Björn Ekmehag

Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo.

BACKGROUND A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. METHODS The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation (ECMO) circuit with STEEN solution (Vitrolife AB, Kungsbacka, Sweden) mixed with erythrocytes. The hyperoncotic solution dehydrates edematous lung tissue. Functional evaluations were performed with deoxygenated perfusate by varying the inspired fraction of oxygen. After the reconditioning, the lungs were kept immersed at 8 degrees C in extracorporeal membrane oxygenation until transplantation was performed. RESULTS Six of nine initially rejected donor lungs were reconditioned to acceptable function, and in six recipients, double lung transplantation was performed. Three-month survival was 100%. One patient has since died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation. CONCLUSIONS The result from the present study is promising, and we continue to transplant reconditioned lungs.

Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial

Background. The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. Methods. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate ≥20 mL/min/1.73m2 and <90 mL/min/1.73 m2) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. Results. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and −0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). Conclusion. Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.

Two-Year Outcomes in Thoracic Transplant Recipients After Conversion to Everolimus With Reduced Calcineurin Inhibitor Within a Multicenter, Open-Label, Randomized Trial

Background. Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. Methods. In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. Results. Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. Conclusions. Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial.

Background. Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. Methods. In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8±4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. Results. No significant difference in CAV progression was evident between the treatment groups (P=0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n=39), CAV progression was attenuated with everolimus versus standard CNI (&Dgr;maximal intimal thickness 0.00±0.04 and 0.04±0.04 mm, &Dgr;percent atheroma volume 0.2%±3.0% and 2.6%±2.5%, and &Dgr;total atheroma volume 0.25±14.1 and 19.8±20.4 mm3, respectively [P<0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (&Dgr;maximal intimal thickness 0.06±0.12 vs. 0.02±0.06 mm and &Dgr;percent atheroma volume 4.0%±6.3% vs. 1.4%±3.1%, respectively; P<0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. Conclusions. Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.

Cardiac output and cardiac index measured with cardiovascular magnetic resonance in healthy subjects, elite athletes and patients with congestive heart failure

BackgroundCardiovascular Magnetic Resonance (CMR) enables non-invasive quantification of cardiac output (CO) and thereby cardiac index (CI, CO indexed to body surface area). The aim of this study was to establish if CI decreases with age and compare the values to CI for athletes and for patients with congestive heart failure (CHF).MethodsCI was measured in 144 healthy volunteers (39 ± 16 years, range 21–81 years, 68 females), in 60 athletes (29 ± 6 years, 30 females) and in 157 CHF patients with ejection fraction (EF) below 40% (60 ± 13 years, 33 females). CI was calculated using aortic flow by velocity-encoded CMR and is presented as mean ± SD. Flow was validated in vitro using a flow phantom and in 25 subjects with aorta and pulmonary flow measurements.ResultsThere was a slight decrease of CI with age in healthy subjects (8 ml/min/m2 per year, r2 = 0.07, p = 0.001). CI in males (3.2 ± 0.5 l/min/m2) and females (3.1 ± 0.4 l/min/m2) did not differ (p = 0.64). The mean ± SD of CI in healthy subjects in the age range of 20–29 was 3.3 ± 0.4 l/min/m2, in 30–39 years 3.3 ± 0.5 l/min/m2, in 40–49 years 3.1 ± 0.5 l/min/m2, 50–59 years 3.0 ± 0.4 l/min/m2 and >60 years 3.0 ± 0.4 l/min/m2. There was no difference in CI between athletes and age-controlled healthy subjects but HR was lower and indexed SV higher in athletes. CI in CHF patients (2.3 ± 0.6 l/min/m2) was lower compared to the healthy population (p < 0.001). There was a weak correlation between CI and EF in CHF patients (r2 = 0.07, p < 0.001) but CI did not differ between patients with NYHA-classes I-II compared to III-IV (n = 97, p = 0.16) or patients with or without hospitalization in the previous year (n = 100, p = 0.72). In vitro phantom validation showed low bias (−0.8 ± 19.8 ml/s) and in vivo validation in 25 subjects also showed low bias (0.26 ± 0.61 l/min, QP/QS 1.04 ± 0.09) between pulmonary and aortic flow.ConclusionsCI decreases in healthy subjects with age but does not differ between males and females. We found no difference in CI between athletes and healthy subjects at rest but CI was lower in patients with congestive heart failure. The presented values can be used as reference values for flow velocity mapping CMR.

