Protecting kidney function after heart transplantation is a clinical priority but remains challenging. Almost half of all heart transplant recipients have moderate renal impairment at the time of transplant,1,2 and in addition to hemodynamic compromise, there is a high prevalence of other risk factors for renal deterioration including metabolic syndrome,3 hypertension,4 and diabetes.4 More than 10% of patients develop end-stage renal disease by year 5,5 incurring a profound increase in mortality risk.5,6
Calcineurin inhibitor (CNI) immunosuppression has been widely believed to increase the risk for chronic kidney disease (CKD) after heart transplantation,2,7 spawning investigation into various immunosuppressive strategies that minimize CNI exposure.8 The extent to which CNI-related nephrotoxicity contributes to long-term loss of renal function, however, has become a matter for discussion9 and is difficult to confirm since most of its hallmark pathological signs are nonspecific.9 Graft biopsies from kidney transplant patients treated with modern CNI-based regimens have shown mixed results regarding long-term histological injuries, with some researchers noting frequent arterial hyalinosis and glomerulosclerosis10 characteristic of CNI-induced lesions,9 while others have predominantly found interstitial fibrosis and tubular atrophy.11 In heart transplantation, CKD has a complex and varied pathologic basis.12 Given this uncertainty, it would be helpful to understand if the early renal benefits seen after CNI withdrawal after heart transplantation are maintained long-term and to examine whether such benefits are obtained at the expense of increased risk of adverse effects such as rejection or graft dysfunction.
In the Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial, patients were randomized to receive the mammalian target of rapamycin (mTOR) inhibitor everolimus with reduced CNI (cyclosporine [CsA]) at week 7–11 posttransplant, at which point CNI therapy was withdrawn. Controls received standard CNI (CsA) therapy. Patients in the everolimus group had significantly higher glomerular filtration rate (GFR) than the control group at the end of the 1-year study, although mild-to-moderate acute rejection was more frequent.13 The renal advantage seen in the everolimus-treated patients was sustained at 3 years follow-up.14 In addition, coronary allograft vasculopathy (CAV) was less frequent in the everolimus-treated cohort.13,14
We describe here the results of a follow-up visit of the SCHEDULE study population at 5−7 years posttransplant. The objective was to examine the long-term effect on renal and heart function, and the occurrence of common major clinical complications of early everolimus initiation with CNI discontinuation compared to a standard CNI-based regimen.
MATERIALS AND METHODS
SCHEDULE was a 12-month, prospective, multicenter, randomized, controlled, parallel-group, open-label trial in de novo adult heart transplant recipients (NCT01266148).14,15 It was undertaken at 5 transplant centers in Norway, Sweden, and Denmark. Follow-up visits were undertaken at year 3 and 5−7 years posttransplant (Figure S1, SDC, http://links.lww.com/TP/B719). The first patient visit of the SCHEDULE study took place in December 2009. The 5−7-year follow-up visit took place in October 2017. The study was conducted in compliance with Good Clinical Practice and in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. The study was approved by the local ethics committees in the participating countries.
Patients were de novo heart transplant recipients aged 18–70 years who had received induction therapy with rabbit antithymocyte globulin (rATG, Thymoglobulin, Genzyme, Genzyme Corporation, Cambridge, MA). Key exclusion criteria were multiorgan transplantation, previous transplantation, donor age >70 years, cold ischemic time >6 hours, severe systemic infection, ABO-incompatible transplantation, severe hypercholesterolemia or hypertriglyceridemia, any past (<5 y) or present malignancy (other than excised basal cell carcinoma), and HIV, hepatitis B, or hepatitis C infection.
At the start of period 2 of the study (wk 7–11 posttransplant), patients were excluded if they had not remained on their randomized immunosuppression regimen, had lost their graft, were receiving ongoing treatment for rejection, had experienced 1 grade 3R rejection, 2 or more grade 2R rejections, or antibody-mediated rejection with hemodynamic compromise, had hemoglobin <8 g/dL (5.0 mmol/L), platelet count <50 × 109/L and white blood cell count <2.5 × 109/L, total cholesterol >9.0 mmol/L or triglycerides >6.0 mmol/L, a spot urinary protein/creatinine or albumin/creatinine ratio ≥300 mg/mmol, were experiencing ongoing wound healing problems or other severe surgical complications, or had clinically severe systemic infection.
