Calcineurin Inhibitor Dose Reduction Research Articles

The kinetics of Torque Teno virus plasma load following calcineurin inhibitor dose change in kidney transplant recipients.

Torque Teno virus (TTV)is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solidorgan transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI)dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV-POETtrial. TTV plasma load was quantified by in-house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log10 c/mL (median; interquartile range[IQR] 4.9-8.1) compared with the baseline of 7.1 log10 c/mL (IQR5.3-8.9) was noted (p = 0.001); there was also a trend towarda higher TTV load following CNI increase (6.6 log10 c/mL, IQR 4.1-9.7 vs. 5.2 log10 c/mL, IQR 4.5-6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring.

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial.

Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m2, P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

Impact of Sirolimus versus Mycophenolate Mofetil on Kidney Function after Calcineurin Inhibitor Dose Reduction in Liver Transplant Recipients.

Impaired kidney function is associated with increased morbidity and mortality in patients undergoing liver transplantation. Although immunosuppressants are essential in these patients, they impair kidney function. This study aimed to compare adverse kidney outcomes between patients treated with a reduced dose of tacrolimus (calcineurin inhibitor) plus sirolimus or mycophenolate mofetil (MMF) in the liver transplant center at Kaohsiung Chang Gung Memorial Hospital between April 2011 and December 2017. Propensity score matching was used to identify 232 patients. The risk of adverse kidney outcomes was estimated using Cox proportional hazards regression, and changes in kidney function over time were analyzed using linear mixed modeling. Acute kidney disease risks in this study cohort were not significantly different for the two immunosuppressants (aHR 1.04; 95% CI: 0.70-1.55, p = 0.8328). However, sirolimus use was significantly associated with a higher risk of estimated glomerular filtration rate decline > 30% than MMF (aHR, 2.09; 95% CI: 1.33-3.28; p = 0.0014). Our results demonstrate that sirolimus use may have worsened long-term kidney outcomes compared to MMF. Close monitoring of kidney function, dose adjustment, and timely transition to MMF is necessary for LT patients receiving sirolimus.

Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus.

Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10-15ng/mL, and corticosteroids, n=203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8ng/mL, delayed until day three, and mycophenolate mofetil 2000mg/day, n=343). Mean mGFR was similar between groups at wait-listing (85.3vs 84.1ml/min/1.73m², p=0.60), but higher in the revised treatment group at 3 (56.8vs 63.4ml/min/1.73m², p=0.004) and 12 months post-transplant (60.9vs 69.7ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p=0.01). Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death.

Body composition and maximal exercise capacity after heart transplantation.

AimsMaximal exercise capacity as measured by peak oxygen consumption (pVO2) in cardiopulmonary exercise testing (CPET) of heart transplant recipients (HTR) is limited to a 50–70% level of healthy age‐matched controls. This study investigated the relationship between body composition and pVO2 during the first decade post‐transplant.Methods and resultsBody composition was determined by dual‐energy X‐ray absorptiometry (DXA) and pVO2 by CPET in 48 HTR (n = 38 males; mean age 51 ± 12 years). A total of 95 assessments were acquired 1–9 years post‐transplant, and the results of four consecutive periods were compared [Period 1: 1–2 years (n = 25); 2: 3–4 years (n = 23); 3: 5–6 years (n = 23); 4: 7–9 years (n = 24)]. Linear regression analysis analysed the correlation between pVO2 and pairs of appendicular lean mass (ALM) and fat mass (FM). The relation between ALM and daily dose of calcineurin inhibitor (CNI) was explored using partial correlation controlling for age, gender, and height. pVO2 increased from 0.98 (0.34) to 1.35 (0.35) L/min (P < 0.01) between Periods 1 and 4 corresponding to 54.5–63.3% of predicted value. Peak heart rate (HR) raised from 115 ± 19 to 131 ± 23 b.p.m. (P = 0.05), and anaerobic threshold (AT = VO2 achieved at AT) increased from 0.57 (0.18) to 0.83 (0.35) L/min (P < 0.01) between Periods 1 and 3. Median FM normalized to height2 (FMI) always remained elevated (>8.8 kg/m2). ALM normalized to body mass index increased from 0.690 (0.188) to 0.848 (0.204) m2 (P = 0.02) between Periods 1 and 4, explaining 45% of the variance of pVO2 (R 2 = 0.455; P < 0.001). Eighty‐one per cent of the variance of pVO2 (R 2 = 0.817; P < 0.001) in multiple regression was explained by AT (β = 0.488), ALM (β = 0.396), peak HR (β = 0.366), and FMI (β = −0.181). ALM was negatively correlated with daily CNI dose (partial R = −0.258; P = 0.01).ConclusionsAfter heart transplantation, the beneficial effect of peripheral skeletal muscle gain on pVO2 is opposed by increased FM. Our findings support lifestyle efforts to fight adiposity and CNI dose reduction in the chronic stable phase to favour positive adaptation of peripheral muscle mass.

