Øystein Bjørtuft

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.

Health-Related Quality of Life in Lung Transplant Candidates and Recipients

Background: Studies on the health-related quality of life in lung transplantation have used general questionnaires, although lung-specific instruments might be more sensitive to small differences. Objectives: To compare the health-related quality of life of lung transplant recipients with lung transplant candidates, using lung-specific and general instruments, and to assess the reliability and validity of these questionnaires. Methods: The study is a cross-sectional postal survey of 31 lung transplant recipients and 15 candidates, using the following outcome measures: St. George’s Respiratory Questionnaire (SGRQ), a lung-specific health status instrument; the Short Form 36 (SF-36), a general measure, and the Hospital Anxiety and Depression scale (HAD). Results: The SGRQ showed a significantly better score (p < 0.05) for transplant recipients in the impacts and activity dimensions and the total score than for candidates. SF-36 scores showed a similar improvement in all subscales of the SF-36 except bodily pain. Cronbach’s α for all dimensions of the SGRQ, SF-36, and HAD were 0.77–0.95. Conclusions: Patients surviving lung transplantations can expect a considerable improvement in most dimensions of health-related quality of life. This finding was consistent using both lung-specific and general measures. The reliability of the questionnaires was acceptable. The associations between scales support the validity of the questionnaires in this setting.

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.

Severe chronic obstructive pulmonary disease: Association with marginal bone loss in periodontitis

An association between chronic marginal periodontitis and chronic obstructive pulmonary disease (COPD) has been suggested. The aim of this study was to investigate whether chronic marginal periodontitis is more prevalent in very severe COPD than in other very severe respiratory diseases, and whether periodontitis in COPD is related to risk factors for periodontitis that are often present in COPD subjects. Orthopantomograms were collected from 130 patients with COPD and 50 patients with non-COPD evaluated for lung transplantation. Chronic marginal periodontitis was defined as a general marginal bone level > or = 4 mm. The prevalence of periodontitis was 44% in the COPD group vs. 7.3% in the non-COPD group. All oral measurements differed significantly between the groups. The difference in mean marginal bone level remained statistically significant when adjusting for age, gender and pack years smoked. In logistic regression analysis mean marginal bone level > or = 4 mm was identified as a factor significantly associated with severe COPD. This study demonstrates that chronic marginal periodontitis is common in patients with severe COPD. The high prevalence of periodontitis in COPD patients appears to be independent of possible risk factors for periodontitis such as age, pack years smoked, body mass index, use of corticosteroids and bone mineral density.

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.

Dietary Support to Underweight Patients with End-Stage Pulmonary Disease Assessed for Lung Transplantation

Background: Undernutrition in hospitalized patients is often not recognized and nutritional support neglected. Chronic obstructive pulmonary disease is frequently characterized by weight loss. No data exist on the effects of nutritional supplementation in underweight lung transplantation candidates during hospitalization. Objective: To evaluate the effects on energy intake and body weight of an intensified nutritional support compared to the regular support during hospitalization. Methods: The participants were underweight (n = 42) and normal-weight (n = 29) patients with end-stage pulmonary disease assessed for lung transplantation. The underweight patients were randomized to receive either an energy-rich diet planned for 10 MJ/day and 45–50 energy percentage fat and offered supplements (group 1), or the normal hospital diet planned for 8.5–9 MJ/day and 30–35 energy percentage fat and regular support (group 2, control group). The normal-weight control patients (group 3) received the normal diet. Food intake was recorded for 3 days. Results: During a mean hospital stay of 12 days, the energy intake was significantly greater for the patients on intensified nutritional support (median 11.2 MJ) than for the underweight patients on the regular support (8.4 MJ; p < 0.02) and the normal-weight patients (7.0 MJ; p < 0.001). The increase in energy intake in group 1 resulted in a significant weight gain (median 1.2 kg) compared with group 2 (p < 0.01) and group 3 (p < 0.001). Conclusions: In a group of underweight patients with lung disease assessed for lung transplantation, it was possible to increase energy intake by an intensified nutritional support which was associated with a significant weight gain, compared to the regular nutritional support during a short hospital stay.

Osteoporosis is a prevalent finding in patients with solid organ failure awaiting transplantation - a population based study.

Dolgos S, Hartmann A, Isaksen GA, Simonsen S, Bjørtuft Ø, Boberg KM, Bollerslev J. Osteoporosis is a prevalent finding in patients with solid organ failure awaiting transplantation – a population based study
Clin Transplant 2010 DOI: 10.1111/j.1399‐0012.2010.01231.x.
© 2010 John Wiley & Sons A/S.

A study of intensified dietary support in underweight candidates for lung transplantation

Background: No data is available on dietary intervention in candidates for lung transplantation and on the effect of different strategies for dietary support in this cohort. Aim: We therefore wanted to evaluate the effects of intensified nutritional support compared with simple support on energy intake and nutritional status. Method: Our participants were underweight (n = 42) and normal-weight (control group, n = 29) candidates for lung transplantation. The underweight patients were randomized into two groups. Group A received intensified dietary counselling, ready-made liquid nutritional supplements free of charge and regular follow-ups, while group B received only one session of individual dietary counselling, no supplements and no follow-ups. Results: The mean intervention time was 21 weeks. Groups A and B both increased their energy intake and gained weight. Group A increased their energy intake from a median of 8.7 to 10.1 MJ (p < 0.01 compared with the control group after intervention) and gained a mean of 2.9 kg body weight (95% CI 1.2; 4.7, p = 0.005 compared with the control group), while group B increased from 7.4 to 10.8 MJ (p = 0.005) and gained 2.3 kg (1.2; 3.3, p = 0.002). Only group B increased their fat-free mass. In this group, an increase in O2 saturation and a decrease in PaCO2 were suggested. None of the groups improved its physical performance. Conclusion: In candidates for lung transplantation we were unable to confirm the hypothesis that intensified nutritional support compared with a simple support increased compliance. Both groups achieved the goal for energy intake and gained weight.

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.

Airway complications after lung transplantation: long-term outcome of silicone stenting.

Background: Airway complications remain a significant cause of morbidity after lung transplantation. The majority of the centres that have published their results have used metal stents. Objectives: We report the long-term outcome of silicone stenting and subsequent stent removal in lung transplant recipients with stenotic airway complications. Method: From 1990 to 2008, 279 patients received 88 single, 170 double, and 21 heart-and-lung transplantations. Of 470 anastomoses at risk, 44 airway complications developed and were treated in 35 patients. Six lesions were treated with Nd:YAG laser and balloon dilatations only. Thirty-two silicone stents of Hood or Dumont type were inserted in 27 patients. Results: Symptoms were relieved and FEV1 increased in all patients (median 0.7 litres, range 0.1-1.8 litres, p < 0.0001). In 8 patients, stents had to be repositioned or reinserted, in 19 patients only one insertion and one removal procedure were necessary. One patient suffered a serious complication with haemorrhage and pneumonectomy, 3 patients had minor airway wall injuries resolving spontaneously. Six patients died with the stents from causes not related to the airway complications. Twenty-five stents could be removed after a median of 6 months (range 1-22) in 21 patients, and 22 airways remained patent. Median FEV1 was 2.3 litres immediately after stent removal, and remained 2.3 litres after 24 months. Conclusion: Stenotic airway complications after lung transplantation can be successfully treated with silicone stents, which can ultimately be removed, leaving a patent airway.