Survival in patients with pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre: prognosis still poor and prediction difficult

Objectives: To describe the survival rate in a cohort of systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) and to evaluate possible predictors for SSc-PAH in a cohort of SSc patients. Methods: Thirty patients with SSc-PAH and 150 SSc patients without PAH were included. Survival and survival on therapy were calculated. Clinical features at baseline were correlated to the risk for development of PAH during follow-up. Results: The 1-, 2-, 3-, and 4-year survival rates were 86, 59, 39, and 22%, respectively, from diagnosis of PAH. The hazard ratio for total mortality in the SSc-PAH group was 3.2 [95% confidence interval (CI) 1.8–5.7] compared to SSc without PAH (p < 0.001). Risk factors at baseline for the development of PAH were: limited skin involvement, low diffusing capacity of the lung for carbon monoxide (DLCO), high N-terminal pro-brain natriuretic peptide (NTProBNP), increased estimated systolic pulmonary arterial pressure (ESPAP), and the presence of teleangiectases. Severe peripheral vascular disease requiring iloprost treatment during follow-up was associated with an eightfold increased risk of PAH. Conclusion: Despite modern treatment and yearly screening by echocardiography, the survival in SSc-PAH is still low in our cohort. The identified risk factors should be assessed to select patients eligible for right heart catheterization (RHC) to make an earlier diagnosis.

Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: The significance of baseline glomerular filtration rate

BACKGROUND The NOCTET (NOrdic Certican Trial in HEart and lung Transplantation) trial demonstrated that everolimus improves renal function in maintenance thoracic transplant (TTx) recipients. Nevertheless, introduction of everolimus is not recommended for patients with advanced renal failure. We evaluated NOCTET data to assess everolimus introduction amongst TTx recipients with advanced renal failure. METHODS This 12-month multicenter Scandinavian study randomized 282 maintenance TTx recipients to everolimus introduction with calcineurin inhibitor (CNI) reduction or standard CNI therapy. The measured glomerular filtration rate (mGFR) was noted at baseline and after 1-year using Cr-ethylenediaminetetraacetic acid clearance. RESULTS In 21 patients with a baseline mGFR of 20 to 29 ml/min/1.73 m(2), renal function improved in the everolimus group compared with the control group ((ΔmGFR 6.7 ± 9.0 vs -1.6 ± 5.1 ml/min/1.73 m(2); p = 0.03). Amongst 173 patients with moderate renal impairment (mGFR 30-59 ml/min/1.73 m(2)), renal function improvement was also greater amongst everolimus patients than in controls (ΔmGFR 5.1 ± 11.1 vs -0.5 ± 8.7 ml/min/1.73 m(2); p < 0.01). In 55 patients with mGFR 60 to 89 ml/min/1.73 m(2), mGFR did not change significantly in either group. Improvement in mGFR was limited to patients with a median time since TTx of less than 4.6 years and was also influenced by CNI reduction during the study period. CONCLUSIONS Everolimus introduction and reduced CNI significantly improved renal function amongst maintenance TTx patients with pre-existing advanced renal failure. This beneficial effect was limited to patients undergoing conversion in less than 5 years after TTx, indicating a window of opportunity that is appropriate for pharmacologic intervention with everolimus.