P1759NEPHROTOXICITY OF CALCINEURIN INHIBITORS AS A RISK FACTOR FOR BK VIRUS REPLICATION AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims BK virus nephropathy (BKVN) represents a serious complication of kidney transplantation and is responsible for significant percentage of transplanted kidneys prematurely terminating their function. Its occurrence is considered a complication of immunosuppressive therapy and is closely related to its intensity. The aim of our prospective study was to evaluate the incidence of subclinical and clinically manifest nephrotoxicity of calcineurin inhibitors (CI) in repeated protocol kidney graft biopsies as a manifestation of excessive immunosuppression and to evaluate its relationship to the PCR confirmed active BKV replication and bioptically proven BKVN during the first year after transplantation. Method In a group of 161 newly transplanted patients we prospectively evaluated 457 consecutive protocol renal biopsies performed within the first year after transplantation. Using the CI nephrotoxicity score, the incidence of nephrotoxicity was monitored. Findings were correlated with laboratory (PCR) and histological evidence of active BK virus (BKV) replication and BKVN. Results When compared to the normal histology, nephrotoxicity was associated with more frequent significant BKV viraemia and viruria (P = 0.02 and P = 0.01, respectively) and more common occurrence of BKVN. The persistence of toxicity in the subsequent biopsy proved to be a negative risk factor of significant BKV viraemia and viruria (P = 0.03 and P = 0.01, respectively), independently of the initial BKV status of the monitored groups. Toxicity could also be used as a predictor of significant viraemia and viruria (P = 0.02 and P = 0.01, respectively) even in the absence of viral replication at the time of initial biopsy. Conclusion Early histological detection of CI nephrotoxicity followed by pre-emptive CI dose reduction might prevent significant BKV reactivation in the risky first posttransplant year. The evaluation whether a regression of histological signs of nephrotoxicity after a CI dose reduction leads to a reduction in BKV replication, and whether a more frequent occurrence of rejection does not complicate further posttransplant course, will be the subject of our further investigation. Supported by grant of Ministry of Health, Czech Republic DRO (FNOL 00098892) – 87-68.

Tacrolimus Monotherapy in Recipients of Liver Transplant: A Single-Center Experience

IntroductionFollowing liver transplantation (LT), the majority of patients are treated with reduced-dose calcineurin inhibitors (CNIs) in combination with mycophenolate mofetil. The optimal timing for subsequent conversion to CNI monotherapy is not clearly defined. This study aims to evaluate the safety of conversion to CNI monotherapy after LT. MethodsThis was a single-center retrospective study of 100 consecutive patients who received CNI and mycophenolate mofetil combination regimen after LT at Singapore General Hospital from 2006 to 2018. Patient demographics, clinical parameters, and posttransplant complications (ie, rates of graft rejection, de novo malignancy, cytomegalovirus infection and renal impairment) were recorded. ResultsOne hundred patients were recruited and mean follow-up time in months ± standard deviation was 60.36 ± 41.73. Patients were divided into 2 groups based on institution of CNI monotherapy within (group 1) or beyond (group 2) 6 months. Twenty-five (25%) patients were on CNI monotherapy within 6 months post-LT. Overall patient survival was 83.7% at 5-years posttransplant. There was no statistical difference in the rates of posttransplant complications including liver graft rejection (4.0% vs 18.7%, P = .11); de novo malignancy (0.0% vs 8.0%, P = .33); cytomegalovirus infection (4.0% vs 1.3%, P = .44); and renal impairment (20.0% vs 40.0%, P = .069) between the 2 groups. ConclusionsSuccessful institution of CNI monotherapy within 6 months is safe, and does not increase the risk of rejection.

