=1), and rheumatoid arthritis (n=1) (group IV).. Ninety-seven percent of patients under tacrolimus were weaned off steroid; however, 23.8% required steroid reintroduction for late rejection, recurrence of autoimmune process(es), renal impairment, or the concomitant presence of other medical conditions. Although the use of other immunosuppressive agents may reduce the rate of reintroduction of steroid, long-term sustained freedom from steroid may not be possible in all patients under tacrolimus secondary to these conditions.

Topics: Adult; Azathioprine; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prednisolone; Retrospective Studies; Steroids; Tacrolimus; Time Factors

Hypertension is an important risk factor for chronic transplant nephropathy. Therapy is usually based on casual office blood pressure (BP) measurements. However, it is not well known how casual BP predicts 24-hour BP in this population. The main focus of this study is to compare casual office BP with 24-hour ambulatory BP monitoring in renal transplant recipients with signs of chronic transplant nephropathy. Moreover, in this group, the day-night BP profile was assessed. In 36 renal transplant recipients with incipient or progressive proteinuria or an increase in serum creatinine level greater than 20%, 24-hour ambulatory BP was performed. Patients were defined as a nondipper if the mean BP decreased by less than 10% during the nighttime period. The correlation between single office and 24-hour ambulatory BPs was 0.61 for systolic BP and 0.55 for diastolic BP (P < 0.001). The mean difference between 24-hour ambulatory and single office BPs was -4.2 +/- 18.6 mm Hg (range, -44 to 36 mm Hg) for systolic BP and -1.1 +/- 10.7 mm Hg (range, -34 to 27 mm Hg) for diastolic BP; 94.5% of patients were classified as nondippers. There was a significant relation between the nightly decline in mean arterial pressure and calculated creatinine clearance (r = 0.34; P < 0.05). In conclusion, in renal transplant recipients with chronic transplant nephropathy, a large difference between office and ambulatory BPs is present, with both overestimation and underestimation of 24-hour BP by office BP measurements. Moreover, a severely disturbed day-night BP rhythm was observed. In transplant recipients with compromised graft function, office BP may not reflect 24-hour BP adequately, and ambulatory BP measurements should be considered.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Chronic Disease; Circadian Rhythm; Cyclosporine; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Tacrolimus

As the survival of renal transplant patients has increased, so has their risk of significant morbidity. Immunosuppressive drugs can exacerbate preexisting conditions and promote development of new disease. Effective long-term care of transplant recipients requires an understanding of how these drugs affect clinical evaluations and treatments.

Topics: Anti-Inflammatory Agents; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Prednisone; Risk Factors; Tacrolimus

Hypertension and hyperlipidemia are more prevalent after liver transplantation with cyclosporine as the primary immunosuppressive agent compared with tacrolimus. To determine whether blood pressure, serum lipid level, or weight improves when patients switch immunosuppression therapy, we retrospectively studied 26 liver transplant recipients with stable graft function who had been converted from cyclosporine to tacrolimus therapy with a median follow-up of 8 months. One of the 26 patients developed pruritus necessitating withdrawal of tacrolimus. The results therefore concern the remaining 25 patients. With the exception of a small decrease in bilirubin level (P <.05), there was no difference in graft or renal function after conversion. Mean systolic blood pressure decreased from 158 +/- 25 to 148 +/- 22 mm Hg over a mean of 8 +/- 3 months after conversion to tacrolimus (P =.015), whereas mean serum cholesterol level decreased from 5.3 +/- 0.9 to 4.9 +/- 0.9 mmol/L (P =.01). Sixty-eight percent of the patients lost weight, from a mean of 79.4 +/- 22.6 to 76.1 +/- 20.1 kg, in the 11 months after switching to tacrolimus therapy (P =.024). Serum triglyceride and blood glucose levels did not change, and no patient developed diabetes mellitus after conversion. These results indicate that switching from cyclosporine to tacrolimus can reduce blood pressure, serum cholesterol level, and weight after liver transplantation.

