ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Comparative analysis of how immune sensitization is defined prior to lung transplantation.

BACKGROUND: Immune sensitization prior to lung transplantation may be associated with worse survival. Using solid phase assays to define sensitization, we assessed the relationship between PRA status, donor specific anti-HLA antibodies (DSA) pre-transplant, cytotoxic cross match results and the clinical outcomes following lung transplantation. METHODS: Luminex assays determined the presence of antibodies to class I and class II MHC molecules prior to lung transplantation. At the time of transplant, the PRA status, the presence of DSA and prospective cytotoxic cross match result were analysed in 195 patients undergoing lung transplantation between June 2008 and June 2012. Clinical outcomes analysed included acute cellular and antibody-mediated rejection, chronic lung allograft dysfunction (CLAD) and mortality. RESULTS: At the time of transplant, 45% of patients had a positive PRA and 29% had DSA. On univariate analysis, the presence of pre-transplant class I or II anti-HLA donor-specific antibodies was not associated with the development of chronic lung allograft dysfunction (CLAD) despite significant associations with PRA status and B-cell crossmatch. CONCLUSION: Defining sensitization using solid phase assays provide additional details regarding donor-specific sensitization but did not provide additional prognostic information to that provided by historically available cell-based cross-match assays.

Donation After Circulatory Determination of Death Lung Transplantation for Pulmonary Arterial Hypertension: Passing the Toughest Test.

Lung transplantation (LTx) is a therapeutic option for severe pulmonary arterial hypertension (PAH) patients failing optimal medical therapy. The use of donation after circulatory determination of death (DCDD) donor lungs for PAH LTx has rarely been reported, primarily reflecting concerns that DCDD lungs represent extended criteria donors, at risk of morbidity and mortality. A retrospective study of all Alfred Hospital DCDD and DNDD (donation after neurologic determination of death) PAH LTx was undertaken. Protocolized fluid/inotrope/ventilator and extracorporeal membrane oxygenation (ECMO) strategies were utilized. Since our first DCDD LTx in 2006, 512 LTx have been performed. Of 31 PAH recipients, 11 received DCDD lungs (11% of DCDD LTx) and 20 received DNDD lungs (5% of DNDD LTx) (p = 0.04). Only one PAH patient died on the LTx waiting list. Peri-LTx ECMO was utilized in 3/11 (27%) DCDD and 6/20 (30%) DNDD PAH LTx (p = 0.68). Primary graft dysfunction, intensive care, and overall stay were the same in both groups. Survival at 1 and 8 years was 100% and 80% for DCDD versus 100% and 70% for DNDD LTx (p = 0.88), respectively. In conclusion, excellent results can be achieved for PAH LTx. DCDD donor lungs are not extended lungs per se having passed the toughest test.

A randomized, double-blind, placebo-controlled, multicenter study of rabbit ATG in the prophylaxis of acute rejection in lung transplantation.

ATG-Fresenius S (ATG-F) is a polyclonal anti-human-T-lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG-F at doses of 5 and 9 mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow-up within 12 months of transplantation. The interim analysis showed the ATG-F 5 mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9 mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG-F 9 mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single-dose induction therapy with ATG-F within the first year after lung transplantation.

Lessons and insights from ABO-incompatible lung transplantation.

With ABO blood group incompatibility (ABOi) between donor and recipient becoming a part of mainstream living-donor renal transplantation, the applicability of ABOi to other areas of transplantation is being reconsidered. Here we present a case of inadvertent ABOi lung retransplantation managed successfully with initial plasmapheresis, antithymocyte globulin and intravenous immunoglobulin; and subsequently with oral cyclophosphamide and sirolimus in addition to tacrolimus and prednisolone. Interestingly, in the setting of solid levels of tacrolimus and sirolimus, the patient developed a fatal thrombotic microangiopathy of uncertain origin subsequent to the cessation of cyclophosphamide at 9 years posttransplant. It is apparent that ABOi lung transplantation can result in surprisingly successful long-term outcomes. Low pretransplant antibody titers likely aid this and, in pediatric neonatal or infant cases, this may not be uncommon. We must proceed cautiously as there are significant risks. Understanding the monitoring, prevention and treatment of lung transplant antibody-mediated rejection, while avoiding the long-term complications of overimmunosuppression, will be the keys to the success of future cases.