Risk Factors of Acute Rejection in Patients with BK Nephropathy After Reduction of Immunosuppression.

BackgroundBK nephropathy (BKN) affects graft function and increases the risk of graft failure. The reduction of immunosuppression is the main treatment for BKN. However, acute rejection may develop following immunosuppression reduction, and data regarding the risk factors of acute rejection during the post-reduction period are insufficient.Material/MethodsOf 758 patients who received a kidney transplantation (KT) between 2008 and 2011, 79 who underwent immunosuppression reduction as BKN treatment were enrolled. The risk factors of acute rejection after immunosuppression reduction were identified using multivariate logistic regression analysis.ResultsDuring the median follow-up period (75 months), acute rejection developed in 21.5% of study group patients and in 22.5% of KT recipients without BKN. The rejection group showed a trend of higher body mass index (24.13±3.92 vs. 22.40±3.31 kg/m2, P=0.070) and lower tacrolimus levels than the no rejection group, although mycophenolate mofetil (MMF) doses were not lower in the rejection group. The rejection group showed worse graft survival than the no rejection group (P=0.001 by the log rank test). A greater number of patients in the rejection group exhibited reduced calcineurin inhibitor (CNI) level by >20% at 1 month after initial BKV detection (34.2% vs. 7.9%, P=0.008). Multivariate analysis indicated that the peak BKV PCR level (odds ratio [OR], 0.136; 95% confidence interval [CI], 0.025–0.732; P=0.020), MMF discontinuation (vs. MMF reduction; OR, 0.112; 95% CI, 0.020–0.618; P=0.012) and CNI level reduction >20% (OR, 33.752; 95% CI, 4.263–267.251; P=0.001) were significantly associated with acute rejection.ConclusionsAcute rejection after immunosuppression reduction for BKN showed worse allograft survival than the patients without acute rejection. In addition, a CNI dose reduction >20% at 1 month after the initial BKV detection can increase the risk of acute rejection.

Efficacy and Safety of Everolimus with Reduced-Dose Calcineurin Inhibitor in De Novo Kidney Transplant Recipients

Efficacy and Safety of Everolimus with Reduced-Dose Calcineurin Inhibitor in De Novo Kidney Transplant Recipients

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Rapamycin induces ILT3highILT4high dendritic cells promoting a new immunoregulatory pathway

ILT3(high)ILT4(high) dendritic cells (DCs) may cause anergy in CD4(+)CD45RO(+)CD25(+) T cells transforming them into regulatory T cells (Tregs). Here, we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients. Forty renal transplant patients with biopsy-proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction. At conversion and 2 years thereafter, we measured the rapamycin effects on circulating DCs (BDCA1/BDCA2 and ILT3/ILT4 expression), CD4(+)/CD25(high)/Foxp3(+) Tregs, CD8(+)/CD28(-) T cells, and the Th1/Th2 balance in graft biopsies. In rapamycin-treated patients, peripheral BDCA2(+) cells were significantly increased along with ILT3/ILT4(+) DCs. The number of circulating CD4(+)/CD25(high)/Foxp3(+)/CTLA4(+) Tregs, CD8(+)CD28(-) T cells, and HLA-G serum levels were higher in the rapamycin-treated group. The number of ILT3/ILT4(+)BDCA2(+) DC was directly and significantly correlated with circulating Tregs and CD8(+)CD28(-) T cells. ILT3/ILT4 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin-treated patients. Thus, rapamycin induces the upregulation of ILT3 and ILT4 on the DC surface, and this effect is associated with an increase in the number of Tregs and expansion of the CD8(+)CD28(-) T cell population. This suggests that mTOR inhibition may promote a novel immunoregulatory pathway.

GW24-e0441 Risk factors for the development of renal dysfunction after heart transplantation

ObjectivesTo access the prevalence and risk factors responsible for renal dysfunction after heart transplantation (HT) in Chinese single centre.MethodsWe studied 248 consecutive adult patients who had undergone HT between June...