Topics: Blood Pressure; Body Weight; Cyclosporine; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Lipids; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal.. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls.. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months.. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biopsy; Child; Cohort Studies; Daclizumab; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infections; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Steroids; Survival Analysis; Tacrolimus

To improve long-term outcome after renal transplantation, attention should be placed on the tailored use of immunosuppressive regimens that have a more favorable impact on the immunological and nonimmunological risk profiles of an individual recipient. Tacrolimus is widely used for maintenance and rejection immunosuppression in solid organ transplantation, and compared with cyclosporine, its use in renal transplantation is associated with a reduced incidence and severity of acute rejection and a more positive effect on known cardiovascular risk factors. Recent experience with tacrolimus-based therapy has demonstrated an improved lipid profile and lower arterial blood pressure, with less requirement for lipid-lowering and antihypertensive medication compared with cyclosporine, without significantly increasing the risk of long-term insulin-dependent posttransplant diabetes mellitus. The advantageous effects of tacrolimus on both immunological and nonimmunological risk factors offer potential benefits for long-term graft function and survival.

Topics: Cardiovascular Diseases; Child; Cyclosporine; Diabetes Mellitus; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Ohio; Postoperative Complications; Risk Factors; Tacrolimus

Topics: Anti-Bacterial Agents; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Incidence; Organ Transplantation; Tacrolimus

Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models.. To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency.. Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment.. The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Topics: Animals; Blood Pressure; Cachexia; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hypertension; Infections; Metabolism, Inborn Errors; Mice; Mice, Inbred C3H; Myocardium; Reference Values; Renal Insufficiency; Tacrolimus

Inhibition of calcineurin-mediated signaling in T lymphocytes is a major mechanism of cyclosporine A (CsA)-induced immunosuppression, and previous rat studies have suggested that inhibition of calcineurin-mediated signaling in central neuronal pools involved in blood pressure regulation plays an important role in causing acute CsA-induced hypertension. However, a central neural mechanism is difficult to reconcile with other data suggesting that CsA-induced hypertension is due to activation of renal and other subdiaphragmtic visceral afferents that reflexively increase efferent sympathetic nerve activity. Accordingly, we now have revised our hypothesis to suggest that CsA stimulates renal afferents by a calcineurin-dependent process. To test this new hypothesis, in anesthetized rats we recorded arterial pressure and multifiber afferent renal nerve activity from the cut distal end of the renal nerve before, during, and after intravenous infusion of either CsA (5 mg/kg over 20 min, n = 8), FK506 (0.15 mg/kg, n = 7), another potent calcineurin inhibitor that is structurally unrelated to CsA, or rapamycin (0.15 mg/kg, n = 4), a structural analog of FK506 that has no effect on calcineurin. We found that renal afferent discharge was increased markedly by intravenous FK506, as well as CsA, but unaffected by rapamycin (or vehicle), indicating calcineurin mediation. After infusion of either calcineurin inhibitor, afferent renal nerve activity remained elevated for up to 2 h, paralleling the prolonged increase in blood pressure. Thus, the major new conclusion of this study is that, in contrast to what has been assumed previously, calcineurin inhibitors enhance sympathetic neurotransmission by a novel action localized to visceral sensory nerve endings rather than to nerve cell bodies or central synapses. In the rat, calcineurin-dependent activation of renal afferents appears to be the primary mechanism producing the large blood-pressure-raising effect of CsA. Because the data suggest that the major side-effect of CsA and FK506--hypertension--is inexorably linked to calcineurin inhibition in extralymphoid tissue, development of agents that selectively inhibit calcineurin only in T lymphocytes could eliminate this important secondary form of hypertension.

