The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

State of the art - Extracorporeal membrane oxygenation as a bridge to thoracic transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has revolutionized the treatment of refractory cardiac and respiratory failure, and its use continues to increase, particularly in adults. However, ECMO-related morbidity and mortality remain high. MAIN TEXT: In this review, we investigate and expand upon the current state of the art in thoracic transplant and extracorporeal life support (ELS). In particular, we examine recent increase in incidence of heart transplant in patients supported by ECMO; the potential changes in patient care and selection for transplant in the years prior to updated United Network for Organ Sharing (UNOS) organ allocation guidelines versus those in the years following, particularly where these guidelines pertain to ECMO; and the newly revived practice of heart-lung block transplants (HLT) and the prevalence and utility of ECMO support in patients listed for HLT. CONCLUSIONS: Our findings highlight encouraging outcomes in patients bridged to transplant with ECMO, considerable changes in treatment surrounding the updated UNOS guidelines, and complex, diverse outcomes among different centers in their care for increasingly ill patients listed for thoracic transplant.

Making the Cut: Parathyroidectomy Before or After Kidney Transplantation?

BACKGROUND: Hyperparathyroidism is common in patients with end-stage kidney disease and may persist after kidney transplantation (KT). Parathyroidectomy (PTx) is curative, but whether PTx should be performed before or after KT remains controversial. There is concern that PTx can adversely affect renal allograft function if performed post-KT and result in persistent hypocalcemia. This study evaluated outcomes and postoperative complications of PTx before and after KT at our institution. METHODS: We performed a retrospective review of patients at our center (1/2012-2/2019) who had PTx either pre-KT or post-KT. Data on patient demographics, surgical outcomes, and postoperative complications of PTx were collected. RESULTS: Ninety-eight patients were included in this study, with 23 patients undergoing PTx before KT and 75 after KT. The length of follow-up after KT was 67.7 ± 25.5 months. In post-KT PTx patients, 30-day allograft function was unchanged after PTx. Calcium oxalate and phosphate crystals were less common on allograft biopsies in pre-KT PTx patients (10.0% vs. 34.8%, p = 0.038). Patients in the pre-KT group required more calcium supplementation after PTx than the post-KT group (p < 0.001). At one-year post-PTx, 17 (19.1%) patients required > 1000 mg elemental calcium per day and 7 (7.9%) patients required > 2000 mg/day. There was no difference in surgical success or postoperative complications between the two groups. CONCLUSIONS: Parathyroidectomy before or after kidney transplantation does not adversely affect allograft function. The incidence of persistent hypocalcemia was low. Parathyroidectomy is safe and effective either before or after kidney transplantation.

Proceedings of the 2022 UAB CRRT Academy: Non-Invasive Hemodynamic Monitoring to Guide Fluid Removal with CRRT and Proliferation of Extracorporeal Blood Purification Devices.

In 2022, we celebrated the 15th anniversary of the University of Alabama at Birmingham (UAB) Continuous Renal Replacement Therapy (CRRT) Academy, a 2-day conference attended yearly by an international audience of over 100 nephrology, critical care, and multidisciplinary trainees and practitioners. This year, we introduce the proceedings of the UAB CRRT Academy, a yearly review of select emerging topics in the field of critical care nephrology that feature prominently in the conference. First, we review the rapidly evolving field of non-invasive hemodynamic monitoring and its potential to guide fluid removal by renal replacement therapy (RRT). We begin by summarizing the accumulating data associating fluid overload with harm in critical illness and the potential for harm from end-organ hypoperfusion caused by excessive fluid removal with RRT, underscoring the importance of accurate, dynamic assessment of volume status. We describe four applications of point-of-care ultrasound used to identify patients in need of urgent fluid removal or likely to tolerate fluid removal: lung ultrasound, inferior vena cava ultrasound, venous excess ultrasonography, and Doppler of the left ventricular outflow track to estimate stroke volume. We briefly introduce other minimally invasive hemodynamic monitoring technologies before concluding that additional prospective data are urgently needed to adapt these technologies to the specific task of fluid removal by RRT and to learn how best to integrate them into practical fluid-management strategies. Second, we focus on the growth of novel extracorporeal blood purification devices, starting with brief reviews of the inflammatory underpinnings of multiorgan dysfunction and the specific applications of pathogen, endotoxin, and/or cytokine removal and immunomodulation. Finally, we review a series of specific adsorptive technologies, several of which have seen substantial clinical use during the COVID-19 pandemic, describing their mechanisms of target removal, the limited existing data supporting their efficacy, ongoing and future studies, and the need for additional prospective trials.

