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Purpose of Review: The gold standard for diagnosis and treatment of obstructive sleep apnea (OSA) is attended overnight polysomnography (PSG) in a sleep laboratory. Alternative diagnostic techniques are urgently needed for both diagnosis and treatment control when initiating positive airway pressure (PAP) in the home setting. Current PAP devices compute data such as residual AHI (apnea-hypopnea index) using their proprietary algorithms to provide an automatic event detection (AED). It was suggested that these should be labeled AHIFLOW., Recent Findings: The current study situation shows an acceptable agreement with the tendency of mildly overestimating the AHI by the PAP devices. But, the literature is still limited in terms of accuracy, especially when considering the lack of standardization and different detection algorithms., Summary: A validation of PAP devices regarding the agreement of AHIFLOW compared to AHIPSG is extremely important, given that the device analysis is exclusively based on the measured flow. There are considerable concerns about assessing the PAP effectiveness in higher risk groups based on the AED function alone. Given these reservations, the use of PAP event detection can be an important addition to the diagnostic spectrum and, in combination with telemonitoring, offers promising potential., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This retrospective analysis investigated the influence of integrative therapies in addition to palliative chemotherapy in patients with advanced pancreatic cancer, treated at a single institution specialized in integrative oncology between January 2015 and December 2019. In total, 206 consecutive patients were included in the study, whereof 142 patients (68.9%) received palliative chemotherapy (gemcitabine/nab-paclitaxel 33.8%; FOLFIRINOX 35.9%; gemcitabine 30.3%) while the remainder were treated with best supportive and integrative care. Integrative therapies were used in 117 of 142 patients (82.4%) in addition to conventional chemotherapy, whereby mistletoe was used in 117 patients (82.4%) and hyperthermia in 74 patients (52.1%). A total of 107/142 patients (86.3%) died during the observation period, whereby survival times differed significantly depending on the additional use of integrative mistletoe or hyperthermia: chemotherapy alone 8.6 months (95% CI 4.7-15.4), chemotherapy and only mistletoe therapy 11.2 months (95% CI 7.1-14.2), or a combination of chemotherapy with mistletoe and hyperthermia 18.9 months (95% CI 15.2-24.5). While the survival times observed for patients with advanced pancreatic cancer receiving chemotherapy alone are consistent with pivotal phase-III studies and German registry data, we found significantly improved survival using additional mistletoe and/or hyperthermia.