Patients who completed the 3-year follow-up visit and attended a routine clinical visit at 5−7 years posttransplant were eligible for the current analysis unless they had undergone retransplantation since completing the core study.
Randomization and Study Treatment
Randomization was performed centrally using a validated, automated system within 5 days of transplantation, with patients stratified according to preoperative measured glomerular filtration rate (mGFR: ≤60 mL/min/1.73 m2 or >60 mL/min/1.73 m2) and preoperative treatment with a left ventricular assist device (yes/no).
Patients were randomized (1:1 ratio) into 1 of the 2 groups: (1) the everolimus group, in which patients received everolimus (Certican, Novartis Pharma AG, Basel, Switzerland), low-exposure CsA (Neoral, Novartis Pharma AG, Basel, Switzerland), mycophenolate mofetil (MMF), and corticosteroids with CsA withdrawal after 7 weeks or (2) the CNI group, in which patients received CsA, MMF, and corticosteroids. In the everolimus group, the everolimus target trough level was 3–6 ng/mL during the first 7 weeks posttransplant and 6–10 ng/mL after CsA withdrawal. CsA withdrawal was to take place at week 7 unless there was ongoing rejection at that time, in which case discontinuation could be postponed up to week 11. In the CNI group, CsA and MMF were continued. The target dose of MMF after week 7–11 was 1000−2000 mg/d in the everolimus group and 2000–3000 mg/d in the CNI group.
If a patient in the everolimus group experienced an acute rejection episode graded 3R, 2 or more episodes graded 2R, or had unacceptable side effects after the everolimus dose was adjusted following cyclosporine discontinuation, he or she could return to the previous regimen of everolimus with low-exposure cyclosporine.
After completion of the core 12-month study, immunosuppression was according to the investigator’s preference.
Patients who were negative for cytomegalovirus (CMV) and received a graft from a CMV-positive donor were given prophylaxis with oral valganciclovir for at least 3 months posttransplant, according to the local protocol.
Year 5−7 Follow-up Assessment
The 5−7 year assessment took place during a routine clinic visit at 5, 6, or 7 years posttransplant. Assessments comprised GFR measured by Cr-EDTA or iohexol clearance, estimated GFR (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) formula,15 occurrence of biopsy-proven acute rejection (BPAR) and treated BPAR, echocardiography, coronary intravascular ultrasound (IVUS), vital signs, laboratory data, current immunosuppression, trough concentrations of everolimus and CsA, concomitant medication, and occurrence of (serious) adverse events between the year 3 visit and the 5−7-year visit. Biopsies were not protocol-specified at the 5−7-year assessment.
Details for the echocardiography and IVUS procedures have been described previously.13,14 CAV was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording.
Endpoints at the Year 5−7 Visit
The primary endpoint was renal function as assessed by mGFR. Secondary endpoints were the presence of CAV (defined as mean MIT ≥0.5 mm) by IVUS analysis, myocardial structure and function according to echocardiography assessment, and the number of adverse events or serious adverse events.
Post hoc, the incidence of major clinical events between weeks 7 and 11 at the 5−7-year visit was analyzed. These were defined as nonfatal major cardiovascular events (ie, acute myocardial infarction, atrial fibrillation, ventricular tachycardia or fibrillation, requirement for pacemaker, left or right ventricular heart failure, cardiac tamponade, stroke, or new-onset peripheral vascular disease) and other major clinical events (malignancy, multiorgan failure, sepsis, renal failure, retransplantation, or death). Events were identified by a blinded independent cardiologist examining adverse event listings.
All analyses were exploratory. The primary endpoint, mGFR at the 5−7-year visit, was assessed using an analysis of covariance. Treatment and randomization strata were included as factors, and the pretransplant mGFR value was included as covariate. Results are shown as least square (LS) means with 95% confidence intervals (CIs) and a 2-sided Pvalue. Where the mGFR was missing, values were substituted with eGFR values (MDRD formula) (this applied to 2 everolimus-treated patients at wk 7 and mo 12 and to 1 CNI-treated patient at y 3). The incidence of CAV at 5–7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification, according to baseline distribution of CAV incidence.
