Calcineurin Inhibitor Reduction Research Articles

Recommendations for Use of Certican ® (Everolimus) After Heart Transplantation: Results From a German and Austrian Consensus Conference

The Certican Consensus Conference has produced guidelines to help physicians apply Certican (everolimus) clinical trial data in clinical practice. Everolimus is indicated in combination with cyclosporine microemulsion (CsA; Neoral) and corticosteroids for prophylaxis of acute rejection after heart transplantation. It has also shown efficacy for prevention of cardiac allograft vasculopathy. Further indications for use pertain to patients with chronic renal failure, to allow reduced calcineurin inhibitor (CNI) exposure; reduce the risk of cytomegalovirus to disease; second transplantation; heart/lung transplantation after occurrence of bronchiolitis obliterans; and in patients with malignancies under immunosuppression. Contraindications include intolerance, severe leukocytopenia and severe thrombocytopenia. The everolimus dose is 0.75 or 1.5 mg twice daily, adjusted according to trough blood levels. Target blood levels are 3 to 8 ng/ml, with 6 to 8 ng/ml considered the optimal range for most patients. Recommended CsA trough blood levels in patients receiving everolimus are 150 to 175 ng/ml for Months 1 to 3 post-transplant, around 135 ng/ml for Months 3 to 6, and <100 ng/ml after Month 6. It may be possible to discontinue steroids in patients receiving long-term everolimus and CsA. Early cytomegalovirus prophylaxis is recommended for patients with a high-risk mismatch, and trimethoprim-sulfamethoxazole should be given to prevent Pneumocystis carinii. Everolimus dose should be reduced by about 50% if administered in conjunction with azoles or erythromycin, and increased 100% to 200% if given with rifampicin. All heart transplant recipients should receive statins unless contraindicated.

Low-Dose Mycophenolate Mofetil is an Effective and Safe Treatment to Permit Phased Reduction in Calcineurin Inhibitors in Chronic Allograft Nephropathy

Chronic allograft nephropathy (CAN) is the most common cause of long-term renal-allograft dysfunction and the second most common cause of transplant loss. There are concerns that prolonged patient exposure to calcineurin inhibitors (CNIs) exacerbates or promotes the process of CAN. In our unit, we carried out an observational study over the period 2000 to 2003 using low-dose mycophenolate mofetil (MMF) to facilitate a phased reduction in the dose of CNI in a group of patients with CAN. Low doses of MMF were chosen to minimize adverse effects and to reduce levels of CNIs without the attendant risks of under-immunosuppression. A step-wise reduction in mean reciprocalised creatinine was evident over the run-in period (mean 1/creatinine before MMF=0.005739-0.000083*month; R=0.77) with a step-wise monthly improvement postintroduction of MMF and dose reduction of CNI (mean 1/creatinine after MMF=0.004609+0.000049*month; R=0.74) (P<0.0001). The mean Cockroft-Gault estimated creatinine clearances were 47.1+/-24.2, 37.2+/-16.3, and 41.6+/-21.1 mL/min at time [t]=-12, t=0 and t=+12 months, respectively. Low-dose MMF therapy was well tolerated (only 7/89 patients stopped MMF because of side-effects in the first 12 months), and acute rejection was noted in only one patient. At latest follow-up, only 17 transplant losses had occurred, of which 6 patients had died with a functioning graft. Low-dose MMF was well tolerated and resulted in prolonged graft survival.

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: Preliminary results of an open prospective study

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI ( n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose ( n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 ± 0.36 versus 1.58 ± 0.33 mg/dL, P < .001) and BUN (39.2 ± 11.8 versus 29.9 ± 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 ± 10.8 versus 61.6 ± 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 ± 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 ± 19 versus 130 ± 14 mm Hg, P < .01) and diastolic (82 ± 9 to 74 ± 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 ± 25.9 versus 25.2 ± 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.

Introduction of MMF in conjunction with stepwise reduction of calcineurin inhibitor in stable liver transplant patients with renal dysfunction

Mycophenolat mofetil (MMF) is a new imunosuppressant without nephrotoxic adverse effects. The aim of this study was to evaluate feasibility and effect of MMF introduction in conjunction with stepwise reduction of calcineurin inhibitors (CNI) in stable liver transplant patients with chronic CNI-induced renal dysfunction (RDF). In the MMF-group ( n=27) but not in the controls ( n=16), mean serum level of creatinine fell from a baseline of 227.4±67.9 μmol/l to 159.2±48.2 μmol/l ( P<0,001), while mean urea level declined significantly from a baseline of 18.5±8.7 mmol/l to 11.4±4.2 mmol/l 6 months after initiation of MMF. Additionally, systolic and diastolic blood pressure values improved. In 52% of patients, dose reduction ( n=11) or withdrawal ( n=3) of MMF was necessary due to gastrointestinal or hematologic adverse effects. But also in patients on low dose MMF, there was a significant improvement of renal function without increased immunological risk.

