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At least 19 recordsLinked to original sources
PubMed2000

Posttransplantation hypertension related to calcineurin inhibitors.

Calcineurin inhibitors are a mainstay of transplant immunosuppression and commonly induce hypertension. They are highly lipid soluble and penetrate vascular smooth muscle cell membranes readily. Changes in vascular tone are universally observed during administration of these agents, particularly within the kidney, leading to diminished glomerular filtration and enhanced sodium retention. Disturbances of endothelial function are prevalent in many tissues, including stimulation of endothelin and impaired nitric oxide synthesis. Multiple additional pathways produce increased vasoconstriction, leading to an increase in arterial pressure. Clinical manifestations include disturbances in circadian blood pressure patterns, left ventricular hypertrophy, and acceleration of atherosclerotic and renal injury. Rapid increases in pressure occasionally produce accelerated hypertension and microangiopathic tissue damage. Principles of therapy require recognition of hazards of changing arterial pressures during calcineurin use and preferential use of vasodilating drugs, particularly dihydropyridine calcium channel blocking agents. Attention must be paid to interactions between antihypertensive agents and calcineurin inhibitor blood levels.

Calcineurin Inhibitors↗
PubMed2003

[Long term management of childhood atopic dermatitis with calcineurin inhibitors].

The calcineurin inhibitors pimecrolimus and tacrolimus are important tools for long-term management of atopic dermatitis in childhood. These drugs are approved in Germany for the intermittent long-term treatment of moderate to severe (tacrolimus ointment) or mild to moderate (pimecrolimus cream) atopic dermatitis in children older than 2 years. Recent study results show that these agents are also effective in infants (aged 3-23 months) with atopic dermatitis. During the long-term treatment of children and infants with calcineurin inhibitors, the therapeutic success can be maintained and there is a continuous increase in the response rate. Long-term use of calcineurin inhibitors in atopic dermatitis is well tolerated locally and systemically, leads to reduction of disease flares and has a corticosteroid sparing effect.

Administration, Topical↗
PubMed2005

[How I treat ... atopic dermatitis by topical pimecrolimus (Elidel). The emerging paradigm of calcineurin inhibitors].

Topical calcineurin inhibitors, also called topical immunomodulators or downregulators, represent an innovative class of non-steroidal anti-inflammatory agents. Pimecrolimus 1% cream (Elidel) is one representative drug available for the treatment of atopic dermatitis. Unlike topical steroids, this drug does not affect collagen synthesis and does not alter the dendritic cell functions and the barrier function of the skin.

Calcineurin Inhibitors↗
PubMed2005

2005 immunosuppressive strategies in kidney transplantation: which role for the calcineurin inhibitors?

The calcineurin inhibitors (CNIs) cyclosporine and tacrolimus have been the cornerstones of immunosuppressive strategies in clinical transplantation. Currently, regimens that are most widely used for induction and maintenance therapy include CNIs. However, many clinical trials aiming at reducing or eliminating CNIs have been performed in recent years. Here, we review and discuss current and future immunosuppressive strategies with a special emphasis on the role of CNIs, in the light of recent studies in the field of kidney transplantation. In the current era, CNIs still play an important role.

Calcineurin Inhibitors↗
PubMed2005

Immunosuppression in liver transplantation: beyond calcineurin inhibitors.

Although calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression in liver transplantation (LTX), their long-term toxicity significantly contributes to morbidity and mortality. The elucidation of mechanisms of alloimmunity and leukocyte migration have provided novel targets for immunosuppression development. The toxicities of these agents differ from that of the CNI and act additively or synergistically. CNI avoidance protocols in LTX have not been achieved routinely; however, pilot trials have begun to delineate the limitations and promises of such approaches. CNI-sparing protocols appear to be much more promising in balancing the early need for minimizing rejection while tapering doses and minimizing long-term toxicity.

Adrenal Cortex Hormones↗
PubMed2001

Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors.