The incidence of major clinical events was compared between groups using the Chi-squared test. Event rates (ie, including recurrent events) were analyzed using a log-link negative binomial regression model with event count specified as the dependent variable and treatment entered as a fixed factor.
The intention-to-treat (ITT) population comprised patients from the ITT population at the year 3 follow-up visit who provided mGFR (or eGFR) data at the 5−7-year follow-up visit. The per protocol (PP) population comprised patients from the PP population at the year 3 follow-up visit who provided mGFR (or eGFR) data, and remained on their randomized treatment with no major protocol violations, at the 5−7-year follow-up visit. The safety population comprised patients from the safety population at the year 3 follow-up visit who were assessed at the 5−7-year follow-up visit.
One hundred-fifteen patients were randomized in the core study, of whom 110 completed the 1-year study (54 everolimus, 56 CNI). In total, 95 patients (48 everolimus, 47 CNI), representing 89% of those who were still alive, attended the follow-up visit at 5–7 years posttransplant and were included in the safety population (Figure 1). The median follow-up time from the time of randomization was 74 (25%–75%: 71–78) months. Follow-up was conducted before 5 years in 1 patient, between 5 and 6 years in 24, between 6 and 7 years in 52, and after 7 years in 18 patients. There was no significant difference in follow-up time between the everolimus and CNI groups (75 versus 73 months, respectively, P = 0.17). Two patients randomized to everolimus did not provide month 12 mGFR value and were excluded from the ITT population, which thus comprised 93 patients (46 everolimus, 47 CNI). The PP population (27 everolimus, 35 CNI) excluded 7 patients in the everolimus group and 11 patients in the CNI group who discontinued study drug prematurely (Figure 1).
In the ITT population, 39/46 patients (84.8%) in the everolimus group were still receiving everolimus at the 5−7-year visit. Eighteen patients randomized to the everolimus group (18/46, 39.1%) were receiving CNI therapy (11 CsA, 7 tacrolimus) (Table 1); 12 of these patients were also still receiving everolimus. In the CNI arm, 33 patients were still receiving CsA at the 5−7-year visit, and 9 were receiving tacrolimus, such that 42/47 (89.4%) were on CNI therapy. The remaining 5 patients were converted to everolimus without CNI. Further 8 patients in the CNI group started everolimus but continued to receive CNI therapy. CNI was withdrawn in 8 patients (5 because of reduced renal function, 3 not reported) between years 3 and 7, and everolimus was withdrawn in 4 patients (1 because of death, 3 not reported) in the same period. Blood concentrations of everolimus, CsA, and tacrolimus are shown in Table 1. The mean CsA concentration for patients in the CNI group who did not start everolimus therapy was relatively low, at 88 ng/mL.
The majority of patients were still receiving mycophenolic acid (44/46 everolimus, 42/47 CNI), while 52.2% and 57.4% of patients in the everolimus and CNI groups were receiving steroids, respectively (Table 1).
Observed mean (standard deviation, SD) mGFR at the 5−7-year visit was 74.7 (23.3) mL/min in the everolimus group versus 62.4 (16.5) mL/min in the CNI group. The between-group difference was 11.8 mL/min in favor of the everolimus group versus the CNI group (P = 0.004) (LS means, analysis of covariance) (Figure 2). A greater between-group difference was observed in the PP population, in which the difference was 17.2 mL/min (P < 0.001; Figure 2).
The main difference in renal function between the patients randomized to everolimus and CNI was obtained in the early phase after transplantation. From pretransplantation to 7–11 weeks after transplantation, mGFR increased by 3.0 (17.0) mL/min in the everolimus group but decreased by 7.4 (20.2) mL/min in the CNI group (P = 0.012). In contrast, there was no significant difference in change in mGFR from 7–11 weeks to 5–7 years (P = 0.4) in the 2 groups (P = 0.99).
Values for eGFR also showed a substantial and significant improvement for the everolimus group versus the CNI arm at the 5–7-year visit (Table 2). The urine albumin/creatinine ratio was comparable between the groups (Table 2). At 5–7 years, 58% and 53% of the patients in the everolimus and the CNI groups were treated with an ACE-inhibitor or an angiotensin receptor blocker, respectively.