Virtual Histology Assessment of Cardiac Allograft Vasculopathy Following Introduction of Everolimus—Results of a Multicenter Trial

In this 12‐month multicenter Scandinavian study, 78 maintenance heart transplant (HTx) recipients randomized to everolimus with reduced calcineurin inhibitor (CNI) exposure or continued standard CNI‐therapy underwent matched virtual histology (VH) examination to evaluate morphological progression of cardiac allograft vasculopathy (CAV). Parallel measurement of a range of inflammatory markers was also performed. A similar rate of quantitative CAV progression was observed in the everolimus (n = 30) and standard CNI group (n = 48) (plaque index 1.9 ± 3.8% and 1.6 ± 3.9%, respectively; p = 0.65). However, VH analysis revealed a significant increase in calcified (2.4 ± 4.0 vs. 0.3 ± 3.1%; p = 0.02) and necrotic component (6.5 ± 8.5 vs. 1.1 ± 8.6%; p = 0.01) among everolimus patients compared to controls. The increase in necrotic and calcified components was most prominent in everolimus patients with time since HTx >5.1 years and was accompanied by a significant increase in levels of von Willebrand (vWF) factor (p = 0.04) and vascular cell adhesion molecule (VCAM) (p = 0.03). Conversion to everolimus and reduced CNI is associated with a significant increase in calcified and necrotic intimal components and is more prominent in patients with a longer time since HTx. A significant increase in vWF and VCAM accompanied these qualitative changes and the prognostic implication of these findings requires further investigation.

Heart transplantation across the antibodies against HLA and ABO.

We have intentionally performed heart transplantation in a 5‐year‐old child, despite the most unfavourable risk factors for patient survival; the presence of high level of antibodies against donors human leucocyte antigen (HLA) class I/II and blood group antigens. Pretransplant treatment by mycophenolate mofetil, prednisolone, tacrolimus, intravenous immunoglobulin, rituximab, protein‐A immunoadsorption (IA) and plasma exchange reduced antibody titres against the donors lymphocytes from 128 to 16 and against the donors blood group antigen from 256 to 0. The patient was urgently transplanted with a heart from an ABO incompatible donor (A1 to O). A standard triple‐drug immunosuppressive protocol was used. No hyperacute rejection was seen. Antibodies against the donors HLA antigens remained at a low level despite three acute rejections. Rising anti‐A1 blood group antibodies preceded the second rejection and were reduced by two blood group‐specific IAs and remained at a low level. The patient is doing well despite the persistence of donor‐reactive antibodies.

Long-term follow-up of lung and heart transplant recipients with pre-transplant malignancies

BACKGROUND Concern regarding recurrence of pre-transplant (Tx) malignancy has disqualified patients from Tx. Because this has been poorly studied in lung and heart Tx recipients our aim was to investigate the influence of pre-Tx malignancy on post-Tx recurrence and long-term survival, focusing on pre-operative cancer-free intervals. METHODS From our lung and heart Tx programs (1983 to 2011) we retrospectively identified 111 (lung, 37; heart, 74) of 3,830 recipients with 113 pre-Tx malignancies. The patients were divided into 3 groups by pre-Tx cancer-free interval: Group I, <12 months (n = 24); Group II, ≥12 to<60 months (n = 18); and Group III, ≥60 months (n = 71). RESULTS Mean age at pre-Tx malignancy was 35±18 years. Mean post-Tx follow-up time was 70±63 months (range, 0-278 months), and malignancy recurrence was 63% in Group I, 26% in Group II, and 6% in Group III. Kaplan-Meier analysis of freedom from post-Tx recurrence revealed the following differences among the groups: Group I vs II, p = 0.08; II vs III, p = 0.002; and I vs III, p<0.001. Overall survival (51 deaths) was significantly poorer in Group I than in Groups II and III (p = 0.044). Survival between Groups II and III did not differ significantly (p = 0.93). CONCLUSIONS Cancer-free survival of ≥5 years pre-Tx is associated with the lowest recurrence. However, recurrence is related to the time the patients were cancer-free, as seen in Groups I and II.