Upfront Calcineurin Inhibitor Dose Reduction of 40% in Pediatric Haematopoietic Stem Cell Transplant Does Not Result in Increased Graft Versus Host Disease in Patients Receiving Voriconazole Maintenance Therapy

Upfront Calcineurin Inhibitor Dose Reduction of 40% in Pediatric Haematopoietic Stem Cell Transplant Does Not Result in Increased Graft Versus Host Disease in Patients Receiving Voriconazole Maintenance Therapy

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Baccarani et al. from the University of Udine reported on their experience with transplantation for 26 hepatitis C virus (HCV)/human immunodeficiency virus (HIV)–coinfected patients. Overall, the 3-year patient survival rate of their cohort (79%) was higher than the rate reported for our US cohort (60%).1 The only factor that they found to predict survival was a pretransplant CD4 count nadir < 100/mm3, which was present in 3 of the recipients (12%) and may have reflected more advanced HIV disease or potentially more severe liver disease. The authors did not comment on the causes of death, so it is difficult to mechanistically determine how the low CD4 nadir was associated with a higher risk of death. In our US cohort, a pretransplant CD4 count < 200/mm3 and a CD4 count nadir < 100/mm3 were not significantly associated with graft loss in coinfected patients. More remarkable from our standpoint is the extremely low rate of acute rejection (only 6.5%) reported for this Italian cohort. This is dramatically different from the findings for our US cohort, for which the 90-day cumulative incidence of rejection was 22% (95% confidence interval = 15%-33%).1 In part, this likely reflects differences between the studies with respect to when and how immunosuppressive drugs were administrated, monitored, and adjusted. As Baccarani et al. emphasized, immunosuppressive drug levels were frequently monitored, especially in the first weeks after transplantation, presumably to facilitate dose adjustments to optimize calcineurin inhibitor (CNI) levels. Similarly to the Italian cohort, patients in the US cohort were monitored frequently (daily in the hospital and biweekly for months), and this led us to conclude that other factors may account for the striking differences in the incidence of rejection. Although appropriate trough levels of CNIs are achieved, patients on protease inhibitor–based antiretroviral regimens typically require a CNI dose reduction (to once daily or as infrequently as once a week with tacrolimus-based regimens). With the use of less-than-daily dosing, we speculate that the overall exposure to adequate CNI drug levels may be suboptimal despite an appropriate trough level. Additionally, it is possible that other viral copathogens or the antiretroviral regimen itself may influence the likelihood of rejection. We wholeheartedly concur with the authors' conclusions that patients with HCV/HIV infections should continue to be offered liver transplantation. HCV ranks as the number 1 indication for liver transplantation among HIV-infected persons in North America and Europe, and as persons with HIV live longer, decompensated cirrhosis and hepatocellular carcinoma will continue to rank high among the causes of morbidity and mortality in those coinfected with HCV. Although we hope that future HCV therapies will offer cures for infection and reduce the rates of cirrhosis in more patients in the years ahead, liver transplantation will remain an important lifesaving treatment option in the interim. Norah Terrault M.D., M.P.H.*, Burc Barin M.S. , Peter Stock M.D., Ph.D.*, * University of California San Francisco San Francisco, CA, EMMES Corporation Rockville, MD.

Clinical outcomes in the use of mycophenolate mofeil in liver transplant patients with chronic renal dysfunction

Objective To evaluate the effect of mycophenolate mofeil (MMF) combined with dose-decreased calcineurin inhibitors (CNIs) in patients who received liver transplanation with chronic kidney malfunction.Methods 28 liver transplant patients with chronic kidney malfunction were prospectively included in this study.MMF was initiated and the dose of the original immunosuppressive drug CNIs decreased.The change in renal function and adverse events were evaluated.Results One patient was discontinued with MMF treatment because of serious myelosuppression.The other 27 patients were treated with MMF with a median of 30.8 months.The basal creatinine values and the basal creatinine clearance were ( 134.26 ± 27.25) μmol/1 and (57.70 ± 16.93) ml/min,respectively.The basal glomerular filtration rate was (53.91±11.63) ml/min.The creatinine values at 1,3,6,12,24 and 36 months were 124.30±28.27 (P=0.006),130.19±29.29 (P=0.174),125.49±38.18 (P=0.194),119.71±31.36 (P=0.010),137.43±42.55 (P＝0.804),and (139.04±39.80) μmol/L (P=0.916).And the creatinine clearance values at 1,3,6,12,24 and 36 months were 62.57±19.29 (P=0.008),61.18± 19.70 (P=0.086),64.27±22.82 (P=0.018),67.48±22.59 (P=0.002),57.18±19.55 (P=0.405),and (54.56±23.48) ml/minute (P=0.708),respectively.The glomerular filtration rate at 1,3,6,12,24 and 36 months were 59.20 ± 14.05 (P=0.006),56.61±14.01 (P=0.04),60.47±17.33 (P=0.016),63.59±17.66 (P=0.002),53.75±13.60 (P=0.369),and (51.70±16.07) ml/min (P＝0.703).One patient (3.7％) had mild acute rejection.5 patients (18.5 ％ ) had mild abdominal distention or diarrhea.2 patients (7.4％) had ischemic cholangitis.No patient had cytomegalo virus infection or tumor recurrence.Conclusion In liver transplant recipients with chronic renal dysfunction,MMF allowed CNIs dose reduction or discontinuation,improved or stabilized renal function in most patients and it had only mild adverse events. Key words: Mycophenolate mofeil; Chronic renal dysfunction; Liver transplant; Cyclosporine; Tacrolimus