From the time of transplantation to the 5–7-year follow-up visit, BPAR (ISHLT grade 1R−3R) occurred in 77% (37/48) of patients in the everolimus group and 66% (31/47) of patients in the CNI group (P = 0.23), with treated BPAR in 50% and 23%, respectively (P < 0.01; Table 3). Based on clinically indicated biopsies, there were no BPAR episodes in the everolimus group between the year 3 visit and the 5−7-year visit. In the CNI group, 1 patient experienced 2 episodes of 1R, and a second patient experienced 3 episodes of BPAR (one 1R, one 2R, and one 3R).
IVUS data were available at week 7–11 posttransplant and at the follow-up visit in 71 patients (everolimus 36, CNI 35). There was no significant difference in the time from the baseline to the 5–7-year follow-up IVUS in the everolimus and the CNI group (73 versus 69 months, respectively, P = 0.08). The mean (SD) increase in MIT was 0.13 (0.15) mm in the everolimus group compared to 0.23 (0.24) mm in the CNI group (P = 0.038). CAV, defined as mean MIT ≥0.5 mm, was detected in 19/36 (53%) patients in the everolimus group and 26/35 (74%) patients in the CNI group (P = 0.037).
Echocardiography indicated no relevant difference in left ventricular end diastolic dimension, left ventricular ejection fraction, or left ventricular end systolic dimension between the everolimus and CNI groups at the 5–7-year visit (Table 4). ECG recordings showed the mean (SD) PQ interval to be 164 (34) ms in the everolimus group and 151 (38) ms in the CNI group; mean QRS interval was 113 (26) ms and 110 (28) ms, respectively. The mean heart rate was 86 beats/min and 84 beats/min in the everolimus and CNI groups, respectively. Mean systolic blood pressure at follow-up was 132 mm Hg versus 132 in the CNI group. The mean diastolic blood pressure was similar (80 mm Hg). At follow-up, 14 and 20 patients were treated with calcium channel blockers, 15 and 17 with beta blockers, and 28 and 25 with ACE-inhibitors/angiotensin receptor blockers, respectively.
Cardiovascular medication use was comparable between treatment arms. Statins were prescribed for 92% and 91% of patients in the everolimus and CNI groups, respectively.
Safety and Laboratory Assessments
The incidence of adverse events (P = 0.752) and serious adverse events (P = 0.917) between the year 3 visit and the 5–7-year visit were similar between treatment groups (Table 5). The most frequent adverse events were pneumonia (18.8% in the everolimus group, 21.3% in the CNI group), diarrhea (10.4% and 17.0%), and peripheral edema (8.3% and 8.5%). Rates of infection were also similar between groups (29.2% and 31.9%); there were no new cases of CMV infection.
During the period from year 3 to the 5–7-year visit, there were 2 deaths in the everolimus group (1 due to graft failure and 1 due to gastrointestinal bleeding) and 2 deaths in the CNI cohort (1 due to sudden death and 1 due to cerebral bleeding). In total, from the time of transplant there were 5 deaths in the everolimus group and 9 in the CNI groups; causes of all deaths are shown in Table S1 (SDC, http://links.lww.com/TP/B719). Additionally, there was 1 retransplantation in the CNI group.
Mean values for total cholesterol (5.1 versus 4.8 mmol/L), LDL-cholesterol (2.8 versus 2.6 mmol/L), and triglycerides (2.2 versus 2.0 mmol/L) were all higher in the everolimus group versus the CNI group. Laboratory data at the 5–7-year visit are summarized in Table S2 (SDC, http://links.lww.com/TP/B719).
Major Adverse Clinical Events
Nonfatal major cardiovascular events occurred in 9 and 13 patients in the everolimus and CNI groups, respectively (P = 0.64; Table 6). Other major clinical events occurred in 14 everolimus-treated patients and 26 CNI-treated patients, respectively; the between-group difference was largely accounted for by more frequent cases of non-melanoma skin cancer, renal failure, and death in the CNI group (Table 6). The total number of cardiovascular and other major clinical events was 23 in the everolimus group compared to 39 in the CNI group (P = 0.11). One patient received a renal transplant and 2 received temporary dialysis (all CNI group).
