Evolution of donor-specific antibodies (DSA) and incidence of de novo DSA in solid organ transplant recipients after switch to everolimus alone or associated with low dose of calcineurin inhibitors.

BACKGROUND: Everolimus (EVR) is used in organ transplantation to minimize calcineurin inhibitors (CNI). Some studies pointed out an increase in rejection and de novo donor-specific antibodies (DSA) incidence in kidney transplant patients after switch to EVR and CNI withdrawal. The aims of our study were to determine the evolution of anti-HLA antibodies and the incidence of de novo DSA in transplant recipients after conversion to EVR. METHODS: Heart, lung, kidney, and liver transplant recipients were included in a retrospective, monocentric case-control study. Anti-HLA antibodies were identified at transplantation, pre-switch, and at three, six, and 12 months post-switch. RESULTS: Conversion to EVR was performed about six yr after the transplant, and low-dose CNI was maintained in 60% of patients. We found no statistical difference for rejection, evolution of preformed anti-HLA antibodies or de novo DSA, after conversion to EVR or not. Incidence of anti-class II DSA tended to increase at month 12 whatever the immunosuppressive regimen. CONCLUSIONS: Late conversion to EVR appears to be safe and to not modify the natural evolution of anti-HLA antibodies in organ transplantation. As 60% of patients received EVR and low doses of CNI, it seems that such combinations could be used with a good outcome.

Deciphering complement interference in anti-human leukocyte antigen antibody detection with flow beads assays.

BACKGROUND: Anti-human leukocyte antigen (HLA) antibody detection in solid-phase flow beads assays can be quenched by complement activation, but the precise mechanism of this interference is not fully elucidated yet. METHODS: Using the Luminex flow beads screening assay for detection of anti-HLA antibodies, we analyzed the binding of high concentrations of the pan class I anti-HLA monoclonal antibody W6/32 in neat normal, ethylenediaminetetraacetic acid-treated normal and complement factors C1q, C4/C3, C2, C3, factor B or C5-depleted human sera, using anti-mouse immunoglobulin G as the detection antibody. Complement activation and binding to beads were revealed using anti-human C1q, C4d, and C3d antibodies. To translate our findings to the human setting, we used the class I and class II HLA single-antigen flow beads assays and sera from four patients with high titers of antibodies. RESULTS: Detection of W6/32 did not suffer any interference with C1q and C4/C3-depleted sera. A partial quenching was observed with C2, C3, and factor B-depleted sera, but was more pronounced with the factor B-depleted serum. W6/32 was undetectable in presence of C5-depleted serum. The binding of activation products derived from C3 principally, and also from C4, impaired immunoglobulin G and C1q detection. Accordingly, C4d detection was hindered by deposition of activated C3. Similar findings were obtained with patients' sera. CONCLUSION: Binding of C4 and C3 activation products is the main responsible for complement interference in flow beads assays. A complete quenching requires complement activation through C3 cleavage and its amplification by the alternative pathway.

Dual-energy CT perfusion and angiography in chronic thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy.

OBJECTIVES: To evaluate the diagnostic accuracy of dual-energy computed tomography (DECT) perfusion and angiography versus ventilation/perfusion (V/Q) scintigraphy in chronic thromboembolic pulmonary hypertension (CTEPH), and to assess the per-segment concordance rate of DECT and scintigraphy. METHODS: Forty consecutive patients with proven pulmonary hypertension underwent V/Q scintigraphy and DECT perfusion and angiography. Each imaging technique was assessed for the location of segmental defects. Diagnosis of CTEPH was established when at least one segmental perfusion defect was detected by scintigraphy. Diagnostic accuracy of DECT perfusion and angiography was assessed and compared with scintigraphy. In CTEPH patients, the per-segment concordance between scintigraphy and DECT perfusion/angiography was calculated. RESULTS: Fourteen patients were diagnosed with CTEPH and 26 with other aetiologies. DECT perfusion and angiography correctly identified all CTEPH patients with sensitivity/specificity values of 1/0.92 and 1/0.93, respectively. At a segmental level, DECT perfusion showed moderate agreement (κ = 0.44) with scintigraphy. Agreement between CT angiography and scintigraphy ranged from fair (κ = 0.31) to slight (κ = 0.09) depending on whether completely or partially occlusive patterns were considered, respectively. CONCLUSIONS: Both DECT perfusion and angiography show satisfactory performance for the diagnosis of CTEPH. DECT perfusion is more accurate than angiography at identifying the segmental location of abnormalities. KEY POINTS: • Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially treatable by surgery. • Dual-energy computed tomography (DECT) allows angiography and perfusion using a single acquisition. • Both DECT perfusion and angiography showed satisfactory diagnostic performance in CTEPH. • DECT perfusion was more accurate than angiography in identifying segmental abnormalities.