Topics: Animals; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Hypertension; Kidney; Male; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus; Time Factors

It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.. In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Topics: Animals; Blood Pressure; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Endomyocardial Fibrosis; Gene Expression Regulation; Heart; Hypertension; Injections, Intramuscular; Male; Myocardium; Rats; Rats, Inbred Dahl; Remission Induction; Sodium Chloride, Dietary; Tacrolimus

There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.. Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg x kg(-1) x d(-1)) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.. Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcineurin Inhibitors; Disease Models, Animal; Drug Administration Schedule; Echocardiography; Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Myocardium; Organ Size; Rats; Rats, Inbred Dahl; RNA, Messenger; Sodium Chloride; Tacrolimus

Histopathological findings in renal allograft with stable function remain unclear. We therefore performed non-episode biopsy in the long-surviving renal allograft to investigate the histopathological changes. Our data show that, although arteriolopathy is characteristic of drug-induced nephropathy, it is unrelated to dosage and concentration of cyclosporine or tacrolimus in non-episode biopsy. We evaluated therefore the clinicopathological findings of arteriolopathy in this study. Non-episode biopsy was defined as follows: as serum creatinine level lower than, 2.0 mg/dl and a urinary protein level lower than 500 mg/day. A total of 65 biopsy specimens were enrolled in this study as non-episode biopsy. Twenty-nine specimens revealed arteriolopathy. There were no statistically significant differences between arteriolopathy and dosage or concentration of cyclosporine or tacrolimus. Arteriolopathy in non-episode biopsy was related to time of biopsy, kidney age, hypertension, and hyperlipidemia, suggesting that it is important for graft survival to strictly control blood pressure and blood lipid level.

Topics: Adult; Arterioles; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Kidney Transplantation; Living Donors; Male; Survivors; Tacrolimus; Transplantation, Homologous; Triglycerides

Topics: ABO Blood-Group System; Adult; Age Factors; Azathioprine; Blood Group Incompatibility; Creatinine; Diabetes Mellitus; Drug Therapy, Combination; Female; Histocompatibility Testing; HLA-DR Antigens; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Risk Factors; Tacrolimus; Tissue Donors; Transplantation, Homologous

Topics: Acute Disease; Adolescent; Adult; Child; Child, Preschool; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Middle Aged; Retrospective Studies; Tacrolimus

-Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clinical utility of FK 506 is complicated by substantial hypertension and nephrotoxicity. To clarify the mechanisms of FK 506-induced hypertension, we studied the chronic effects of FK 506 on the synthesis of endothelin-1 (ET-1), the expression of mRNA of ET-1 and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression of mRNA of eNOS and C-type natriuretic peptide (CNP) in rat blood vessels. In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506-induced hypertension in rats was studied. FK 506, 5 mg. kg-1. d-1 given for 4 weeks, elevated blood pressure from 102+/-13 to 152+/-15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mRNA in the mesenteric artery (240% and 230%, respectively). Little change was observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased eNOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respectively). The administration of FR 139317 (10 mg. kg-1. d-1) prevented FK 506-induced hypertension in rats. These results indicate that FK 506 may increase blood pressure not only by increasing ET-1 production but also by decreasing NO synthesis in the vasculature.

Topics: Animals; Aorta, Abdominal; Aspartic Acid Endopeptidases; Azepines; Base Sequence; Blood Pressure; Blotting, Southern; Data Interpretation, Statistical; DNA, Complementary; Endothelin-1; Endothelin-Converting Enzymes; Hypertension; Immunosuppressive Agents; Indoles; Kidney; Male; Mesenteric Artery, Superior; Metalloendopeptidases; Molecular Sequence Data; Natriuretic Peptide, C-Type; Nitric Oxide Synthase; Polymerase Chain Reaction; Rats; Rats, Inbred WKY; RNA, Messenger; Tacrolimus

Our report describes the outcome of a twin pregnancy in a woman who was maintained on tacrolimus after a living related renal transplant. Both babies born at 32 weeks of gestation developed severe respiratory distress requiring ventilator assistance and went on to develop congestive heart failure. Echocardiograms on both babies showed dilated heart chambers. Twin A succumbed to complications, but twin B, who was treated more aggressively with vasopressors, recovered. Autopsy findings on twin A revealed a thrombotic cardiomyopathy with degeneration of cardiac muscle. We believe that the unusual outcome in this set of twins may have been a result of cardiomyopathy secondary to tacrolimus used by the mother during her pregnancy.