These long-term results from the randomized SCHEDULE trial show that de novo heart transplant patients receiving everolimus with low-exposure CNI followed by CNI-free therapy after 7−11 weeks maintain significantly better renal function than patients given standard CNI-based immunosuppression. The everolimus-treated patients also had a significantly lower incidence of CAV at the 5−7 years visit. The higher incidence of BPAR under everolimus during the first year after transplantation did not translate to impaired long-term graft function, and no graft in either group was lost to rejection. There were numerically fewer major clinical events during long-term follow-up in the everolimus cohort versus the CNI arm.
In the everolimus group, mean mGFR increased by 12.7 mL/min from pretransplant levels to the 5−7-year follow-up visit. Mean mGFR in the CNI group was virtually unchanged from baseline to the follow-up visit; absence of the expected decline may have been due to relatively low CNI exposure levels, for example, the mean CsA concentration was 88 ng/mL in patients who did not start everolimus. At last follow-up, mean mGFR was 12 mL/min higher in the everolimus cohort. This difference was somewhat smaller than at years 1 and 3 (~17 mL/min at both time points), likely in part related to the reintroduction of CNI therapy in 39% of everolimus-treated patients by 5−7 years. In the subgroup of patients who restarted low-exposure CNI with everolimus, the renal benefit was approximately half that seen in those who remained CNI-free. In most cases, this switch back to low-exposure CNI occurred during year 1 due to adverse events or repeated rejection episodes.7 However, even if CNI-free treatment is not maintained long-term, initial therapy with everolimus and low-exposure CNI is advantageous (mean mGFR was 10 mL/min higher at wk 7−11 with this regimen versus controls), and those who restarted CNI still had higher mGFR than the control group at last follow-up. Of note, the between-group difference in mGFR also diminished over time in the PP population, from 24 mL/min at year 1 to 17 mL/min at last follow-up, likely reflecting the impact of other risk factors for progressive renal decline that applied equally to all patients. When the difference in mGFR was analyzed separately for the early and later phases after transplantation, it was clear that the majority of improvement with an everolimus-based regimen is obtained early after transplantation due to the low CNI levels used during the first week, but this improvement is maintained over time by the CNI-free regimen.
The low rate of BPAR after the year 3 visit was as expected in this population of maintenance patients. BPAR was significantly more frequent in the everolimus group during year 1 and numerically more frequent during 1–3 years, but it did not cause hemodynamic compromise in any case. Echocardiography at the 5–7-year follow-up visit confirmed that there was no effect on long-term graft function versus the control arm. CNI therapy was discontinued abruptly, as is routine in trials of early conversion to everolimus in kidney transplant patients,16,17 but gradual CNI elimination over 8 weeks in de novo liver transplant patients did not incur any increase in BPAR,18 and such an approach may merit exploration in heart transplantation.
The left ventricular ejection fraction was slightly reduced at 5–7 years in both groups. Whether a potential protective effect on cardiac structure of function associated with everolimus treatment was offset by the larger number of rejection episodes cannot be determined from the current study but might be detectable after longer term follow-up.