Sirolimus in chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the most common cause of late renal transplant loss. Calcineurin inhibitor (CNI) nephrotoxicity is known to contribute to CAN. A sirolimus-based regimen way allow for early CNI reduction or elimination. The aim of the present study was to determine the efficacy and safety of a sirolimus-based regimen for CAN. From December 2001 to August 2003, kidney transplant (KTx) recipients with CAN were enrolled for treatment with sirolimus. Among 32 studied patients, 24 (75%) underwent graft biopsy before the initiation of sirolimus. Baseline maintenance immunosuppression consisted of cyclosporine/tacrolimus and prednisone with or without mycophenolate mofetil. The follow-up duration on sirolimus therapy was 8.5 ± 5.9 months (range: 1 to 22 months). The average dosage of sirolimus was 1.8 ± 0.5 mg/d at the end of follow-up. The mean trough level of sirolimus was 5.1 ± 2.1 ng/mL. Sirolimus was effective in 16 (50%) patients while 3 (9.4%) patients improved (serum creatinine [Cr] decrease > 10%) and 13 (40.6%) maintained stable (change of serum Cr within 10%). Sirolimus was effective in 5 (35.7%) patients whose serum Cr was over 3.0 mg/dL but failed to rescue all four patients whose serum Cr was over 4.0 mg/dL. Eleven (68.8%) of 16 responders showed a reduction (29.8% ± 13.8%) in CNI dosage. The most common adverse events were hyperlipidemia (37.5%), anemia (25%), and diarrhea (21.8%). Twelve patients discontinued sirolimus due to graft failure (4), severe infection (3), stroke related mortality (1), anemia (2), diarrhea (1), and edema (1). In conclusion, sirolimus is effective in 50% of KTx recipients with CAN, especially when the serum Cr is less than 3.0 mg/dL. However, the increased incidence of infection, diarrhea, and hyperlipidemia are of major concern.

MYCOPHENOLATE MOFETYL (MMF) THERAPY USED IN A PRIMARY IMMUNOSUPPRESSIVE REGIMEN FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT)

A191 Aims: MMF is a new immunosuppressive (IS) drug for use following OLT which may decrease acute rejection and lead to a reduction in calcineurin inhibitors (CNI) in case of nephrotoxicity. Few studies have evaluated its early use in a primary IS regimen on a large cohort of liver transplant recipients. The aims of this study were: a) to evaluate the impact of MMF on patient survival, frequency of acute and chronic allograft rejection, rate of post-transplant infectious events; and b) to quantify CNI reduction in case of nephrotoxicity. Methods: Patients with MMF in a primary IS regimen (group A) were compared to those without initial MMF (group B). Prognostic analysis used χ2, Kruskal-Wallis, T test and log-rank tests, and the Kaplan Meier method. Results: From 1995 to 2003, 169 adult recipients (173 OLT) were followed for 34 months (109 males, 60 females; age: 48 years). An IS regimen with MMF-CNI-corticosteroids was prescribed in group A (95 consecutive patients, mean follow-up 30.5±10 months), and an azathioprine-CNI-corticosteroid regimen was used in group B (74 patients, mean follow-up 44.4±16 months). Within group B, MMF was never used in 48 patients and secondarily introduced in 26 patients in order to reduce CNI (nephrotoxicity in 20% of cases). Post-transplant survival was significantly higher in group A than in group B at 1 year (90.1±3,1% vs 78.4±4.8%, p=0.02) and 2 years (87±3.8% vs 77±4.9%, p=0..05). Acute and chronic rejection rates were significantly lower in group A than in group B (18.9% vs 43.2%, p= 0.0005 and 0% vs 3.9%, p=0.05). The retransplantation rate did not differ in the two groups (1.1% vs 4.1%). The global rate of early bacterial and CMV-induced events did not differ in the two groups (group A: 34% and 35% versus group B: 31% et 29%). In group A, a decrease in the dose of MMF dose was required in 35% of cases and total arrest in 23% of cases. Frequencies of renal dysfunction and severe renal dysfunction (clearance of creatinine <80 ml/min or <30 ml/min) did not differ in the 2 groups at one year (51.7% vs 48.3% and 0% vs 0%), 2 years (37.7% vs 62.3% and 0% vs 1.9%) or 3 years (72.7% vs 83.7%, and 9.1% vs 6.4%). In group B, secondary use of MMF (mean 36 months post-OLT) in 20 transplant recipients with renal dysfunction led to a reduction in CNI (cyclosporine 0.6 mgkg-1d-1 vs 2.6 mgkg-1d-1, p=0.002, tacrolimus 0.02 mgkg-1d-1 vs 0.08, p=0.009) and a stabilization of renal function with an increase in creatinine clearance of 8 ml/min in 1 year compared to patients from group B without MMF. Conclusions: MMF is an efficient and safe immunosuppressant following OLT which reduces rejection and improves 1- and 2-year survival without significantly increased infectious hazard. Moreover, it enables reduction of CNI and maintenance of renal function in cases of nephrotoxicity.

Mycophenolatemofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients.

Mycophenolatemofetil (MMF) combined with calcineurin inhibitors (CNIs) as immunosuppression after orthotopic liver transplantation (OLT) is still under discussion. We retrospectively investigated the immunosuppressive potency of MMF for treatment of steroid-resistant acute rejection (AR) or chronic rejection (CR), chronic graft dysfunction, and CNI-induced toxicity in patients after OLT. Between 1988 and 2001 we performed 1386 OLTs in 1258 patients. Since 1995, 191 patients have received MMF after OLT for steroid-resistant AR or CR, chronic graft dysfunction (115 patients), and CNI-induced toxicity (76 patients). The mean follow-up time was 56 months. Of 47 patients with steroid-resistant AR, 12 had been treated with OKT3, without resolving the rejection. Overall, bilirubin and transaminases decreased significantly within 2 weeks after the addition of MMF, and liver function normalized in 38 patients. Five of eight patients with CR demonstrated stable liver function after a follow-up of 55+/-8 months; 52 of 60 patients with chronic graft dysfunction improved within 3 months; and 46 of 59 patients with CNI-induced nephrotoxicity improved after MMF treatment and a reduction of CNIs (with a significant decrease in serum creatinine within 2 weeks and an increase of creatinine clearance within 3 months). Clinical symptoms improved in 10 of 12 patients with neurotoxicity and four of five patients with hepatotoxicity. Side effects of MMF, such as gastrointestinal disorders or bone marrow toxicity, occurred in 60 patients (31.4%). The incidence of infections did not increase. Patient survival was 93%, and graft survival was 88.2%. MMF is a potent and safe immunosuppressive agent in OLT recipients for rescue therapy in AR, CR, or chronic graft dysfunction and helps to reduce the serious toxic side effects of CNIs.

Is chronic calcineurin inhibitor toxicity responsible for long-term deterioration of renal function in transplant recipients?

Dose reduction or discontinuation of calcineurin inhibitors (CIs) in renal allograft recipients results in a measurable improvement in renal function, as assessed by a decrease in serum creatinine or improvement in glomerular filtration rate. In general, this effect has been presumed to result from a discontinuation of the acute vasoconstrictive action of CIs on the afferent arteriole. Does it reflect the resolution of chronic CI toxicity? Does chronic CI toxicity explain part of the syndrome of chronic allograft nephropathy (CAN)? We have observed evidence of a continued improvement in renal function or a lack of further deterioration after CI dose reduction or discontinuation in patients with CAN. This improvement in renal function remains evident for up to several years after the intervention and is observed even when the period of acute vasoconstriction (6 months after intervention; the period when the greatest rate of change occurs) is taken into account. These findings suggest a detrimental effect of CIs on renal function that may be, at least in part, reversible and independent of vasoconstriction. In this review, we examine the data concerning the relationship between CI and chronic graft dysfunction.

Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies.

Cyclosporine and tacrolimus reduce allograft rejection, improve allograft half-life and patient survival. Ironically, the nephrotoxicity of these agents may adversely affect allograft survival in renal transplant recipients or cause end-stage renal diseases in other solid organ and bone marrow transplant recipients. Acute dose-dependent and chronic non-dose-dependent nephrotoxicity has been reported in both transplant recipients and patients with autoimmune disorders. Preliminary evidence suggests that drug therapeutic monitoring has little value in the diagnosis or management of nephrotoxicity associated with calcineurin inhibitors. Although the exact mechanism of nephrotoxicity is not fully understood, several factors have been implicated in the pathogenesis of immunosuppressive-induced nephrotoxicity. Renal and systemic vasoconstriction, increased release of endothelin-1, decreased production of nitric acid and increased expression of TGF-beta are the major adverse pathophysiologic abnormalities of these agents. Reducing the dose of a calcineurin inhibitor, or using protocols without calcineurin inhibition may ultimately minimize the risk of drug toxicity and improve allograft and patient survival. New experiences with non-nephrotoxic agents and protocols including mycophenolate and sirolimus allow for early calcineurin inhibitor reduction or elimination without increasing the risk of allograft rejection.

Methods and outcomes of calcineurin inhibitor reduction or withdrawal in patients with chronic allograft nephropathy after the first year posttransplantation

Methods and outcomes of calcineurin inhibitor reduction or withdrawal in patients with chronic allograft nephropathy after the first year posttransplantation

Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy

Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment. One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18). Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method. This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.