Purpose: Monitored polysomnography (PSG) is considered the gold standard technique to diagnose obstructive sleep apnea (OSA) and titrate continuous positive airway pressure (CPAP), the accepted primary treatment method. Currently, the American Academy of Sleep Medicine (AASM) considers automatic PAP therapy initiation at home comparable to laboratory titration and recommends telemonitoring-guided interventions. Advanced CPAP devices evaluate and report the residual apnea-hypopnea index (AHI). However, in order to control the effectiveness of the prescribed therapy outside of a PSG setting, the automatic event detection must provide reliable data., Methods: A CPAP titration was performed in the sleep laboratory by PSG in patients with OSA. The residual event indices detected by the tested device (prismaLine, Loewenstein Medical Technology) were compared to the manually scored PSG indices. Results of the device (AHI FLOW ) were compared according to the AASM scoring criteria 1A (AHI 1A , hypopneas with a flow signal reduction of ≥ 30% with ≥ 3% oxygen reduction and/or an arousal) and 1B (AHI 1B , hypopneas with a flow signal decrease by ≥ 30% with a ≥ 4% oxygen desaturation)., Results: In 50 patients with OSA, the mean PSG AHI 1A was 10.5 ± 13.8/h and the PSG AHI 1B was 7.4 ± 12.6/h compared to a mean device AHI Flow of 8.4 ± 10.0/h. The correlation coefficient regarding PSG AHI 1A and AHI Flow was 0.968. The correlation regarding central hypopneas on the other hand was 0.153. There were few central events to be compared in this patient group., Conclusion: The device-based analysis showed a high correlation in the determination of residual obstructive AHI under therapy. The recorded residual respiratory event indices in combination with the data about leakage and adherence of the studied device provide reliable information for the implementation and follow-up of CPAP therapy in a typical group of patients with OSA., Trial Registration Number: ClinicalTrials.gov Identifier: NCT04407949, May 29, 2020, retrospectively registered., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: To increase CO 2 elimination and to reduce work of breathing in hypercapnic patients, non-invasive ventilation (NIV) can be applied via mask either with non-vented CO 2 exhalation systems or with vented systems with leak port. The effect of the exhalation system on CO 2 rebreathing in the mask and total gas exchange remains widely unknown. Aim of this study was to compare the exhalation systems in terms of inspiratory O 2 and CO 2 concentrations, breathing patterns and gas exchange., Methods: We prospectively examined 10 healthy subjects and 10 hypercapnic patients with both exhalation systems. O 2 and CO 2 were measured in the nose, in the mask, and in the ventilation circuit, and respiratory rate, tidal volume, and transcutaneous capnometry (PtcCO 2 ) were recorded during the experiments., Results: Using the non-vented system, CO 2 concentrations in the mask were significantly higher in both subject groups, and PtcCO 2 values in the patient group increased up to 3.6 mmHg compared to the vented system (p = 0.011). O 2 concentrations increased with higher O 2 flow rates, but were significantly lower in the vented settings in both groups. No effect in breathing pattern could be demonstrated during the measurement time., Conclusion: Using NIV, the chosen exhalation system influences CO 2 and O 2 concentrations under the mask, CO 2 rebreathing from the mask and could influence the effectiveness of the ventilation support with regards to hypercapnia treatment. To compensate for relevant hypoxia, the O 2 supplementation must be set up to a sufficient level under a vented system., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nasal high flow (NHF) is an efficient oxygenation tool for the treatment of respiratory failure. The study investigated the effect of breathing pattern on positive airway pressure and dead-space clearance by NHF. The breathing cycle during NHF was characterized in 26 patients with acute respiratory failure (ARF) and stable COPD and after mechanical ventilation (post-MV) via tracheostomy where also pressure was measured in the trachea. Dead-space clearance was measured in airway models during different breathing patterns. NHF reduced the respiratory rate (RR) and T I /T E through prolonging the T E ; the T I /T E ranged between ≤0.5 observed in the COPD patients and ∼1.0 in the ARF patients. NHF via a standard medium-sized cannula interface generated a low-level expiratory pressure proportional to NHF rate and breathing flow; the median generated positive end-expiratory pressure was only 1.71 cmH 2 O at NHF 45 L/min. The dilution and purging of expired gas from a nasal cavity model were observed to occur at the end of expiration as expiratory flow slowed and the dynamic pressure decreased. The higher RR with shorter end-expiratory period resulted in reduced dead-space clearance by NHF; 20 L/min cleared 43 ± 2 mL at RR 15 min -1 vs. 9 ± 5 mL at RR 45 min -1 , P < 0.001, which was increased at higher NHF rate. At lower RR, the clearance was similar between NHF rates 20 and 60 L/min. Higher NHF rates elevate positive airway pressure, and at the increased RR can improve the clearance. This may enhance gas exchange and lead to a reduction in the work of breathing. NEW & NOTEWORTHY During nasal high flow (NHF) an increased breathing frequency, which is commonly observed in acute respiratory failure, can lead to decreased dead-space clearance. Higher NHF rates increase the clearance and reduce the rebreathing which may eventually lower the respiratory rate and the work of breathing. Monitoring of the respiratory rate could be an important indicator of not only the respiratory function but also the NHF rate selection and the therapy efficacy.