Everolimus restricts the proliferation of fibroblasts and smooth muscle cells,19 as well as reducing rates of CMV infection,13,20,21 a known risk factor for CAV.22 In previous randomized trials, furthermore, everolimus has been shown to lower the incidence of CAV.23,24 It has been suggested that the effect of everolimus applies largely to early CAV (ie, during y 1)25 and that it does not influence CAV progression in maintenance patients.26,27 If so, everolimus may exert different effects on the remodeling process within coronary vessels during early and late CAV.28,29 Early intimal hyperplasia appears to be closely associated with immune-mediated injury, while late intimal proliferation may be primarily caused by nonimmune influences, notably metabolic risk factors,25,28,30 as indicated by the growing prevalence of atheromatous components in CAV plaques over time.31,32 Compatible with this hypothesis, the incidence of CAV in our population was significantly lower under everolimus versus CNI therapy over long-term follow-up. The mean increase in MIT at 1-year posttransplant, which is associated with subsequent progression of CAV and poor long-term prognosis,30,33 and the mean increase to the follow-up visit at 5−7 years were also significantly smaller in the everolimus-treated cohort. Rates of late adverse events and serious adverse events were comparable between treatment groups, with little difference in the incidence of those associated with mTOR inhibition, such as pneumonia and peripheral edema. Numerically more basal cell carcinomas and skin cancers were reported in the CNI group. It has been suggested that everolimus therapy may lower the risk for skin cancers and nonskin cancers after kidney34,35 and heart transplantation,36,37 but absolute numbers in the current cohort are too small to draw any conclusions. Here, there were numerical trends in favor of everolimus regarding major cardiovascular events and other major clinical events such as malignancy in a post hoc analysis. This observation, while not a prespecified endpoint and nonsignificant, is compatible with the improved preservation of renal function under everolimus and with published evidence that everolimus-based therapy is associated with fewer malignancies after heart transplantation36,37 and fewer MACE in kidney transplant patients.12 A similar approach to grouping major clinical events has been employed elsewhere in heart transplantation.38 In the current study, a significant difference in mortality between the groups was not seen, but the trial was not powered to study mortality. In kidney transplantation, observational data have suggested an excess mortality in patients managed with an mTOR inhibitor as their primary immunosuppressant compared with CNI,39 but a recent meta-analysis of data from long-term trials comparing mTOR inhibitors and CNI did not demonstrate any difference in survival (HR = 1.00).40 Clearly, further studies of the effect of mTOR-based, CNI-free regimens on survival after heart transplantation are needed.
This long-term analysis had a high rate of follow-up (83% of randomized patients), with the majority of drop-outs due to death. The proportion of patients providing follow-up data was similar in both treatment arms, reducing the risk for bias. Inevitably over a period of up to 7 years, there were switches in the immunosuppressive regimen, but 85% and 89% of patients were still receiving everolimus and CNI therapy, respectively. The study had the important advantage of measuring GFR directly. The correlation between mGFR and eGFR calculated using the MDRD, Cockcroft-Gault, or Chronic Kidney Disease Epidemiology Collaboration formulae is relatively poor in heart transplant recipients, with all formulae tending to overestimate renal function.41 Here, the eGFR values calculated using the MDRD equation suggested that mean eGFR was 18.4 mL/min/1.73 m2 higher in the everolimus group versus controls, compared to the actual value of 11.8 mL/min. While less convenient, the effort required to measure GFR directly in the research setting is justified.
In terms of the study population, patients with urinary protein/creatinine or albumin/creatinine ratio ≥300 mg/mmol were not randomized in the study. Poor pretransplant or early posttransplant renal function is a leading risk factor for CKD,1,4,42 so the results cannot necessarily be extrapolated to patients with significantly impaired renal dysfunction at baseline. These exclusion criteria may also explain why no patient progressed to severe CKD during follow-up. In the current study, we measured through levels of cyclosporine. As these correlate poorly to AUC for cyclosporine (ie, compared with C2 values), we cannot exclude that improved renal outcomes in the CNI group would have been obtained had we relied on C2 values in the CNI group.43
Information about panel reactive or HLA antibodies prior transplantation were neither available nor was systematic information about development of donor-specific antibodies posttransplant. The study excluded patients at high risk for rejection, and the everolimus-based regimen has not been assessed in these higher-risk individuals. Given the increased rate of BPAR during year 1—even with rATG induction and concomitant MMF and steroid therapy—it seems unlikely that this protocol should be attempted in patients at higher immunological risk.
In conclusion, the significant improvement in renal function seen early after heart transplantation in patients given everolimus with low-exposure CNI followed by CNI-free therapy versus patients given standard CNI therapy was maintained long-term. Patients who continued CNI-free therapy (ie, the PP population) experienced the greatest renal advantage. The incidence of CAV progression was significantly lower in the everolimus-treated cohort at the 5−7-year visit, and the increased rate of BPAR during the first year in the everolimus arm did not translate into any difference between groups regarding ventricular function. This protocol is an appropriate option for heart transplant patients at low or moderate immunological risk, particularly if considered likely to show at risk for deteriorating renal function after transplantation.
