Respiratory oscillometry with CT image analysis in idiopathic pulmonary fibrosis following single lung transplant.

Oscillometry is an emerging pulmonary function testing tool that is conducted during tidal breaths with minimal patient effort. It is highly sensitive to changes in lung mechanics. Oscillometry was recently shown to be highly associated with disease severity in idiopathic pulmonary fibrosis (IPF). The usefulness of oscillometry after single lung transplant in IPF patients is not well understood. Our study demonstrated that oscillometry can detect changes in the graft despite presence of a native fibrotic lung to provide useful information to complement spirometry.

Correlation of respiratory oscillometry with CT image analysis in a prospective cohort of idiopathic pulmonary fibrosis.

BACKGROUND: Markers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative and independent prognostic structural indicator derived from automated CT analysis. The current prospective cross-sectional study investigated whether respiratory oscillometry provides complementary data to pulmonary function tests (PFTs) and is correlated with PVV. METHODS: From September 2019 to March 2020, we enrolled 89 patients with IPF diagnosed according to international guidelines. We performed standard spectral (5-37 Hz) and novel intrabreath tracking (10 Hz) oscillometry followed by PFTs. Patients were characterised with the gender-age-physiology (GAP) score. CT images within 6 months of oscillometry were analysed in a subgroup (26 patients) using automated lung texture analysis. Correlations between PFTs, oscillometry and imaging variables were investigated using different regression models. FINDINGS: The cohort (29F/60M; age=71.7±7.8 years) had mild IPF (%FVC=70±17, %DLCO=62±17). Spectral oscillometry revealed normal respiratory resistance, low reactance, especially during inspiration at 5 Hz (X5in), elevated reactance area and resonance frequency. Intrabreath oscillometry identified markedly low reactance at end-inspiration (XeI). XeI and X5in strongly correlated with FVC (r2=0.499 and 0.435) while XeI was highly (p=0.004) and uniquely correlated with the GAP score. XeI and PVV exhibited the strongest structural-functional relationship (r2=0.690), which remained significant after adjusting for %FVC, %DLCO and GAP score. INTERPRETATION: XeI is an independent marker of IPF severity that offers additional information to standard PFTs. The data provide a cogent rationale for adding oscillometry in IPF assessment.

A simplified strategy for donor-recipient size-matching in lung transplant for interstitial lung disease.

BACKGROUND: Donor-recipient size-matching has been repeatedly reported to improve outcomes following lung transplantation (LTx). However, there is significant variability in practice and the optimal strategy for size-matching is yet to be defined. For recipients with ILD, size-matching decisions are complicated by concerns regarding the potential impact of pre-LTx pulmonary restriction. We evaluate whether a specific donor-to-recipient size-matching strategy, based on predicted total lung capacity, benefits this patient group. METHODS: This retrospective, single-centre, cohort study describes the post-LTx outcomes of adults who underwent LTx for ILD between 1983 and 2020. Only patients with restrictive physiology, based on pre-LTx pulmonary function testing were included. Post-LTx outcomes were compared based on donor-recipient predicted TLC (D-R pTLC) ratio. A D-R pTLC ratio of ≥0.8 or <1.2 for DLTx, and a D-R pTLC ratio of ≥0.8 or <1.0 for SLTx were classified as 'size-matched'. RESULTS: Five-hundred and fifty LTx recipients met inclusion criteria. Of these, 404 underwent DLTx and 146 underwent SLTx. Size-matching was achieved in 78% of DLTx and 47% of SLTx. Overall survival (p = 0.007) and CLAD-free survival (p < 0.001) was significantly improved following a size-matched DLTx, compared to those with D-R pTLC ratios <0.8 or ≥1.2. Size-matching based on a D-R pTLC ratio 0.8≥ <1.0 for SLTX did not significantly improve survival. CONCLUSIONS: D-R pTLC size-matching, based on a ratio of 0.8≥ <1.2 improved post-DLTx outcomes for patients with restrictive lung disease. This is simple to do, and if applied clinically, could improve overall outcomes in lung transplantation.

Extending cytomegalovirus prophylaxis in high-risk (D+/R-) lung transplant recipients from 6 to 9 months reduces cytomegalovirus disease: A retrospective study.