Topics: Azathioprine; Cesarean Section; Cyclosporine; Fatal Outcome; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Kidney Transplantation; Labetalol; Living Donors; Male; Nuclear Family; Prednisone; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Tacrolimus; Twins

The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described.. Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described.. Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant.. We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Topics: Adolescent; Adult; Cytomegalovirus Infections; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Transplantation, Homologous

Renal toxicity is a serious side effect of therapy with tacrolimus (FK506), an immunosuppressive agent administered to renal transplant recipients. We investigated the effect of hepatocyte growth factor (HGF) on tacrolimus-induced nephrotoxicity in spontaneously hypertensive rats (SHR). After a right nephrectomy, rats received a continuous perfusion of either HGF in a dose of 5 microg/kg daily (tacrolimus + HGF group) or normal saline (tacrolimus group) into the left renal artery at a rate of 1 microl/h for 7 days after surgery. Tacrolimus was injected intramuscularly in a dose of 4 mg/kg daily for 10 days after surgery. HGF significantly inhibited the tacrolimus-induced increase in the serum creatinine (SCr) level (P < 0.05). HGF also prevented the tacrolimus-induced loss in body weight. The bromodeoxyuridine (BrdU) index was significantly higher in kidney specimens from the tacrolimus + HGF group. These findings suggest that HGF induces the regeneration of renal tubular cells and suppresses tacrolimus-induced renal toxicity in SHR.

Topics: Animals; Body Weight; Creatinine; Hepatocyte Growth Factor; Humans; Hypertension; Immunosuppressive Agents; Injections, Intramuscular; Kidney; Kidney Tubules; Lymphocyte Culture Test, Mixed; Lymphocytes; Mitotic Index; Nephrectomy; Rats; Rats, Inbred SHR; Recombinant Proteins; Tacrolimus; Weight Loss

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.

Topics: Animals; Aorta, Thoracic; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Disease Models, Animal; Hypertension; Hypertrophy, Left Ventricular; Ligation; Male; Postoperative Complications; Random Allocation; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Tacrolimus

Topics: Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Cirrhosis; Liver Transplantation; Tacrolimus; Trimetazidine; Vasodilator Agents

Topics: Adult; Aged; Azathioprine; Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lipids; Middle Aged; Prednisolone; Tacrolimus; Triglycerides

Topics: Adult; Age Factors; Aged; Child; Creatinine; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant; Liver Transplantation; Postoperative Complications; Prednisone; Survival Rate; Tacrolimus; Time Factors

Topics: Cholesterol; Cyclosporine; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Function Tests; Liver Transplantation; Nervous System Diseases; Retrospective Studies; Tacrolimus; Triglycerides

Tacrolimus is metabolized by cytochrome P450 3A4 and 2D6 and has a narrow therapeutic range. We report a serious kinetic interaction between tacrolimus and mibefradil, a potent cytochrome P450 inhibitor.. A 62-year-old women who had undergone liver transplantation was treated with tacrolimus for immunosuppression. For control of blood pressure, the patient was treated with nifedipine. She developed ankle edema, and nifedipine was replaced by mibefradil. Four days later, she presented with mental confusion, renal failure, and hyperglycemia, compatible with tacrolimus toxicity. In agreement with this assumption, the tacrolimus blood concentration was 100 ng/ml. Mibefradil and tacrolimus were both stopped, and the patient recovered within 1 week. Eight days after stopping mibefradil, tacrolimus was restarted at the same dosage and the subsequent plasma concentrations remained in the therapeutic range.. Mibefradil increases the tacrolimus blood concentration by inhibiting its metabolism and should, therefore, not be used in patients treated with tacrolimus.