Purpose of Review: The COVID-19 pandemic has clearly demonstrated that the technological progress in digitization is also essential for the medical sector. In the field of sleep-disordered breathing, the novel eHealth methods already do offer smart solutions for currently insufficiently addressed problems., Recent Findings: In general, the potential of telemedicine tools can be focused on three basic aspects: interaction between clinicians, interaction between clinician and patient, and interaction between patient and the mobile health technology. The pandemic situation resulted in a rapid development of reimbursement for telehealth services. In recent years, evidence on the positive benefits of using telemedicine-based support as part of respiratory therapy follow-up is increasing. It is important to consider patient groups, telemedicine methodology, type of intervention, and targeting criteria in all studies conducted., Summary: Given the scarcity of resources for leading common diseases, we must keep an eye on the new digitization concepts in respiratory medicine care. It must be implemented precisely, cost-effectively, and also more connecting between sectors and disciplines and at eye level with our patients. By means of patient engagement systems, an important part of modern precision medicine can be established. Digital support systems are valuable for supporting medical staff. They are not meant to replace medical staff but to facilitate their work and improve its quality., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Sleep disorders and circadian dysrhythmias are extremely prevalent in critically ill patients. Impaired sleep has a variety of etiologies, exhibits a wide range of negative effects and, moreover, might deteriorate the patient's prognosis. Despite a number of scientific findings and increased awareness, the importance of sleep optimization is still lower on the list of priories in the intensive care unit (ICU). The techniques of measuring and the evaluation of sleep quantity and quality are a great challenge in the ICU setting. The subjective and objective tools of sleep validation continue to suffer from deficiencies. Treatment approaches to improve the critically ill patient's sleep have focused on non-pharmacologic and pharmacologic strategies with some promising results. But pharmacological interventions alone could not provide sufficient patient benefit. Being aware and knowing of sleep problems and the beneficial effect of the necessary therapies in ICU patients requires greater acceptance. The application of available methods and the development of new methods to prevent sleep disorders in the ICU offer the potential to improve the critically ill patient's outcome., Competing Interests: Prof. Dr Georg Nilius report I have perceived funds from Löwenstein, Fisher & Paykel, ResMed and JAZZ Pharma. The projects are not associated with the submitted publication. The authors report no other conflicts of interest in this work., (© 2021 Nilius et al.)

Background: The prevalence of obstructive sleep apnea (OSA) is very high in stroke patients, whereas the acceptance of positive airway pressure (PAP) therapy is low. Although telemedicine offers new options to increase acceptance, effective concepts and patient groups are not yet known., Objective: The aim of this study was to investigate the effect of a telemedicine concept consisting of telemonitoring and support when usage time drops., Methods: PAP naive stroke patients with apnea-hypopnea index (AHI) >15 were randomized in a prospective parallel design comparing home therapy with standard care (SC) as opposed to telemedicine care (TC) over a period of 6 months. The TC group received a standardized phone call to offer help and advice if the average weekly usage of PAP fell below 4 h/night., Results: Eighty patients were included, 5 were lost to follow-up, 75 (20 females, age: 57.0 ± 9.9, body mass index: 30.9 ± 6.0 kg/m2, AHI: 39.4 ± 18.6) were evaluated. While inpatient usage was similar in both groups, a significant difference was identified after 6 months of receiving home therapy (TC: 4.4 ± 2.5 h, SC: 2.1 ± 2.2 h; p < 0.000063). On average, 4.7 ± 3.1 interventional phone calls were needed (173 calls in total, ranging from 0 to 10 calls per patient), primarily for the purpose of motivation (61.3%), mask problems (16.2%), nasopharyngeal complaints or humidification issues (11.2%), and technical questions (10.6%). Sleepiness (Epworth Sleepiness Scale [ESS]) differed significantly (TC: 3.7 + 3.2, SC: 6.1 + 4.1; p = 0.008), as well as systolic blood pressure, which was available in a subgroup of 55 patients (TC: 129.5 + 15.2 mm Hg, SC: 138.8 + 16.1 mm Hg; p = 0.034)., Conclusion: A concept of telemonitoring and short telephone calls from the sleep lab raised PAP therapy adherence significantly in a group of stroke patients with moderate to severe OSA., (© 2019 S. Karger AG, Basel.)