The authors are grateful to the SCHEDULE investigators, coinvestigators, and study nurses: Copenhagen, Lene Larsen; Göteborg, Villborg Sigurdardottir, Nedim Selimovic, Entela Bollano, Sven-Erik Bartfay, Smita Dutta Roy, Helena Rexius, Annie Janssen, Marita Rosenberg; Aarhus, Else Marie Tram, Dorte Mølgård, Lene Konrad, Bente Mortensen; Lund, Liselotte Persson, Mette Koch, Björn Kornhall, Björn Ekmehag, Öyvind Reitan; Oslo, Wenche Stueflotten, Elisabeth Bjørkelund, Anne Relbo, Ingelin Grov, Ingrid Erikstad, Ole Geir Solberg, Asgrimur Ragnarsson, Svend Aakhus, and Richard Massey. The authors thank the independent clinician Professor Emeritus John Kjekshus who oversaw the study, and Marie Sandgren who undertook the statistical analysis of data.
1. Jokinen JJ, Tikkanen J, Kukkonen S, et al. Natural course and risk factors for impaired renal function during the first year after heart transplantation. J Heart Lung Transplant. 2010; 29:633–640
2. Kolsrud O, Karason K, Holmberg E, et al. Renal function and outcome after heart transplantation. J Thorac Cardiovasc Surg. 2018; 155:1593–1604.e1
3. Martínez-Dolz L, Sánchez-Lázaro IJ, Almenar-Bonet L, et al. Metabolic syndrome in heart transplantation: impact on survival and renal function. Transpl Int. 2013; 26:910–918
4. Lachance K, White M, de Denus S. Risk factors for chronic renal insufficiency following cardiac transplantation. Ann Transplant. 2015; 20:576–587
5. Lund LH, Edwards LB, Kucheryavaya AY, et al; International Society of Heart and Lung Transplantation. The registry of the international society for heart and lung transplantation: thirty-first official adult heart transplant report–2014; focus theme: retransplantation. J Heart Lung Transplant. 2014; 33:996–1008
6. Janus N, Launay-Vacher V, Sebbag L, et al. Renal insufficiency, mortality, and drug management in heart transplant. Results of the CARIN study. Transpl Int. 2014; 27:931–938
7. González-Vílchez F, Vázquez de Prada JA. Chronic renal insufficiency in heart transplant recipients: risk factors and management options. Drugs. 2014; 74:1481–1494
8. Reichart D, Reichenspurner H, Barten MJ. Renal protection strategies after heart transplantation. Clin Transplant. 2018; 32:e13157
9. Chapman JR. Chronic calcineurin inhibitor nephrotoxicity-lest we forget. Am J Transplant. 2011; 11:693–697
10. Stegall MD, Cornell LD, Park WD, et al. Renal allograft histology at 10 years after transplantation in the tacrolimus era: evidence of pervasive chronic injury. Am J Transplant. 2018; 18:180–188
11. Chow KV, Flint SM, Shen A, et al. Histological and extended clinical outcomes after ABO-incompatible renal transplantation without splenectomy or rituximab. Transplantation. 2017; 101:1433–1440
12. Pinney SP, Balakrishnan R, Dikman S, et al. Histopathology of renal failure after heart transplantation: a diverse spectrum. J Heart Lung Transplant. 2012; 31:233–237
13. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014; 14:1828–1838
14. Andreassen AK, Andersson B, Gustafsson F, et al; SCHEDULE Investigators. Everolimus initiation with early calcineurin inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study. Am J Transplant. 2016; 16:1238–1247
15. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med. 1999; 130:461–470
16. Mjörnstedt L, Sørensen SS, von Zur Mühlen B, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant. 2012; 12:2744–2753
17. de Fijter JW, Holdaas H, Øyen O, et al; ELEVATE Study Group. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation: results of the randomized ELEVATE trial. Am J Transplant. 2017; 17:1853–1867
18. Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation–PROTECT. Am J Transplant. 2012; 12:1855–1865
19. Neumayer HH. Introducing everolimus (certican) in organ transplantation: an overview of preclinical and early clinical developments. Transplantation. 2005; 799 SupplS72–S75
20. Hill JA, Hummel M, Starling RC, et al. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation. 2007; 84:1436–1442
21. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013; 13:1203–1216