Topics: Benzimidazoles; Calcium Channel Blockers; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Mibefradil; Middle Aged; Tacrolimus; Tetrahydronaphthalenes

In a retrospective study the records of 302 adult patients (167 male, 135 female) after orthotopic liver transplantation (OLT) with a minimum follow-up of 6 months (median follow-up 18 months, maximum 5 yr) were reviewed with regard to cardiovascular risk factors. In 197 patients data concerning the occurrence of arterial hypertension, hyperglycemia, or hypercholesterolemia prior to OLT were available. We found a highly significant increase of cardiovascular risk factors following OLT. Obesity was found in 17.4% of male and 22.2% of female recipients after OLT. Hypercholesterolemia was evident in 66.2% of liver graft recipients. Hypertriglyceridemia occurred in 49.7% of all male patients. In females there was a significantly different prevalence of hypertriglyceridemia comparing patients with a follow-up period up to 2 yr and more than 2 yr (50% vs. 24.6%, p = 0.018). Nearly 45% of all patients met the criteria for arterial hypertension, with a slight increase in male patients beyond the second year of survival (p = 0.094). Hyperglycemia had a significantly higher frequency in male than in female patients (30.5% vs. 10.4%, p < 0.005). Furthermore we observed a clear trend towards reduction of occurrence of hyperglycemia more than 24 months after OLT, but not reaching statistical significance. No correlation was detected when serum levels of triglycerides, and cholesterol, body-mass-index, and arterial blood pressure were compared with applied dosages of immunosuppressive agents [cyclosporin A (CyA), tacrolimus, and prednisolone]. Only decreasing tacrolimus application was significantly correlated with decreasing glucosemia (p = 0.041). Patients receiving tacrolimus instead of CyA as primary immunosuppressant showed a significantly lower prevalence of hypercholesterolemia. Even hypertension, hyperglycemia, hypertriglyceridemia, and obesity had a lower occurrence in patients treated with tacrolimus although not reaching statistical significance.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cardiovascular Diseases; Cyclosporine; Female; Follow-Up Studies; Glucocorticoids; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus

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

Cyclosporine (CsA)-associated side effects include nephrotoxicity, hypertension, neurological disorders, and hyperlipidemia. A considerable share of early and long-term posttransplant morbidity is likely to be drug related.. In 31 patients with stable graft function, conversion from CsA to tacrolimus was implemented due to nephrotoxicity (n=19), hypertension (n=9), and neurological disorders (n=8).. Three months after conversion, a response was evident in 26 patients (84%), whereas 5 patients (16%) were nonresponsive. In 13 of 19 patients (68%) suffering from nephrotoxicity, serum creatinine levels decreased significantly from 2.0+/-0.5 mg/dl to 1.5+/-0.4 mg/dl (P<0.005), whereas in 6 of 19 patients (32%) no improvement was observed. Antihypertensive therapy was reduced in six of nine patients and neurological disorders improved in six of eight patients. When analyzing all patients, average levels of cholesterol and triglycerides were significantly lower after conversion when compared with at the time of conversion (P<0.05). Conversion to tacrolimus reduced drug-related side effects in the majority of patients, while graft function remained stable. Conversion to tacrolimus may be considered for CsA-related side effects as a potential beneficial approach.

Topics: Adult; Aged; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Morbidity; Nervous System Diseases; Retrospective Studies; Tacrolimus; Time Factors

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immuno-suppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined.

Topics: Adult; Benzothiadiazines; Blood Glucose; Blood Pressure; Body Weight; Cyclosporine; Diabetes Mellitus; Diuretics; Female; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Lipids; Liver Transplantation; Male; Middle Aged; Obesity; Prednisone; Risk Factors; Sex Factors; Sodium Chloride Symporter Inhibitors; Tacrolimus

An analysis of the efficacy of tacrolimus treatment in three patients with difficult and severe systemic lupus erythematosus (SLE) whose active disease had been previously poorly controlled by cyclosporine and cyclophosphamide.. A review of patient notes.. Two patients are well controlled after six and nine months of treatment with tacrolimus 0.06 mg/kg/day and 0.18 mg/kg/day. Previous persistent vasculitis had resolved and other features of active disease were controlled. The third patient's vasculitis had not improved significantly after two months of treatment and tacrolimus 0.17 mg/kg/day was discontinued because of nephrotoxicity.. Tacrolimus may be a useful additional immunosuppressive agent in some patients whose SLE is not well controlled by conventional treatments.