Purpose: Mucosal drying during continuous positive airway pressure (CPAP) therapy is problematic for many patients. This study assessed the influence of ambient relative humidity (rH) and air temperature (T) in winter and summer on mask humidity during CPAP, with and without mask leak, and with or without heated humidification ± heated tubing., Methods: CPAP (8 and 12 cmH 2 O) without humidification (no humidity [nH]), with heated humidification controlled by ambient temperature and humidity (heated humidity [HH]) and HH plus heated tubing climate line (CL), with and without leakage, were compared in 18 subjects with OSA during summer and winter., Results: The absolute humidity (aH) and the T inside the mask during CPAP were significantly lower in winter versus summer under all applied conditions. Overall, absolute humidity differences between summer and winter were statistically significant in both HH and CL vs. nH ( p < 0.05) in the presence and absence of mouth leak. There were no significant differences in aH between HH and CL. However, in-mask temperature during CL was higher ( p < 0.05) and rH lower than during HH. In winter, CPAP with CL was more likely to keep rH constant at 80% than CPAP without humidification or with standard HH., Conclusion: Clinically-relevant reductions in aH were documented during CPAP given under winter conditions. The addition of heated humidification, using a heated tube to avoid condensation is recommended to increase aH, which could be useful in CPAP users complaining of nose and throat symptoms., Competing Interests: Disclosure G Nilius has received research funding from Fisher & Paykel Healthcare, Heinen und Löwenstein, and Weinmann; this has gone into department funds. H Woehrle and A Graml are employees of ResMed. KJ Franke, U Domanski, and M Schroeder have no financial or other potential conflicts of interest in this work.

Background: Obstructive sleep apnea (OSA) is a highly prevalent condition; however, the majority of patients remain undiagnosed. There is a potential to expand the diagnostic capacity of sleep laboratories. The study objective was to validate a portable respiratory monitoring device (Alice PDX) against polysomnography (PSG) in the laboratory and to assess its reliability at home., Methods: A total of 85 patients with suspected OSA (80% male, mean age 49.1±13.5 years, body mass index 29.7±6.9 kg/m 2 , Epworth Sleepiness Scale 10.0±5.1) were randomized to 3 diagnostic nights: 1 night simultaneous in-laboratory PSG and PDX recording; 1 night self-applied PDX at home, and 1 night in-laboratory PSG. Study data were manually scored according to American Academy of Sleep Medicine criteria., Results: The Alice PDX was in diagnostic agreement with simultaneously recorded reference PSG in 96.4% of studies. In 2.4% of studies the in-laboratory PDX underestimated and in 1.2% of studies it overestimated the apnea hypopnea index (AHI). The difference between the AHI from the reference PSG and the home study was similar to the difference between the PSGs (2.79 vs 0.79, p =0.08)., Conclusion: In a population with a high suspicion of OSA, the Alice PDX showed a high level of diagnostic agreement with a simultaneous PSG and performed valid home diagnostic studies for OSA. If manually scored, the portable device can be used by sleep specialists for diagnosing moderate-to-severe obstructive sleep apnea in cases with a high pretest probability for the disease over a wide range of disease severity. The technology can be deployed reliably outside of the sleep laboratory setting., Competing Interests: Disclosure The company had no influence on the data acquisition, study conduct, and interpretation of the data. The authors report no conflicts of interest in this work.