22. Potena L, Grigioni F, Ortolani P, et al. Relevance of cytomegalovirus infection and coronary-artery remodeling in the first year after heart transplantation: a prospective three-dimensional intravascular ultrasound study. Transplantation. 2003; 75:839–843
23. Kobashigawa JA, Pauly DF, Starling RC, et al; A2310 IVUS Substudy Investigators. Cardiac allograft vasculopathy by intravascular ultrasound in heart transplant patients: substudy from the everolimus versus mycophenolate mofetil randomized, multicenter trial. JACC Heart Fail. 2013; 1:389–399
24. Viganò M, Tuzcu M, Benza R, et al; RAD B253 Study Group. Prevention of acute rejection and allograft vasculopathy by everolimus in cardiac transplants recipients: a 24-month analysis. J Heart Lung Transplant. 2007; 26:584–592
25. Masetti M, Potena L, Nardozza M, et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice. Am J Transplant. 2013; 13:1217–1226
26. Arora S, Ueland T, Wennerblom B, et al. Effect of everolimus introduction on cardiac allograft vasculopathy–results of a randomized, multicenter trial. Transplantation. 2011; 92:235–243
27. Arora S, Erikstad I, Ueland T, et al. Virtual histology assessment of cardiac allograft vasculopathy following introduction of everolimus–results of a multicenter trial. Am J Transplant. 2012; 12:2700–2709
28. Caforio AL, Tona F, Fortina AB, et al. Immune and nonimmune predictors of cardiac allograft vasculopathy onset and severity: multivariate risk factor analysis and role of immunosuppression. Am J Transplant. 2004; 4:962–970
29. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant “atheroma”. Transplantation. 2003; 76:891–899
30. Potena L, Masetti M, Sabatino M, et al. Interplay of coronary angiography and intravascular ultrasound in predicting long-term outcomes after heart transplantation. J Heart Lung Transplant. 2015; 34:1146–1153
31. Hernandez JM, de Prada JA, Burgos V, et al. Virtual histology intravascular ultrasound assessment of cardiac allograft vasculopathy from 1 to 20 years after heart transplantation. J Heart Lung Transplant. 2009; 28:156–162
32. König A, Kilian E, Sohn HY, et al. Assessment and characterization of time-related differences in plaque composition by intravascular ultrasound-derived radiofrequency analysis in heart transplant recipients. J Heart Lung Transplant. 2008; 27:302–309
33. Tuzcu EM, Kapadia SR, Sachar R, et al. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol. 2005; 45:1538–1542
34. Lim WH, Russ GR, Wong G, et al. The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine. Kidney Int. 2017; 91:954–963
35. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005; 80:883–889
36. Rivinius R, Helmschrott M, Ruhparwar A, et al. Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy. Drug Des Devel Ther. 2015; 9:93–102
37. Wang YJ, Chi NH, Chou NK, et al. Malignancy after heart transplantation under everolimus versus mycophenolate mofetil immunosuppression. Transplant Proc. 2016; 48:969–973
38. Peled Y, Lavee J, Arad M, et al. The impact of gender mismatching on early and late outcomes following heart transplantation. ESC Heart Fail. 2017; 4:31–39
39. Isakova T, Xie H, Messinger S, et al. Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation. Am J Transplant. 2013; 13:100–110
40. Wolf S, Hoffmann VS, Habicht A, et al. Effects of mTOR-is on malignancy and survival following renal transplantation: a systematic review and meta-analysis of randomized trials with a minimum follow-up of 24 months. Plos One. 2018; 13:e0194975
41. Kolsrud O, Ricksten SE, Holmberg E, et al. Measured and not estimated glomerular filtration rate should be used to assess renal function in heart transplant recipients. Nephrol Dial Transplant. 2016; 31:1182–1189
42. Rubel JR, Milford EL, McKay DB, et al. Renal insufficiency and end-stage renal disease in the heart transplant population. J Heart Lung Transplant. 2004; 23:289–300
43. Mardigyan V, Giannetti N, Cecere R, et al. Best single time points to predict the area-under-the-curve in long-term heart transplant patients taking mycophenolate mofetil in combination with cyclosporine or tacrolimus. J Heart Lung Transplant. 2005; 24:1614–1618