Topics: Adolescent; Adult; Drug Administration Schedule; Evaluation Studies as Topic; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Male; Tacrolimus

Topics: Actuarial Analysis; Age Factors; Antihypertensive Agents; Blood Pressure; Cyclosporine; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Incidence; Kidney Transplantation; Male; Postoperative Complications; Risk Factors; Sex Factors; Tacrolimus; Time Factors

Cyclosporine A (CsA) seems to exert direct effects on blood pressure and diurnal blood pressure alterations. After kidney transplant about 60% of the recipients are suffering from such alterations. In the present study, blood pressure profiles of 15 FK506-treated kidney transplant patients were compared to recipients with CsA immunosuppression. Both groups showed no statistical differences in number, kidney function, age, body weight, sex distribution and time after transplantation. Mean arterial blood pressure in FK506-treated patients at daytime was 105 +/- 2.5 mmHg, at night 109 +/- 3.0 mmHg. Systolic blood pressure difference was 2.3 mmHg, diastolic day/night blood pressure difference 0.6 mmHg, and the difference of the heart frequency 6.8 beats/min. Cyclosporin A-treated patients showed a mean arterial blood pressure during the day of 107 + 2.6 mmHg, at night-time a mean arterial blood pressure of 107 + 3.4 mmHg was measured. The diurnal blood pressure alterations of systolic blood pressure were 0.9 mmHg, diastolic blood pressure difference 3.5 mmHg respectively, the heart frequency showed a difference of 4.4 beats/min. Both, FK506-treated patients and patients with CsA immunosuppression exhibit reduced diurnal blood pressure alterations. Furthermore, mean arterial pressure in both, FK506 and CsA-treated patients was elevated and showed no statistical differences between the groups. In FK506-treated patients, however, antihypertensive therapy was less intensive. Concerning arterial blood pressure and diurnal blood pressure alterations, FK506 offers no advantages as compared to cyclosporine A. The reduced usage of antihypertensive drugs, however, may give evidence for lower hypertensive properties of FK506 as compared to CsA.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood Urea Nitrogen; Creatinine; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Tacrolimus; Uric Acid

The aim of this study was to investigate the mechanism of hypertension and thromboembolic events induced by cyclosporin (CyA) and tacrolimus (FK506) in respect to their action on the serotonergic blood system. The study was carried out on healthy rats and those with experimental chronic renal failure. CyA injected into healthy and uremic rats caused an increase in serotonin (5-HT) concentration levels in whole blood and platelets. Concomitantly a rise in systolic blood pressure was observed. Platelet aggregation values were significantly higher in uremic rats given CyA. FK506 had no influence on 5-HT blood content, blood pressure or platelet aggregation values. It is concluded that 5-HT may play a role in the development of hypertension and thrombotic events caused by CyA. Furthermore, lower incidence of these complications during FK506 treatment could be the result of this drug's limited effect on the serotonergic blood system.

Topics: Animals; Cyclosporine; Hypertension; Immunosuppressive Agents; Male; Rats; Rats, Wistar; Serotonin; Tacrolimus; Thrombosis; Uremia

Topics: Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Cyclosporine; Follow-Up Studies; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Obesity; Prevalence; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Tacrolimus

Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.

Topics: Blood Pressure; Cyclosporine; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Prednisone; Tacrolimus

We studied rejection, allograft function and side effects, such as hypertension, renal dysfunction and hypercholesterolemia, in seven patients switched from cyclosporine-based triple-drug immunosuppression to FK 506.. A subset of pediatric heart transplant recipients treated with triple-drug immunosuppression consisting of cyclosporine, azathioprine and prednisone experience either persistent rejection when attempts are made to taper corticosteroids or morbidity from cyclosporine and corticosteroids. Experience with the new immunosuppressive agent FK 506 has demonstrated its effectiveness as a single agent in heart transplant recipients, and anecdotal evidence has shown that side effects such as hypertension and hypercholesterolemia may be lower.. Seven patients whom we deemed corticosteroid dependent were switched to FK 506-based therapy. Allograft function, episodes of rejection, need for corticosteroids and incidence of side effects from FK 506 were monitored. The switch to FK 506 was performed using an established protocol. Follow-up time has ranged from 15 to 41 months. Serial right heart catheterizations and endomyocardial biopsies were performed after each reduction of corticosteroid dosing.. Catheterization data showed no significant change in pulmonary wedge pressure, mean right atrial pressure or cardiac index, indicating no decline in allograft function. Serial echocardiographic variables of allograft function were also stable. At present, all seven patients are free of the corticosteroid portion of their immune suppression. There have been only two episodes of significant acute rejection requiring treatment with intravenous corticosteroids. Antihypertensive medications have been discontinued in five of six patients previously treated with these drugs. Plasma cholesterol, low density lipoprotein and triglyceride levels were decreased, and renal function was stable.. Preliminary studies suggest that FK 506 may be an alternative immunosuppressive agent for pediatric and adolescent patients experiencing ongoing rejection or significant morbidity from cyclosporine and corticosteroids and in those patients dependent on corticosteroids for immune suppression.