BACKGROUND: Calcineurin inhibitors (CNI) and azole antifungal agents have been reported to interact in a disparate manner. The azole dose and route and the level of involvement of the liver and intestines have been implicated, although data are limited. A significant interaction may result in CNI toxicity, and withdrawal of the azole may result in subtherapeutic CNI concentrations. Fluconazole, available in both intravenous and oral formulations, is commonly used in transplant recipients and is ideal for determining the presence of a disparate effect on CNI concentrations. We retrospectively investigated the interaction of CNIs with fluconazole, evaluating CNI blood troughs corrected for daily CNI dose, the factors influencing the interaction, and the effect on clinical outcomes in renal and simultaneous pancreas kidney transplant recipients. METHODS: Twenty-eight patients received a CNI and fluconazole during the calendar year 1999, but only 19 patients had documented CNI blood troughs and outpatient follow-up. There were 25 episodes of use in the 19 included patients. CNI blood troughs were evaluated for changes induced by fluconazole, given by both routes, and clinical outcomes were tracked. RESULTS: Data demonstrated both intravenous and oral fluconazole alter CNI blood concentrations. Two metabolic patterns were observed, and we termed these convergent and divergent. Divergent metabolizers did not have significant interaction (n=5), and convergent metabolizers did have a significant interaction (n=15). One patient had a divergent episode after a previous convergent episode. The main contributors to the lack of interaction appeared to be female sex and African American ethnicity. Additionally, tacrolimus levels were significantly more affected than cyclosporine, during and after fluconazole administration. No patient experienced nephrotoxicity or cellular rejection related to antifungal therapy. CONCLUSIONS: Oral and intravenous fluconazole appear to increase oral CNI trough concentrations to a similar extent even after adjusting for daily calcineurin dose. These interactions appear to be chiefly influenced by sex and ethnicity. Further prospective study is necessary to clarify this issue.

Adult↗
PubMed2005

Concentration-controlled everolimus (Certican): combination with reduced dose calcineurin inhibitors.

The calcineurin inhibitors (CNIs) have been the cornerstone of immunosuppressive therapy in recent years, though their association with dose-related nephrotoxicity is a major factor in the development of chronic allograft nephropathy in kidney transplant recipients. The novel proliferation signal inhibitor everolimus (Certican) has a mode of action distinct and complementary to the CNIs, which is thought to underlie the demonstrated synergy between everolimus and cyclosporine (CsA) in preclinical models. This finding suggests that everolimus may allow for CNI dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Two prospective, multicenter, randomized studies have investigated the efficacy and safety of everolimus (1.5 or 3.0 mg/day) combined with reduced-exposure CsA (Neoral) in de novo renal transplant patients. In these studies, the everolimus trough level was maintained at > or =3 ng/ml with therapeutic drug monitoring and the CsA dose optimized with C(2) monitoring. The incidence of efficacy failure with this regimen was shown to be comparable with that provided by regimens employing full-dose CNIs, but with good renal function. Furthermore, everolimus (trough levels 3-8 ng/ml) plus reduced-exposure CsA was associated with a marked reduction in acute rejection compared with regimens using fixed-dose everolimus or mycophenolate mofetil plus full-dose CsA. At 12 months follow-up, CsA trough level was 57% lower in these trials than in previous trials in which patients received full-dose CsA. This suggests that concentration-controlled everolimus can be successfully combined with optimized administration of CsA and that this regimen may maximize immunosuppression, whilst preserving renal function.

Calcineurin Inhibitors↗
PubMed2005

Are anemic patients more sensitive to calcineurin inhibitors?

A calcineurin inhibitor (CNI) is characterized by high affinity binding to red blood cells. There is a possibility that hematocrit levels might affect the immunosuppressive effects of cyclosporine (CsA). The purpose of this study was to examine whether the treatment with CNI was more effective in preventing acute rejection in anemic compared with nonanemic patients and to find a suitable method to monitoring immunosuppression. Ninety-five living donor renal transplant recipients who were treated with CsA were divided into five groups depending on their Ht levels. The incidences of biopsy-proven acute rejection were 1/8 (12.5%), 8/31 (25.8%), 6/28 (21.4%), 10/22 (45.5%), and 2/6 (33.3%) for Ht < or = 25%, 25% < Ht < or = 30%, 30% < Ht < or = 35%, 35% < Ht < or = 40%, and 40% < Ht, respectively. In vitro IL-2 mRNA inhibition tests were performed to evaluate lymphocyte function after stimulation of whole-blood with phorbol myristate acetate and Ca-ionophore in the presence of various concentrations of CsA. Whole blood CsA levels causing 50% inhibition of IL-2 mRNA (IC50) were 256, 310, 175, and 55 ng/mL for Ht 50%, 40%, 30%, and 20%, respectively. It is speculated that plasma concentrations of CsA may increase at low Ht levels, because lower incidences of acute rejection and lower IC50 values of CsA were observed in the anemic state. When the dosage of CsA was adjusted to its whole-blood concentration, the anemic state is likely to enhance the immunosuppressive effect of CsA. A pharmacodynamic study, such as the IL-2 mRNA inhibition test, is preferable for CsA monitoring.

Anemia↗
PubMed2004

Incapacitating lower limb pain syndrome in cord blood stem cell transplant recipients with calcineurin inhibitor.