Everolimus for Cardiac Allograft Vasculopathy—Every Patient, at any Time?

In this issue, Arora et al. (1) attempt to address the question of whether the addition of everolimus to a calcineurin-based immunosuppression regimen can attenuate the progression of cardiac allograft vasculopathy (CAV) years after heart transplantation. Currently, CAV remains one of the most important factors limiting long-term survival in heart transplant patients. Despite significant advances in immunosuppression and posttransplant care resulting in a progressive decline in allograft rejection and improved survival, the incidence of CAV has changed little, with 30% of patients developing the disease within 5 years of transplantation. A major advance in the management of CAV came with the availability of proliferation signal inhibitors (PSIs), sirolimus and everolimus. These agents are a class of antiproliferative agents shown to inhibit smooth muscle cell proliferation, a key component in the development of CAV. In a study by Keogh et al. (2), the use of sirolimus in 136 de novo heart transplant patients was associated with decreased development of CAV at 2 years compared with patients receiving azathioprine. In a subsequent sentinel multicenter study by Eisen et al. (3), more than 600 patients were randomized to everolimus or azathioprine (both in combination with cyclosporine) within 72 hr of transplantation. Intravascular ultrasonography (IVUS) showed that the average increase in maximal intimal thickness at 12 months was significantly smaller with everolimus compared with azathioprine. This finding was important as it has been demonstrated that a significant increase in maximal intimal thickness at 1 year is associated with higher posttransplant mortality at 5 years (4). Although the benefit of early use of PSIs in heart transplantation seems established, it is unclear whether they provide any benefit to prevent or slow the progression of CAV when initiated later after heart transplantation. In a small study by Mancini et al. (5), 46 patients with severe CAV at a mean 4.3 years after transplantation were randomly assigned to sirolimus or continued on maintenance therapy with mycophenolate mofetil (MMF) or azathioprine (all groups with continued cyclosporine therapy). Patients treated with sirolimus demonstrated slowed angiographic disease progression and improved clinical outcomes. However, to date, no randomized study using IVUS has assessed late immunosuppression change to slow the development of CAV. In this study, to address the aforementioned point, Arora et al. randomized 111 patients on calcineurin inhibitor (CNI) and azathioprine or MMF who were more than 5 years from transplant to the addition of everolimus with reduced-dose CNI or continuing CNI with azathioprine or MMF. All study patients underwent IVUS at study entry and 12 months later. This study represented a subpopulation of the Nordic Certican Trial in Heart and Lung Transplantation randomized trial, a study investigating the efficacy of everolimus with reduced-dose CNI in reducing renal dysfunction in heart and lung transplant recipients. The authors found that the addition of everolimus and reduced CNI at a mean 5.8 years after transplant did not influence CAV progression by IVUS. However, in the subgroup of patients receiving everolimus, reduced-dose CNI, and concomitant azathioprine therapy, CAV progression and a number of inflammatory markers implicated in CAV were attenuated compared with the control CNI group. To the contrary, the subgroup of patients receiving everolimus, reduced-dose CNI, and MMF was associated with accelerated CAV and a parallel increase in inflammatory markers. Although these results are of great interest, the applicability of these findings to the contemporary management of heart transplant recipients remains in question. Unique to this study, the design of the protocol allowed addition of everolimus to preexisting therapy with MMF or azathioprine both in combination with cyclosporine. In clinical practice, most clinicians switch antiproliferative medications as opposed to adding them. The discordant effects of everolimus and azathioprine to everolimus and MMF (both with continued cyclosporine therapy) raise the question of a yet unidentified adverse drug interaction in which MMF may abrogate the effects of everolimus. The findings are certainly hypothesis generating and merit further investigation. The study also includes predominantly cyclosporine-treated patients. In the current era, most heart transplant programs use tacrolimus-based immunosuppression. The three-arm study (6) suggested that patients on tacrolimus with sirolimus and tacrolimus with MMF benefited from lower rates of rejection when compared with cyclosporine with MMF with respect to lower rates of rejection. Although this study raises some important questions, the results should be kept in perspective. The evidence to date suggests benefit for the use of PSI for prevention of CAV when used early after heart transplantation. Confirmation of the results of this study would require adequately powered studies to evaluate the use of combination antiproliferative agents and CNI, with appropriate predefined endpoints, and mechanistic studies to elucidate potential drug interaction.

Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients

Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy. Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent. One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m(2) vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr. conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI.

Conversion to Combined Mycophenolate Mofetil and Low-Dose Calcineurin Inhibitor Therapy for Renal Dysfunction in Liver Transplant Patients: Never Too Late?

A progressively increasing life expectancy after liver transplantation (LT) leads to previously underestimated long-term complications, in particular renal damage as well as metabolic and cardiovascular disease [1]. Although the etiology of kidney damage in LT patients may be multifactorial, calcineurin-inhibitor (CNI)-induced nephrotoxicity significantly contributes to the development of renal dysfunction after LT [2]. CNIs may cause acute and chronic nephrotoxicity, with the latter usually being associated with structural changes in the kidney [3]. Acute nephrotoxicity comprises vascular effects such as vasoconstriction of the afferent arterioles, an increased secretion of vasoconstrictor factors including endothelin and thromboxane, activation of the renin-angiotensin system (RAS), and reduction of vasodilatation factors such as nitric oxide, prostacyclin and prostaglandin E2. Acute CNI-induced nephrotoxicity may further lead to tubular damage and/or dysfunction and thrombotic microangiopathy. Chronic CNI-related nephrotoxicity including arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, and glomerular sclerosis is observed in most LT recipients with long-term CNI therapy [2]. Chronic CNI-related renal damage is thought to be a consequence of both CNI-induced hemodynamic changes and direct toxic effects on renal tubular epithelium. Despite the fact that chronic CNI-related nephrotoxicity is associated with parenchymal damage, various clinical studies have shown that CNI dose reduction or discontinuation results in an improvement of renal function in the majority of LT patients, thus suggesting a partly dose-dependent nephrotoxic effect and reversible functional kidney impairment [4]. In addition, CNI reduction or withdrawal is also associated with decreased cardiovascular risk in LT patients [5].

Sustained Renal Response to Mycophenolate Mofetil and CNI Taper Promotes Survival in Liver Transplant Patients with CNI-Related Renal Dysfunction

The aim of this trial was to evaluate the impact of conversion from a calcineurin-inhibitor (CNI)-based immunosuppressive regimen to mycophenolate mofetil (MMF) and reduced-dose CNI on long-term renal function and survival in a series of 63 liver transplant patients with CNI-induced renal dysfunction. CNI dosage was significantly tapered after introduction of 2,000 mg MMF per day. Renal function was assessed by determination of serum creatinine levels and calculated creatinine clearance (CCl). The impact of relevant clinical parameters on renal function and survival post-conversion was analyzed by univariate and multivariate analysis. At 60 months post-conversion, mean creatinine level had significantly declined from 197.2±58.3 μmol/l at baseline to 160.0±76.5 μmol/l, and mean CCl has significantly increased from 38.4±13.4 ml/min at baseline to 47.9±21.1 ml/min (p<0.001), respectively. Forty-six patients (73.1%) demonstrated sustained renal response to modified immunosuppression. Full-dose MMF medication (p=0.006) and the early conversion (p=0.02) were identified as independent predictors of persistent renal function improvement. Sustained renal response to MMF plus reduced-dose CNI was identified as the most relevant independent promoter of long-term survival (hazard ratio 6.9). Five-year survival rate post-conversion was 93.9% in renal responders and 64.3% in renal non-responders (log rank<0.001). Sustained renal response to MMF and CNI dose reduction promotes long-term survival in liver transplant patients with CNI-induced renal dysfunction.