Preemptive treatment with voriconazole in lung transplant recipients.

BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality in lung transplant (LTx) recipients. Data for voriconazole use in preemptive treatment remain scant. METHOD: A single-center, retrospective cohort study was conducted to investigate the efficacy and safety of voriconazole preemptive treatment for post-LTx colonization. RESULTS: We reviewed 62 adult LTx patients, who received their first course of voriconazole prophylaxis (i.e., as preemptive treatment) between July 2003 and June 2010. Outcomes were determined at 6 and 12 months after commencing therapy. Aspergillus fumigatus (75.8%) was the most common colonizing isolate. Median duration of voriconazole prophylaxis was 85 days. At 6 months, 1 LTx patient (1.6%) had IFI, 47 (75.8%) cleared their colonizing isolate, 3 (4.8%) had persistent colonization, 7 (11.3%) had recurrent colonization, 1 (1.6%) had new colonization, 2 (3.2%) had aspergilloma, and 1 (1.6%) was clinically unstable with no culture results. Sixteen (25.8%) had died by 12 months. Ten (16.1%) had likely drug-related hepatotoxicity. LTx patients with diabetes mellitus within 30 days before commencing prophylaxis were at higher risk of recurrent Aspergillus colonization at 6 months (P = 0.030). Chronic rejection within 30 days before prophylaxis was associated with 12-month mortality (P = 0.007). CONCLUSIONS: Voriconazole preemptive treatment resulted in low incidence of IFI and IFI-related mortality.

Quantification of voriconazole in human bronchoalveolar lavage fluid using high-performance liquid chromatography with fluorescence detection.

The quantification of voriconazole concentration in lung epithelial lining fluid to facilitate the management of pulmonary fungal colonisation or aspergillosis is of increasing interest. An accurate and reproducible high-performance liquid chromatography method to quantify voriconazole in human bronchoalveolar lavage (BAL) fluid was developed and validated. BAL samples were concentrated by freeze-drying and reconstituted with water prior to deproteinisation. Separation was achieved with a C18 column employing fluorescence detection (excitation: 260nm, emission: 370nm). The calibration curves were linear from 2.5 to 500ng/mL. The intra- and inter-day precisions were within 7%. Accuracies ranged from 102% to 107%. The clinical applicability was established by successful measurement of voriconazole concentrations in lung transplant recipients. The assay provides an alternative approach for those with negligible access to liquid chromatography-tandem mass spectrometry instrumentation.

Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.

Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18-89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.

Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome.

Early studies reported cytomegalovirus (CMV) pneumonitis as a risk factor for development of bronchiolitis obliterans syndrome (BOS) following lung transplantation. While improvements in antiviral prophylaxis have resulted in a decreased incidence of CMV pneumonitis, molecular diagnostic techniques allow diagnosis of subclinical CMV replication in the allograft. We hypothesized that this subclinical CMV replication was associated with development of BOS. We retrospectively evaluated 192 lung transplant recipients (LTR) from a single center between 2001 and 2009. Quantitative (PCR) analysis of CMV viral load and histological evidence of CMV pneumonitis and acute cellular rejection was determined on 1749 bronchoalveolar lavage (BAL) specimens and 1536 transbronchial biopsies. CMV was detected in the BAL of 41% of LTR and was significantly associated with the development of BOS (HR 1.8 [1.1-2.8], p = 0.02). This association persisted when CMV was considered more accurately as a time-dependent variable (HR 2.1 [1.3-3.3], p = 0.003) and after adjustment for significant covariates in a multivariate model. CMV replication in the lung allograft is common following lung transplantation and is associated with increased risk of BOS. As antiviral prophylaxis adequately suppresses CMV longer prophylactic strategies may improve long-term outcome in lung transplantation.