Calcineurin-inhibitor induced pain syndrome (CIPS) is a newly described entity with a characteristic feature of sudden onset of severe lower limb pain, and high levels of cyclosporine or tacrolimus may be involved in the pathogenesis. This syndrome is rarely seen in recipients of hematopoietic stem cell transplantation (HSCT) compared with other organ transplant recipients, however, heightened awareness of this complication after HSCT may be needed for hematologists, as misdiagnosis can result in catastrophic consequences. We report herein two cases of lower limb pain syndrome, with some clinical features resembling CIPS, occurring during the early phase of cord blood stem cell transplantation for hematological malignancy.

Adolescent↗
PubMed2005

Comparative study of clinical outcome in kidney transplantation between early steroid withdrawal protocol using basiliximab, calcineurin inhibitor, and mycophenolate mofetil and triple regimen consisting of calcineurin inhibitor, mycophenolate mofetil, and steroid.

AIMS: Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen. METHODS: Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection. RESULTS: In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2. CONCLUSIONS: Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Clinical evaluation of marginal parodontium condition in patients after kidney graft treated with calcineurine inhibitors and calcium channel blockers.

Renal transplantation is a method of treating the chronic renal failure. Gingival overgrowth is a common side effect of immunosuppressive treatment with cyclosporine A. Calcium channel blockers also cause gingival overgrowth or intensify it. Tacrolimus is a new inhibitor of calcineurine used as an alternative to cyclosporine A. 124 patients were treated with cyclosporine A, and 38 patients were given tacrolimus. At the same time, patients were given calcium channel blockers. Impact of age, sex, calcineurine inhibitors dosage, sort of calcium channel blocker used as well as treatment duration on gingival overgrowth were studied. Also, periodontal status: oral cavity hygiene, gingivitis degree as well as extent and level of gingival overgrowth were evaluated. Gingival overgrowth of different degree was present in 58 patients (46.7%) treated with CsA and in none of the patients treated with tacrolimus. Hygiene and inflammation indices were significantly higher in the group of patients with gingival overgrowth as compared to the group without gingival overgrowth treated with CsA. In the group of patients treated with tacrolimus, these indices were the lowest, and the gingivae were sort of shrunk and paler. Patients with risk factors in gingival overgrowth and patients with severe overgrowth should be converted to tacrolimus treatment.

Adult↗
PubMed2006

Early renal benefit of rapamycin combined with reduced calcineurin inhibitor dose in pediatric heart transplantation patients.

BACKGROUND: Calcineurin inhibitors such as cyclosporine are effective in preventing rejection in recipients of solid organ transplants. Unfortunately, the prolonged use of calcineurin inhibitors may result in progressive renal injury. METHODS: We studied the renal function of 15 pediatric heart transplant recipients who were taking calcineurin inhibitors. Their renal function was studied before and after rapamycin was introduced to their immunosuppression regimen. With the introduction of rapamycin, the patients were given a lower dose of calcineurin inhibitors, and the calcineurin inhibitor was discontinued in 5 patients. RESULTS: Renal function improved significantly in the patients by 30 days after these changes in the calcineurin inhibitor dose were instituted. Mean levels of blood urea nitrogen and mean serum creatinine decreased, and mean creatinine clearance increased. Pre-rapamycin, the patients' mean level of blood urea nitrogen was 27.1 +/- 12.4 mg/dl and post-rapamycin they decreased to 18.6 +/- 11.1 mg/dl (p = 0.014). Similarly, creatinine decreased from 1.0 +/- 0.5 mg/dl to 0.8 +/- 0.3 mg/dl (p = 0.019). Their creatinine clearance increased from 88 +/- 28 ml/min/1.73 mol/liter2 to 105 +/- 27 ml/min/1.73 mol/liter2 (p = 0.008). The patients' lipid levels did not change after they were prescribed rapamycin. Biopsy-negative rejection developed in 2 patients. CONCLUSIONS: The introduction of rapamycin to the immunosuppressive regimen of patients taking calcineurin inhibitors, with a concomitant reduction of the calcineurin inhibitor dose, may improve renal function within 30 days, without a significant increase in rejection.

Blood Urea Nitrogen↗
PubMed2006

Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts.

Calcineurin inhibitors (ciclosporin and tacrolimus) can cause acute and chronic nephrotoxicity. The serum levels of these drugs do not correlate well with the extent of renal damage caused, and the clinical manifestation is nonspecific. Renal biopsy is a reliable tool with which to diagnose calcineurin-inhibitor-induced nephrotoxicity. Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy. As maintenance doses of calcineurin inhibitors in renal transplant recipients have been lowered during the past decade, the incidence of acute toxicity has decreased markedly. Chronic toxicity, however, is still prevalent, and causes chronic allograft damage.