RATIONALE: Cytomegalovirus (CMV)-seronegative recipients receiving a seropositive allograft (D+/R-) are at a high risk of developing CMV disease. Our program increased the duration of CMV prophylaxis from 6 to 9 months in May 2013. Here, we present the impact on the incidence of CMV infection, disease, side effects, rejection, and other factors. METHODS: Retrospective cohort of 241 CMV (D+/R-) patients transplanted between January 1, 2008, and December 31, 2017. Blood CMV testing was done according to protocol. All patients received ganciclovir/valganciclovir as prophylaxis. We compared the incidence and timing of CMV infection and disease up to 6 months after cessation of prophylaxis between patients who received 9 months (May 2013 onwards) and a historical control group who received 6 months of prophylaxis (prior to May 2013). CMV infection was defined as detectable CMV viremia in the absence of symptoms. CMV disease was defined as CMV syndrome or tissue-invasive disease. Side effects of prophylaxis and CMV resistance were recorded. RESULTS: A total of 116 patients were included in the 6-month group and 125 in the 9-month group. The extended 9-month CMV prophylaxis delayed the onset of CMV infection (median time to CMV infection after lung transplantation 295 vs 353 days, P < .01) but did not significantly reduce the incidence of CMV infection (65% vs 64%, P = .06, log-rank). The 9-month prophylaxis delayed the onset and decreased the incidence of CMV disease from 50% in the 6-month group to 42% (P = .02 log-rank). There was no difference in the rate of adverse effects (leukopenia in 32% in both groups, P = .53) or development of CMV resistance between the two groups (4 cases in both groups, P = .92). There were no significant differences in overall survival or the rate of chronic lung allograft dysfunction between the groups. CONCLUSIONS: Extending duration of CMV prophylaxis from 6 to 9 months resulted in a delayed and decreased incidence of CMV disease in our lung transplant population. The absolute risk reduction achieved by extended CMV prophylaxis was 8%. The incidence of CMV infection, and ganciclovir resistance and side effects were similar between the two groups. Our results suggest that extending CMV prophylaxis in the highest risk CMV D+/R- group is effective in reducing CMV disease.

Lung transplantation for cystic fibrosis.

BACKGROUND: The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. We aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. METHODS: A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests. RESULTS: From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF retransplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and retransplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction. CONCLUSIONS: Lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.

BACKGROUND: A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation. METHODS: We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044. FINDINGS: From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV-positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16·76-24·75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20-12 000] vs 4390 IU/mL [1170-112 000] at day 7; p=0·048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV-positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV-negative donors. The most common grade 3-4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment. INTERPRETATION: Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor-recipient transmission. FUNDING: Canadian Institutes of Health Research.

Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion.

Importance: The mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes. Objective: To assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP. Design, Setting, and Participants: This retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP. Exposure: Donor lungs undergoing EVLP. Main Outcomes and Measures: The incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development. Results: This study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups. Conclusions and Relevance: Since 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.

Epstein-Barr virus-associated smooth muscle tumors after lung transplantation.

BACKGROUND: Recipients of solid organ transplants are prone to various complications that are seldom encountered in immunocompetent individuals. Post-transplant lymphoproliferative disorder (PTLD) is the best known and commonest Epstein-Barr Virus (EBV)-associated malignancy post solid organ transplant. EBV-associated smooth muscle tumors (EBV-SMT) including leiomyomas and leiomyosarcomas are rare and much less studied than PTLD. We recently encountered two cases of EBV-SMT post lung transplantation and here we summarize their clinical features and course together with a literature review. METHOD: Clinical data and treatment details of two patients who developed EBV-SMT were reviewed and retrieved up to December 31, 2017. English literature was searched through the PubMed database from 1965 to 2017 for studies of the association between lung transplant and EBV-SMT. RESULTS: The incidence of PTLD is higher among lung transplant recipients compared to kidney transplant recipients, an observation that has been attributed to stronger immune suppression in the lung patients. EBV-SMT showed a higher incidence among kidney recipients than among lung recipients, suggesting that the degree of immunosuppression may be a less important factor in the development of EBV-SMT. EBV-SMT has most often been seen among lung transplant recipients with EBV mismatch. CONCLUSIONS: Because EBV-SMT is a rare tumor, its incidence, risk factors, and optimal management have not been well-defined and further study is needed.

Comprehensive outcomes after lung retransplantation: A single-center review.