Topics: Adolescent; Adult; Antihypertensive Agents; Azathioprine; Cardiac Catheterization; Child; Cyclosporine; Drug Therapy, Combination; Echocardiography; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Kidney Diseases; Lymphoproliferative Disorders; Prednisone; Tacrolimus; Time Factors

Hypertension is common after orthotopic liver transplantation and may be due, in part, to cyclosporin A-induced renal dysfunction and/or enhanced proximal tubular sodium reabsorption. To determine whether enhanced proximal tubular sodium reabsorption is central to the development of posttransplant hypertension, measurements of renal hemodynamics and fractional clearances of lithium and sodium were compared 1 month after orthotopic liver transplantation in previously normotensive patients receiving either cyclosporin A (N = 24) or FK506 (N = 18), an immunosuppressive agent that is structurally unlike cyclosporin A and that has a lower reported incidence of hypertension. Median prednisone doses were 20 and 13 mg/day in the cyclosporin A and FK506 groups, respectively (P < 0.05). At 1 month, mean arterial blood pressure was higher in the cyclosporin A versus the FK506 group: 108 +/- 2 versus 95 +/- 3 mm Hg (P < 0.05). GFR, RBF, and renal vascular resistance were not different between the two groups: 59 +/- 4 and 53 +/- 5 mL/min per 1.73 m2, 439 +/- 28 and 440 +/- 41 mL/min per 1.73 m2, and 22,429 +/- 1,822 and 22,977 +/- 3,506 dyne s/cm5 per 1.73 m2, respectively. Fractional lithium excretion was similar in the cyclosporin A and FK506 groups: 19.9 +/- 2.2 and 19.4 +/- 2.0% (P = not significant) although both values were lower than those of normal controls (25.5 +/- 1.1%) (P < 0.05). Fractional sodium excretion was 2.7 +/- 0.3 and 2.3 +/- 0.4% in the cyclosporin A and FK506 groups, respectively (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Pressure; Case-Control Studies; Cyclosporine; Electrolytes; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Renal Circulation; Sodium; Tacrolimus

1. Cyclosporine A induced a highly significant additional increase in blood pressure in spontaneously hypertensive rats (SHR) and elevated clearly the blood pressure in the genetically related normotensive controls, Wistar-Kyoto (WKY) rats, after both single (i.v.) and long-term administration (oral). 2. Acceleration of rise in blood pressure by cyclosporine is caused by sympatho-adrenal activation. Evidence for this mechanism of action came from the following pharmacological interventions: After chemical sympathectomy with 6-hydroxydopamine increase in blood pressure by cyclosporine was significantly reduced. Depletion of catecholamine stores by reserpine also diminished significantly the cyclosporine induced hypertension. Selective alpha1-adrenergic receptor blockade by prazosin blunted acute hypertension induced by cyclosporine. 3. Norepinephrine concentrations in the spleen of both WKY and SHR were reduced by long-term administration of cyclosporine. In the kidneys of WKY rats the level of norepinephrine was decreased but increased in the kidneys of SHR after long-term administration of cyclosporine. 4. Also the immunosuppressive agent FK506 with a macrolide-like structure induced acute hypertension in normotensive rats. The hypertensive effect was blunted by the vasoselective calcium channel blocker felodipine. 5. It is concluded that immunosuppressive agents like cyclosporine or FK506 activate the sympatho-adrenal system in normotensive and genetically hypertensive rats, thereby inducing hypertension. The mechanism of action may contribute to the hypertension seen in patients treated with cyclosporine after transplantation of heart, kidney or liver.