Calcineurin Inhibitors↗
PubMed2003

Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei.

Azoles target the ergosterol biosynthetic enzyme lanosterol 14alpha-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.

Antifungal Agents↗
PubMed2004

Maximizing the clinical outcome with mTOR inhibitors in the renal transplant recipient: defining the role of calcineurin inhibitors.

The synergistic action of mTOR inhibitors and calcineurin inhibitors (CNIs) provide a rationale for combination therapy, with the potential for CNI-dose reduction and corresponding clinical benefits. CNI therapy is necessary in the early post-transplant phase to deliver sufficient immunosuppressive potency, but use of standard-dose cyclosporine (CsA) with either sirolimus or everolimus has been associated with inferior renal function. Withdrawal of CsA from an mTOR-based regimen reduces renal toxicity, but this may be achieved at the price of increased late rejection and sirolimus-related adverse events. Use of a concentration-controlled mTOR inhibitor with low-exposure CsA seems to be effective in preventing rejection with good renal function. Currently, routine withdrawal of CNIs from an mTOR-inhibitor based regimen, or substitution of an mTOR inhibitor for a CNI, is not justified except in patients who experience toxicity (particularly nephrotoxicity) and who do not respond to CNI dose optimization.

Calcineurin↗
PubMed2005

Calcineurin-inhibitor-sparing immunosuppressive protocols.

Calcineurin inhibitors (CNI) have played an important role in improving graft survival. However, the balance between preventing immunologic allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. There are three major CNI-sparing strategies. CNI MINIMIZATION: The advent of mycophenolate mofetil (MMF) allows cyclosporine (CsA) reduction to ameliorate renal function in patients with chronic renal allograft dysfunction, without increasing acute rejection rates. In combination with mTOR inhibitors, very low CNI levels may be sufficient to prevent acute rejection. However, in this association, CNI nephrotoxicity is magnified by pharmacokinetic interaction. CNI WITHDRAWAL: CNI withdrawal has been attempted in regimens containing MMF or sirolimus (SRL). Introduction of MMF in patients with chronic allograft nephropathy (CAN) followed by CNI withdrawal resulted in stabilization or improvement of renal function and hypertension profile, although there is some risk of acute rejection. In regimes based on SRL, CNI withdrawal is a safety strategy, achieving a sustained improvement of renal function, histology, and graft survival. There is not consensus at all whether MMF should be added or not in patients converted from CNI to mTOR inhibitor. CNI AVOIDANCE: Polyclonal-based regimens with MMF and steroids have shown acceptable acute rejection rates, but high rates of cytomegalovirus (CMV) and opportunistic infections. Conversely, anti-IL-2R in combination with MMF and steroids resulted in 50% incidence of acute rejection, thus suggesting that CNI avoidance is not feasible in a regimen based on MMF. Alternatively, a protocol based on anti-IL-2R induction therapy combined with SRL, MMF, and prednisone has shown an efficient prevention of acute rejection, higher creatinine clearance and lower rate of CAN in comparison with a group treated with CNI. New strategies using costimulation blockade may help in the development of safe CNI-free regimens. In summary, in renal transplantation the new immunosuppressive medications have made feasible old aspirations such as minimization, withdrawal, or even avoidance of CNI.

Calcineurin Inhibitors↗
PubMed2006

Reverse diastolic intrarenal flow due to calcineurin inhibitor (CNI) toxicity.

Renal calcineurin inhibitor (CNI) toxicity is a frequent side effect of immunosuppression with CNIs in solid organ transplantation, leading to acute and chronic renal failure. Acute CNI toxicity is due to vasoconstriction of the vasa afferens and efferens and vacuolization of smooth muscle cells with medial hyalinosis, leading to vessel lumen narrowing. Our case had an acute renal failure 8 months after deceased donor kidney transplantation under treatment with tacrolimus, sirolimus and prednisolone. In Doppler sonography, we observed reverse diastolic intrarenal blood flow, reflecting intense vessel narrowing. There were histological signs of acute CNI toxicity. Within days of reducing the tacrolimus trough level, renal function improved markedly and Doppler sonography showed orthograde intrarenal blood flow. This is the first case of functional, Doppler sonographic evidence for CNI-induced, rapidly reversible narrowing of intrarenal vessels. This case illustrates the potential role of tacrolimus and sirolimus dosing in combination therapy to produce severe intrarenal vasoconstriction.

Biopsy↗