Background: COPD patients who develop chronic hypercapnic respiratory failure have a poor prognosis. Treatment of choice, especially the best form of ventilation, is not well known., Objectives: This study compared the effects of pressure-controlled (spontaneous timed [ST]) non-invasive ventilation (NIV) and NIV with intelligent volume-assured pressure support (IVAPS) in chronic hypercapnic COPD patients regarding the effects on alveolar ventilation, adverse patient/ventilator interactions and sleep quality., Methods: This prospective, single-center, crossover study randomized patients to one night of NIV using ST then one night with the IVAPS function activated, or vice versa. Patients were monitored using polysomnography (PSG) and transcutaneous carbon dioxide pressure (PtcCO 2 ) measurement. Patients rated their subjective experience (total score, 0-45; lower scores indicate better acceptability)., Results: Fourteen patients were included (4 females, age 59.4±8.9 years). The total number of respiratory events was low, and similar under pressure-controlled (5.4±6.7) and IVAPS (8.3±10.2) conditions ( P =0.064). There were also no clinically relevant differences in PtcCO 2 between pressure-controlled and IVAPS NIV (52.9±6.2 versus 49.1±6.4 mmHg). Respiratory rate was lower under IVAPS overall; between-group differences reached statistical significance during wakefulness and non-rapid eye movement sleep. Ventilation pressures were 2.6 cmH 2 O higher under IVAPS versus pressure-controlled ventilation, resulting in a 20.1 mL increase in breathing volume. Sleep efficiency was slightly higher under pressure-controlled ventilation versus IVAPS. Respiratory arousals were uncommon (24.4/h [pressure-controlled] versus 25.4/h [IVAPS]). Overall patient assessment scores were similar, although there was a trend toward less discomfort during IVAPS., Conclusion: Our results show that IVAPS NIV allows application of higher nocturnal ventilation pressures versus ST without affecting sleep quality or inducing ventilation- associated events., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Regular physical activity is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). Interventions to reduce time spent in sedentary behavior could improve outcomes. The primary purpose was to investigate the impact of telemonitoring with supportive phone calls on daily exercise times with newly established home exercise bicycle training. The secondary aim was to examine the potential improvement in health-related quality of life and physical activity compared to baseline., Methods: This prospective crossover-randomized study was performed over 6 months in stable COPD patients. The intervention phase (domiciliary training with supporting telephone calls) and the control phase (training without phone calls) were randomly assigned to the first or the last 3 months. In the intervention phase, patients were called once a week if they did not achieve a real-time monitored daily cycle time of 20 minutes. Secondary aims were evaluated at baseline and after 3 and 6 months. Health-related quality of life was measured by the COPD Assessment Test (CAT), physical activity by the Godin Leisure Time Exercise Questionnaire (GLTEQ)., Results: Of the 53 included patients, 44 patients completed the study (forced expiratory volume in 1 second 47.5%±15.8% predicted). In the intervention phase, daily exercise time was significantly higher compared to the control phase (24.2±9.4 versus 19.6±10.3 minutes). Compared to baseline (17.6±6.1), the CAT-score improved in the intervention phase to 15.3±7.6 and in the control phase to 15.7±7.3 units. The GLTEQ-score increased from 12.2±12.1 points to 36.3±16.3 and 33.7±17.3., Conclusion: Telemonitoring is a simple method to enhance home exercise training and physical activity, improving health-related quality of life., Competing Interests: Karl-Josef Franke, Ulrike Domanski, Maik Schroeder, Volker Jansen, Frank Artmann, Uwe Weber, Rainer Ettler and Georg Nilius declare that they have no financial involvement in the subject discussed in the submitted manuscript and that there are no conflicts of interest in this work.

Purpose: Positive airway pressure (PAP) therapy adherence can be affected by rhinitis sicca and xerostomia complaints. Additional heated humidification (HH) is the appropriate method when such complaints arise. The aim of this study was to determine if HH with a supplementary heated breathing tube can increase adherence, reduce subjective nasopharyngeal complaints (NPC), and improve sleepiness (ESS: Epworth Sleepiness Scale) and quality of life (FOSQ: Functional Outcome of Sleep Questionnaire)., Methods: We subdivided 72 obstructive sleep apnea (OSA) patients into two groups before therapy initiation. The NPC risk group consists of subjects with NPC and the low-risk group without. The risk group was identified by a score of >9 in a 5-item 25-point NPC questionnaire and pathological ESS. All patients were eligible for automatic CPAP devices (APAP), which were randomly configured with or without HH during 6 weeks., Results: The adherence differences with and without HH were not significant in the NPC risk group (330 ± 103 vs. 281 ± 118 min/night) and in the low-risk group (330 ± 116 vs. 321 ± 89). NPC and ESS scores in the risk group were both significantly reduced with HH. Daily function (FOSQ) in the risk group was significantly improved with HH (90.0 ± 11.9 vs. 82.0 ± 12.0 (p < 0.05))., Conclusion: HH showed a tendency to improve APAP adherence. The adherence in both groups was quite high, and for that reason, it is difficult to show a statistically significant effect. A differentiation into NPC risk groups before starting PAP treatment is useful. HH reduces side effects and sleepiness and improves quality of life in an NPC risk group.

Purpose: Increasingly frequent, it is clinically indicated to obtain tissue from a peripheral lung lesion (PLL) to yield a pathological diagnosis. The aim of the present study was to evaluate the diagnostic sensitivity of transbronchial needle aspiration (TBNA) and transbronchial catheter aspiration (TBCA) in addition to transbronchial forceps biopsy (TBB) at conventional bronchoscopy., Methods: Eligible patients showing a PLL on computed tomography scans were included in the study. In all patients, following TBB, TBNA and TBCA were employed in randomised order under fluoroscopy., Results: Fourty-eight patients were enrolled, of whom 46 patients with 46 PLLs were included in the analysis. The mean ± SD diameter of the PLL was 27.0 ± 13.3 mm. The overall sensitivity for all modalities was 69.6%; PLL ≤20 or >20 and ≤30 mm in diameter showed a sensitivity of 60.0 and 72.2%, respectively. For malignant PLL (n = 33), the combined sensitivity of TBNA + TBCA versus TBB was significantly higher (63.6 vs. 33.3%, p ≤ 0.05), and could not further be improved by TBB. For benign PLL, TBB was superior to TBNA + TBCA (76.9 vs. 38.5%)., Conclusions: TBB, TBNA and TBCA are complementary to one another. Combining the three techniques, even allows transbronchial specimen collection of PLL <3 cm in diameter at conventional bronchoscopy.