Impact of the early reduction of cyclosporine on renal function in heart transplant patients: a French randomised controlled trial.

BACKGROUND: Using reduced doses of Cyclosporine A immediately after heart transplantation in clinical trials may suggest benefits for renal function by reducing serum creatinine levels without a significant change in clinical endpoints. However, these trials were not sufficiently powered to prove clinical outcomes. METHODS: In a prospective, multicentre, open-label, parallel-group controlled trial, 95 patients aged 18 to 65 years old, undergoing de novo heart transplantation were centrally randomised to receive either a low (130 < trough CsA concentrations <200 µg/L, n = 47) or a standard dose of Cyclosporine A (200 < trough CsA concentrations <300 µg/L, n = 48) for the three first post-transplant months along with mycophenolate mofetil and corticosteroids. Participants had a stable haemodynamic status, a serum creatinine level <250 µmol/L and the donors' cold ischemia time was under six hours; multiorgan transplants were excluded. The change in serum creatinine level over 12 months was used as the main criterion for renal function. Intention-to-treat analysis was performed on the 95 randomised patients and a mixed generalised linear model of covariance was applied. RESULTS: At 12 months, the mean (± SD) creatinine value was 120.7 µmol/L (± 35.8) in the low-dose group and 132.3 µmol/L (± 49.1) in the standard-dose group (P = 0.162). Post hoc analyses suggested that patients with higher creatinine levels at baseline benefited significantly from the lower Cyclosporine A target. The number of patients with at least one rejection episode was not significantly different but one patient in the low-dose group and six in the standard-dose group required dialysis. CONCLUSIONS: In patients with de novo cardiac transplantation, early Cyclosporine A dose reduction was not associated with renal benefit at 12 months. However, the strategy may benefit patients with high creatinine levels before transplantation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00159159.

Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study.

OBJECTIVES: It was previously shown that dehydroepiandrosterone (DHEA) reverses chronic hypoxia-induced pulmonary hypertension (PH) in rats, but whether DHEA can improve the clinical and hemodynamic status of patients with PH associated to chronic obstructive pulmonary disease (PH-COPD) has not been studied whereas it is a very severe poorly treated disease. PATIENTS AND METHODS: Eight patients with PH-COPD were treated with DHEA (200mg daily orally) for 3 months. The primary end-point was the change in the 6-minute walk test (6-MWT) distance. Secondary end-points included pulmonary hemodynamics, lung function tests and tolerance of treatment. RESULTS: The 6-MWT increased in all cases, from 333m (median [IQR]) (257; 378) to 390m (362; 440) (P<0.05). Mean pulmonary artery pressure decreased from 26mmHg (25; 27) to 21.5mmHg (20; 25) (P<0.05) and pulmonary vascular resistance from 4.2UI (3.5; 4.4) to 2.6UI (2.5; 3.8) (P<0.05). The carbon monoxide diffusing capacity of the lung (DLCO % predicted) increased significantly from 27.4% (20.1; 29.3) to 36.4% (14.6; 39.6) (P<0.05). DHEA treatment did not change respiratory parameters of gas exchange and the 200mg per day of DHEA used was perfectly tolerated with no side effect reported. CONCLUSION: DHEA treatment significantly improves 6-MWT distance, pulmonary hemodynamics and DLCO of patients with PH-COPD, without worsening gas exchange, as do other pharmacological treatments of PH (trial registration NCT00581087).