Topics: Adrenal Glands; Animals; Blood Pressure; Cyclosporine; Hypertension; Immunosuppressive Agents; Infusions, Intravenous; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; Tacrolimus

The safety and efficacy of conversion to FK506 after failing immunosuppression with cyclosporine was prospectively evaluated in 31 pediatric liver transplant recipients between April 1991 and March 1993. The patients, who ranged in age from 40 days to 14 years, accounted for 28 primary transplantations and 3 retransplantations. The initial immunosuppression regimen consisted of cyclosporine in combination with prednisone. The indications for conversion were acute or chronic rejection refractory to OKT3, Minnesota antilymphocyte globulin, or steroids (13 patients); hypertension (8 patients); inability to reach a therapeutic level of cyclosporine (6 patients); hirsutism (3 patients); and growth retardation (1 patient). After an average follow-up of 10 months (range, 2 to 25 months), 27 (87%) of the patients are alive and have functioning grafts. Of the 13 patients who were converted for refractory rejection, 9 are alive. Six of these 9 patients experienced a complete biochemical reversal of the rejection process within 3 months of conversion; 2 had a partial response to conversion, and 1 patient failed but underwent successful retransplantation. Three of the 4 patients who died did so without showing any improvement. The remaining 18 patients who were converted for various other reasons are alive and have functioning grafts. Of the 8 patients who developed hypertension on cyclosporine and prednisone, 6 experienced a resolution of this problem within 3 months of conversion. Three of the 18 children who underwent rescue therapy for reasons other than refractory rejection experienced rejection episodes after conversion to FK506. Two of these 3 children achieved resolution with either steroid therapy or an increased dosage of FK506, while the third child developed chronic rejection. The side effects of FK506 were generally minor and resolved by lowering the dose. Lymphoproliferative disease developed in 2 patients (6%). The present study suggests that FK506 is a relatively safe and effective rescue therapy for pediatric liver transplant recipients who have failed immunosuppression with cyclosporine. Longer follow-up is needed to assess the effect of FK506 on growth.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Drug Evaluation; Female; Graft Rejection; Humans; Hypertension; Infant; Liver Transplantation; Male; Postoperative Period; Prospective Studies; Tacrolimus

To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterioles; Blood Urea Nitrogen; Creatinine; Hypertension; Kidney; Kidney Diseases; Male; Nifedipine; Rats; Rats, Inbred SHR; Renal Artery; Renin; Tacrolimus; Thromboxane B2; Vasoconstriction

Topics: Actuarial Analysis; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Kidney; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Potassium; Tacrolimus

An account is given of the 6- to 12-month survival, and causes of failure in 110 consecutive patients who underwent primary liver transplantation under treatment from the outset with FK 506 and steroids. The patient survival is 92.7%, and the first graft survival is 87.3%. At a very high frequency, the patients achieved good graft function, and they had a relatively low morbidity that was partially ascribable to minimal use and early discontinuance (in 60% of cases) of steroids. Renal dysfunction and other adverse findings were largely confined to patients with poor initial graft function and consequent apparent alteration of the kinetics of FK 506 elimination, causing functional overdosage. Results compare very favorably with our past record using conventional immunosuppression, and support the belief that FK 506 is a superior immunosuppressive agent which is suitable for chronic administration.

Topics: Adult; Alanine Transaminase; Anti-Bacterial Agents; Aspartate Aminotransferases; Bilirubin; Blood Urea Nitrogen; Cause of Death; Cholesterol; Creatine; Cyclosporins; gamma-Glutamyltransferase; Graft Survival; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Jaundice; Kidney; Liver Transplantation; Prednisone; Survival Analysis; Tacrolimus; Uric Acid

Topics: Anti-Bacterial Agents; Diabetes Complications; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Risk Factors; Tacrolimus