Antifungal prophylaxis in lung transplantation--a world-wide survey.

While variations in antifungal prophylaxis have been previously reported in lung transplant (LTx) recipients, recent clinical practice is unknown. Our aim was to determine current antifungal prophylactic practice in LTx centers world-wide. One nominated LTx clinician from each active center was invited by e-mail to participate in a web-based survey between September 2009 and January 2010. Fifty-seven percent (58/102) responded. The majority of responses were from medical directors of LTx centers (72.4%), and from the United States (44.8%). Within the first 6 months post-LTx, most centers (58.6%) employed universal prophylaxis, with 97.1% targeting Aspergillus species. Voriconazole alone, and in combination with inhaled amphotericin B (AmB), were the preferred first-line agents. Intolerance to side effects of voriconazole (69.2%) was the main reason for switching to alternatives. Beyond 6 months post-LTx, most (51.8%) did not employ antifungal prophylaxis. Fifteen centers (26.0%) conducted routine antifungal therapeutic drug monitoring during prophylactic period. There are differences in strategies employed between U.S. and European centers. Most respondents indicated a need for antifungal prophylactic guidelines. In comparison to earlier findings, there was a major shift toward prophylaxis with voriconazole and an increased use of echinocandins, posaconazole and inhaled lipid formulation AmB.

Lung transplantation in pulmonary fibrosis: challenging early outcomes counterbalanced by surprisingly good outcomes beyond 15 years.

Interstitial lung disease (ILD) has been reported to have a poor outcome following lung transplantation due to difficulties getting ill recipients to transplantation and challenging early postoperative outcomes. To assess long-term outcomes for this cohort, we performed a retrospective 18-year chart review of all ILD lung transplant recipients. ILD single (SLT) and bilateral sequential lung transplantations (BSLT) were compared with all other lung transplant patients and International Society for Heart and Lung Transplantation (ISHLT) Registry data over the same time period. Of 585 lung transplantations, 90 (15%) were ILD (53 SLT, 37 BSLT); 67 (74%) were idiopathic pulmonary fibrosis (IPF), 9 (10%) were sarcoidosis, 9 (10%) were lymphangioleiomyomatosis, and 5 (6%) had other indications. Mean age was 52 years (range, 34-69 years). Actuarial survival at 1, 5, 10, 15, and 18 years compared favorably to all other lung transplantations performed (77% vs 83%, 51% vs 50%, 42% vs 26%, 28% vs 17%, and 28% vs 8%, respectively). IPF actuarial survival at 1, 5, and 10 years appeared superior to ISHLT Registry data (76% vs 72%, 50% vs 44%, and 34% vs 20%, respectively). There was equivocal survival between SLT and BSLT at 1, 5, and 10 years (78% vs 68%, 49% vs 50%, and 29% vs 50%, respectively). Our ILD figures compared favorably to lung transplantation for other diseases and international standards, while survival from SLT was as successful as BSLT both in the short and the longer term. Consideration should be given to utilizing SLT to maximize the allocation of donor lungs and to decrease waiting list mortality associated with IPF.

Association between primary graft dysfunction among lung, kidney and heart recipients from the same multiorgan donor.

Even organs from an ideal donor will occasionally develop primary graft dysfunction (PGD) causing a significant morbidity and mortality after transplantation. It is likely that this situation represents subtle undetectable levels of ongoing donor organ dysfunction. The aim of this study is to investigate the association of PGD between lung, kidney and heart recipients from the one donor. From 202 multiorgan donors, contributed 231 consecutive lung transplants at the Alfred Hospital, 378 kidney and 114 heart transplants were subsequently performed at multiple centers across Australia and New Zealand. Eight hundred seventy-five organs were used for 723 transplants. The incidence of PGD after lung, kidney and heart transplants was 20% (47/231), 24% (92/378) and 20% (23/114), respectively. In paired single organ recipients, PGD in one of the pair was a significant risk factor for the development of PGD in the other [lung: odds ratio = 5.63 (1.72-18.43), p = 0.004; kidney: odds ratio = 3.19 (1.90-5.35), p < 0.0001]. In multivariate analysis, same donor heart PGD [3.37 (1.19-9.50), p = 0.02] was an independent risk factor for lung PGD and same donor lung PGD was significant risk factor for kidney PGD [1.94 (1.01-3.73), p = 0.04], if the PGD status of the paired kidney was not known. There was a significant association for the development of PGD across different organs transplanted from the same donor.