Endovascular treatment of an aneurysm of the descending thoracic aorta in a heart transplant recipient: long-term result.

Heart-transplanted patients have a known higher incidence of aortic aneurysms. However, there is paucity of information regarding thoracic localisation in this clinical setting and of the endovascular option in such patients with chronically high level of immunosuppressive agents. We describe long-term follow-up of a 72-year-old man who developed an aneurysm of the descending part of the thoracic aorta 10 years after an orthotopic cardiac transplantation. Because of comorbid medical conditions, classical open-chest procedure could not be performed. An alternative treatment by endovascular repair was applied successfully and allowed a perfect exclusion of the aneurysm. Chronically high level of immunosuppressive agents seems not to be a contraindication to the endovascular option. Consequently, extended cardiovascular screening of heart-transplanted patients is desirable to facilitate early detection and elective endovascular repair.

Surgical ablation of atrial fibrillation with off-pump, epicardial, high-intensity focused ultrasound: results of a multicenter trial.

BACKGROUND: A simplified alternative to the Cox maze procedure to treat atrial fibrillation with epicardial high-intensity focused ultrasound was evaluated clinically, and the initial clinical results were assessed at the 6-month follow-up visit. METHODS: From September 2002 through February 2004, 103 patients were prospectively enrolled in a multicenter study. Atrial fibrillation duration ranged from 6 to 240 months (mean, 44 months) and was permanent in 76 (74%) patients, paroxysmal in 22 (21%) patients, and persistent in 5 (5%) patients. All patients had concomitant operations, and ablation was performed epicardially on the beating heart before the concomitant procedure. The device automatically created a circumferential left atrial ablation around the pulmonary veins in an average of 10 minutes, and an additional mitral line was created epicardially in 35 (34%) patients with a handheld device by using the same technology. RESULTS: No complications or deaths were device or procedure related. There were 4 (3.8%) early deaths and 2 late extracardiac deaths. The 6-month follow-up was complete in all survivors. At the 6-month visit, freedom from atrial fibrillation was 85% in the entire study group (80% in patients with permanent atrial fibrillation, 88% in the 35 patients who had the additional mitral line, and 100% in patients with paroxysmal atrial fibrillation). A pacemaker was implanted in 8 patients. Only the duration and type of atrial fibrillation significantly increased the risk of recurrence. CONCLUSION: Epicardial, off-pump, beating-heart ablation with acoustic energy is safe and cures 80% of patients with permanent atrial fibrillation associated with long-standing structural heart disease.

Prospective study of hemodynamic performances of standard ATS and AP-ATS valves.

BACKGROUND AND AIM OF THE STUDY: Following aortic valve replacement (AVR), a residual transprosthetic gradient can develop which has detrimental long-term effects, especially with regard to left ventricular mass regression and subsequent mortality. The Advanced Performance-ATS valve (AP-ATS) was developed to overcome this potential patient-prosthesis mismatch. In the present study, the early postoperative transprosthetic gradient was determined after AVR with ATS valves 18 to 25, to confirm the promise of superior hemodynamic performance of the AP series and to define respective indications. METHODS: This prospective study included 302 consecutive patients operated on for AVR between December 1997 and December 2000. In all patients, body surface area (BSA), associated with mean transprosthetic gradient and paravalvular leaks (measured echocardiographically) was monitored, between the 5th and 8th postoperative days. RESULTS: A significantly lower mean transprosthetic gradient was found for size 22 and 24 valves, compared with size 23 and 25 valves. Results for size 18 and 20 valves were in concordance with those obtained for size 22 and 24 valves. For size 23 valves the mean gradient was significantly higher when the BSA was >1.9 m2, but the use of size 22 valves in these patients overcame this potential patient-prosthesis mismatch. No patient was reoperated on for paravalvular leakage, and no greater degree of paravalvular leakage was found with AP-ATS than with Standard ATS valves. CONCLUSION: These results confirm the global good hemodynamic performances of Standard ATS and especially of the AP-ATS valves. However, the significantly lower mean gradient found in the AP-ATS valves recommends their use in patients with larger BSA.