Objective: Enzymatically oxygenated lipid products derived from omega-3 and omega-6 fatty acids play an important role in inflammation dampening. This study examined the anti-inflammatory effects of n-6 docosapentaenoic acid-derived (17S)-hydroxy-docosapentaenoic acid (17-HDPAn-6) and (10,17S)-dihydroxy-docosapentaenoic acid (10,17-HDPAn-6) as well as n-3 docosahexaenoic acid-derived 17(R/S)-hydroxy-docosahexaenoic acid (17-HDHA)., Materials and Methods: The effects of 17-HDPAn-6, 10,17-HDPAn-6 or 17-HDHA on activity and M1/M2 polarization of murine macrophage cell line RAW 264.7 were examined by phagocytosis assay and real-time PCR. To assess anti-inflammatory effects in vivo, dextran sodium sulfate (DSS) colitis was induced in mice treated with 17-HDPAn-6, 10,17-HDPAn-6, 17-HDHA or NaCl., Results: Our results show that 17-HDPAn-6, 10,17-HDPAn-6 and 17-HDHA increase phagocytosis in macrophages in vitro and promote polarization towards the anti-inflammatory M2 phenotype with decreased gene expression of TNF-α and inducible Nitric oxide synthase and increased expression of the chemokine IL-1 receptor antagonist and the Scavenger receptor Type A. Intraperitoneal treatment with 17-HDPAn-6, 10,17-HDPAn-6, or 17-HDHA alleviated DSS-colitis and significantly improved body weight loss, colon epithelial damage, and macrophage infiltration., Conclusion: These results suggest that DPAn-6-derived 17-HDPAn-6 and 10,17-HDPAn-6 as well as the DHA-derived 17-HDHA have inflammation-dampening and resolution-promoting effects that could be used to treat inflammatory conditions such as inflammatory bowel disease.

Background: Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders., Methods: We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti-CD146-coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA-1) was performed in parallel. Twenty-one healthy controls were also studied., Results: On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72+/-39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25+/-20 cells/mL) than healthy controls (7+/-5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs., Conclusions: The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.

Microvascular endothelial cells play a key role in transplant immunology. They are also important targets for calcineurin inhibitors. We recently demonstrated elevated numbers of circulating endothelial cells in renal transplant recipients with and without rejection in comparison with healthy controls. Because these patients received either cyclosporine or tacrolimus, we speculated that endothelial damage from calcineurin inhibitors might be responsible for these findings. In the present study, we tested the hypothesis that treatment with calcineurin inhibitors leads to an increase in circulating endothelial cells. We studied 57 renal transplant recipients: 19 on a calcineurin inhibitor-free immunosuppressive regimen and 38 patients on a standard immunosuppressive regimen, including cyclosporine, and matched them for age and serum creatinine. Endothelial cells were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads and were counted by fluorescence microscopy. Patients with cyclosporine therapy had elevated numbers of circulating endothelial cells (median 26, range 12 to 82 cells/mL) compared with healthy controls (median 6, range 0 to 82 cells/mL; P<0.001). Patients without calcineurin inhibitor treatment had significantly lower cell numbers (median 12, range 0 to 32 cells/mL; P<0.003) and were not significantly different from normal, untreated controls. In conclusion, renal transplant recipients who do not receive calcineurin inhibitors have significantly lower numbers of circulating endothelial cells than their age- and creatinine-matched counterparts who receive these drugs. We suggest that elevated numbers of circulating endothelial cells indicate damage from calcineurin inhibitors in renal transplant recipients and that circulating endothelial cells are a novel marker of endothelial damage.