INTRODUCTION: Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. METHODS: We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n = 38). We analyzed the postoperative course, graft function, renal function, microbiology, donor-specific antibodies (DSA), quality of life, and survival compared to a control cohort of primary transplant recipients matched for age and era. RESULTS: Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 92%). The postoperative course was more complex after retransplant than primary (ventilation time, 8 vs 2 days, P < .01; ICU stay 14 vs 4 days, P < 0.01), and peak lung function was lower (FEV1 2.2L vs 3L, P < .01). Quality of life scores were comparable, as were renal function, microbiology, and donor-specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (P = .39). CONCLUSIONS: Lung retransplantation is associated with a more complex postoperative course and lower peak lung function, but the long-term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure.

Quantitative chest CT for subtyping chronic lung allograft dysfunction and its association with survival.

Chronic lung allograft dysfunction (CLAD) is a major cause of mortality in lung transplant recipients. CLAD can be sub-divided into at least 2 subtypes with distinct mortality risk characteristics: restrictive allograft syndrome (RAS), which demonstrates increased overall computed tomography (CT) lung density in contrast with bronchiolitis obliterans syndrome (BOS), which demonstrates reduced overall CT lung density. This study aimed to evaluate a reader-independent quantitative density metric (QDM) derived from CT histograms to associate with CLAD survival. A retrospective study evaluated CT scans corresponding to CLAD onset using pulmonary function tests in 74 patients (23 RAS, 51 BOS). Two different QDM values (QDM1 and QDM2) were calculated using CT lung density histograms. Calculation of QDM1 includes the extreme edges of the histogram. Calculation of QDM2 includes the central region of the histogram. Kaplan-Meier analysis and Cox regression analysis were used for CLAD prognosis. Higher QDM values were significantly associated with decreased survival. The hazard ratio for death was 3.2 times higher at the 75th percentile compared to the 25th percentile using QDM1 in a univariate model. QDM may associate with CLAD patient prognosis.

Translation of Knowledge to Practice-Improving Awareness in NSCLC Molecular Testing.

BACKGROUND: Molecular testing in advanced lung cancer is standard in guiding treatment selection. However, population-wide implementation of testing remains a challenge. We developed a knowledge translation intervention to improve understanding among diagnostic specialists about molecular testing and appropriate diagnostic sampling in lung cancer. METHODS: Specialty-specific education programs were developed from existing literature and input from Canadian leaders in lung pathology, respirology, interventional radiology, thoracic surgery, radiation oncology, and medical oncology. The programs, including key messages, review of current data, existing guidelines, group discussion, and participant feedback, were administered at provincial and national specialty meetings. Participant knowledge was assessed before and after the intervention by using anonymous questionnaires. Molecular (EGFR) testing rates in Ontario were also evaluated before and after the intervention period. RESULTS: Ten programs were administered to diagnostic specialists, including respirologists, pathologists, thoracic surgeons, radiologists, radiation oncologists, and medical oncologists, with completion of 255 preintervention and 219 postintervention surveys. At baseline, 30% were unsure of tissue handling methods for molecular testing, 20% chose an incorrect technique, and half were unfamiliar with how to initiate testing. After intervention, specialist knowledge improved regarding tissue handling and appropriate fixation techniques and uncertainty decreased from 30% to 2% (p < 0.001). A 12% increase (relative increase 57%) in molecular (EGFR) testing requests in Ontario was observed over the intervention period (p = 0.0032). CONCLUSIONS: Significant knowledge gaps exist among diagnostic specialists regarding molecular testing and targeted therapy in lung cancer. This initiative significantly improved understanding of the importance and methods of successful molecular testing and correlated with increased testing rates.

The role of biomechanical anatomical modeling via computed tomography for identification of restrictive allograft syndrome.

Chronic lung allograft dysfunction (CLAD) reduces long-term graft survival. It is important to distinguish CLAD subtypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) as RAS has a worse prognosis and accurate subtyping could facilitate targeted treatments. However, the current diagnosis of CLAD subtypes is based on pulmonary function test (PFT) results that reflect global estimates of lung function; anatomical modeling based on computed tomography (CT) has the potential to provide detailed analysis of global and regional lung function. The purpose of this study is to evaluate the utility of CT-based anatomical modeling for the identification of RAS. This retrospective study included 51 patients (CLAD: 17 BOS and 17 RAS, control: 17 No-CLAD). CT data were assessed using a biomechanical model-based platform (MORFEUS) to characterize changes in lung deformation between baseline and disease onset. Lung deformation demonstrated high sensitivity and specificity (>80%) in differentiating RAS from BOS (P<.0001) and No-CLAD (P<.0001). There were matching radiological reading and inward deformation abnormalities in 79% of lung sections in patients with RAS. Anatomical modeling is complementary to conventional assessment in the diagnosis of RAS and potentially provides quantitative data that can help in the characterization and detailed assessment of heterogeneous lung parenchymal disease.

Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome.

Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22-inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ(-/-) and Il22(-/-) mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIγ decreased lung inflammatory gene expression and protected Il22(-/-) mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

RATIONALE: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. OBJECTIVES: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. METHODS: We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. CONCLUSIONS: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction.

BACKGROUND: The long-term success of lung transplantation is challenged by the development of chronic lung allograft dysfunction (CLAD) and its distinct subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). However, the current diagnostic criteria for CLAD subtypes rely on total lung capacity (TLC), which is not always measured during routine post-transplant assessment. Our aim was to investigate the utility of low-dose 3-dimensional computed tomography (CT) lung volumetry for differentiating RAS from BOS. METHODS: This study was a retrospective evaluation of 63 patients who had developed CLAD after bilateral lung or heart‒lung transplantation between 2006 and 2011, including 44 BOS and 19 RAS cases. Median post-transplant follow-up was 65 months in BOS and 27 months in RAS. The median interval between baseline and the disease-onset time-point for CT volumetry was 11 months in both BOS and RAS. Chronologic changes and diagnostic accuracy of CT lung volume (measured as percent of baseline) were investigated. RESULTS: RAS showed a significant decrease in CT lung volume at disease onset compared with baseline (mean 3,916 ml vs 3,055 ml when excluding opacities, p < 0.0001), whereas BOS showed no significant post-transplant change (mean 4,318 ml vs 4,396 ml, p = 0.214). The area under the receiver operating characteristic curve of CT lung volume for differentiating RAS from BOS was 0.959 (95% confidence interval 0.912 to 1.01, p < 0.0001) and the calculated accuracy was 0.938 at a threshold of 85%. CONCLUSION: In bilateral lung or heart‒lung transplant patients with CLAD, low-dose CT volumetry is a useful tool to differentiate patients who develop RAS from those who develop BOS.

Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation.

BACKGROUND: Ex vivo lung perfusion (EVLP) is an effective method to assess and improve the function of otherwise unacceptable lungs, alleviating the shortage of donor lungs. The early results with EVLP have been encouraging, but longer-term results, including functional and patient-reported outcomes, are not well characterized. METHODS: This retrospective single-center study included all lung transplants performed between September 2008 and December 2012. We investigated whether survival or rate of chronic lung allograft dysfunction (CLAD) differed in recipients of EVLP-treated lungs compared with contemporaneous recipients of conventional donor lungs. We also studied functional (highest forced expiratory volume in 1 second predicted, change in 6-minute walk distance, number of acute rejection episodes) and quality of life outcomes. RESULTS: Of 403 lung transplants that were performed, 63 patients (15.6%) received EVLP-treated allografts. Allograft survival for EVLP and conventional donor lung recipients was 79% vs 85%, 71% vs 73%, and 58% vs 57% at 1, 3, and 5 years after transplant, respectively (log-rank p = not significant). Freedom from CLAD was also similar (log-rank p = 0.53). There were no significant differences in functional outcomes such as highest forced expiratory volume in 1 second predicted (76.5% ± 23.8% vs 75.8% ± 22.8%, p = 0.85), change in 6-minute walk distance (194 ± 108 meters vs 183 ± 126 meters, p = 0.57), or the number of acute rejection episodes (1.5 ± 1.4 vs 1.3 ± 1.3, p = 0.36). The EVLP and conventional donor groups both reported a significantly improved quality of life after transplantation, but there was no intergroup difference. CONCLUSION: EVLP is a safe and effective method of assessing and using high-risk donor lungs before transplantation and leads to acceptable long-term survival, graft function, and improvements of quality of life that are comparable with conventionally selected donor lungs.

Loss of the podocyte-expressed transcription factor Tcf21/Pod1 results in podocyte differentiation defects and FSGS.

Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo. Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors (wnt4creTcf21) results in a profound developmental arrest of podocyte differentiation and renal failure in 100% of mice during the perinatal period. Taken together, our results demonstrate a critical role for Tcf21 in the differentiation and maintenance of podocytes. Identification of direct targets of this transcription factor may provide new therapeutic avenues for proteinuric renal disease, including FSGS.