Early lung transplantation success utilizing controlled donation after cardiac death donors.

Donation-after cardiac death (DCD) donor organs have potential to significantly alleviate the shortage of transplantable lungs. However, only limited data so far describes DCD lung transplantation (LTx) techniques and results. This study aims to describe the Alfred Hospital's early and intermediate outcomes following DCD donor LTx. Following careful experimentation and consultation DCD guidelines were created to utilize Maastricht category III lung donors from either the ICU or operating room(OR), with a warm ischemic time(WIT) of <60 min. Between May 2006 and December 2007, 22 referred DCD donors led to 11 attempted retrievals after withdrawal, resulting in 8 actual bilateral LTx (2 donors did not arrest in prescribed period and 1 donor had nonacceptable lungs). ICU WIT = 38.4 min (range 20-54, OR WIT = 12.7 min (11-15), p < 0.05. Post-LTx, 1 pulmonary hypertensive patient required ECMO for PGD3. The mean group pO2/FiO2 ratio at 24 hours was 307.7 (240-507) with an ICU stay of 9.5 days (2-21) and ward stay of 21.5 days (11-76). All 8 survive at a mean of 311 days (10-573) with good performance status and lung function. In conclusion, the use of Maastricht category III lungs for human LTx is associated with acceptable early clinical outcomes.

The dynamics and associations of airway neutrophilia post lung transplantation.

UNLABELLED: Bronchoalveolar lavage (BAL) neutrophilia has been repeatedly observed in lung transplant recipients with established bronchiolitis obliterans syndrome (BOS). Little is known of the fluctuations in BAL and airway neutrophilic inflammation post-transplant. This prospective longitudinal study aimed to evaluate the dynamic changes of lung allograft neutrophils with time, immunosuppression, infection and BOS. A total of 28, initially healthy, BOS 0, lung transplant recipients underwent 134 bronchoscopic assessments, including BAL and endobronchial biopsies (EBB) (with immunohistochemistry) over 3-year follow up. Subsequently, 21 developed BOS 0p and 16 ultimately BOS. Compared to controls, there was early and persistent BAL neutrophilia (p < 0.05), contrasting with an initially normal EBB that shows a progressive increased airway wall neutrophil infiltrate. BAL neutrophilia (but not airway wall neutrophilia) was most striking when there was concomitant bronchopulmonary infection, particularly in the patients with BOS. Univariate and multivariate analyses suggested that BAL neutrophilia was linked to markers of infection while EBB neutrophilia was linked with coexistent inflammation with macrophages and lymphocytes. IN CONCLUSION: (i) BAL neutrophilia is predominantly associated with infection; (ii) Airway wall neutrophilia (as monitored by EBB) increases with time post-transplant and is not associated with infection; (iii) By itself, BOS is not the major contributor to BAL and EBB neutrophilia.

Non-heart beating organ donation.

Increasing the levels of non-heart beating organ donation (NHBOD) is a potential means of improving the supply of transplantable organs. NHBOD may provide a mechanism to enable a patient's prior wishes to be realised and to provide comfort to a family in grief. There is an overriding ethical principle to strictly divide the responsibility for the care of the dying patient and the potential transplant recipient. Medical protocols need to be written, and institutional ethics committees and our national organ procurement system need to be involved if we are to protect public confidence and see NHBOD realise its full potential.

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.