Continuous renal replacement therapy in patients treated with extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy utilized for patients with severe life-threatening cardiorespiratory failure. Patients treated with ECMO are among the most severely ill encountered in critical care and are at high-risk of developing multiple organ dysfunction, including acute kidney injury (AKI) and fluid overload. Continuous renal replacement therapy (CRRT) is increasingly utilized inpatients on ECMO to manage AKI and treat fluid overload. The indications for renal replacement therapy for patients on ECMO are similar to those of other critically ill populations; however, there is wide practice variation in how renal supportive therapies are utilized during ECMO. For patients requiring both CRRT and ECMO, CRRT may be connected directly to the ECMO circuit, or CRRT and ECMO may be performed independently. This review will summarize current knowledge of the epidemiology of AKI, indications and timing of CRRT, delivery of CRRT, and the outcomes of patients requiring CRRT with ECMO.

Extracorporeal photopheresis to attenuate decline in lung function due to refractory obstructive allograft dysfunction.

BACKGROUND: This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. STUDY DESIGN AND METHODS: Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. RESULTS: Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non-random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP-treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non-survivors (-212 ± 177 ml/month) when compared to the survivors (-95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. CONCLUSIONS: These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

Differences in airway microbiome and metabolome of single lung transplant recipients.

BACKGROUND: Recent studies suggest that alterations in lung microbiome are associated with occurrence of chronic lung diseases and transplant rejection. To investigate the host-microbiome interactions, we characterized the airway microbiome and metabolome of the allograft (transplanted lung) and native lung of single lung transplant recipients. METHODS: BAL was collected from the allograft and native lungs of SLTs and healthy controls. 16S rRNA microbiome analysis was performed on BAL bacterial pellets and supernatant used for metabolome, cytokines and acetylated proline-glycine-proline (Ac-PGP) measurement by liquid chromatography-high-resolution mass spectrometry. RESULTS: In our cohort, the allograft airway microbiome was distinct with a significantly higher bacterial burden and relative abundance of genera Acinetobacter & Pseudomonas. Likewise, the expression of the pro-inflammatory cytokine VEGF and the neutrophil chemoattractant matrikine Ac-PGP in the allograft was significantly higher. Airway metabolome distinguished the native lung from the allografts and an increased concentration of sphingosine-like metabolites that negatively correlated with abundance of bacteria from phyla Proteobacteria. CONCLUSIONS: Allograft lungs have a distinct microbiome signature, a higher bacterial biomass and an increased Ac-PGP compared to the native lungs in SLTs compared to the native lungs in SLTs. Airway metabolome distinguishes the allografts from native lungs and is associated with distinct microbial communities, suggesting a functional relationship between the local microbiome and metabolome.

Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant.

RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.

RATIONALE: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. OBJECTIVES: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. METHODS: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. MEASUREMENTS AND MAIN RESULTS: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. CONCLUSIONS: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

Clinical risk factors for primary graft dysfunction after lung transplantation.

RATIONALE: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. OBJECTIVES: We sought to identify donor, recipient, and perioperative risk factors for PGD. METHODS: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression. MEASUREMENTS AND MAIN RESULTS: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0-1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality. CONCLUSIONS: We identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).

Strategies and outcomes of extracorporeal membrane oxygenation use in peripartum patients: a single institution experience.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) use in peripartum patients is rare, and there is a gap in the literature on the outcomes and guidance on using ECMO in peripartum patients. This study describes ECMO strategies our institution uses for peripartum patients and reports outcomes of ECMO use in peripartum patients with respiratory and/or cardiac failure. METHODS: A case series of all peripartum patients, defined as pregnant or up to 6 weeks after delivery of an infant >20 weeks gestation, from 2018 to 2023 from a single center requiring ECMO support. Patients were included if ECMO was initiated in the setting of cardiac, pulmonary, or combined failure. Patient demographics, operative details, ECMO data, and adverse outcomes for maternal, fetus, and neonates were all collected. RESULTS: Eighteen patients met the inclusion criteria. The cohort had a mean maternal age of 30.7 years old and was racially diverse. A majority of this cohort tested positive for COVID-19 (n = 10, 55%). ECMO was a bridge to recovery for all patients, of whom 14 (78%) were discharged out of the hospital alive. No patients received transplantation or a durable mechanical device. The most common complications were infection (25%) and postpartum hemorrhage (22%). CONCLUSIONS: ECMO use in peripartum patients in a single tertiary center was associated with a high survival rate. Furthermore, a strong multidisciplinary team, careful reevaluation of clinical trajectory, and consideration of complications and risks associated with using ECMO in peripartum patients are possible frameworks to use when challenged with critically ill peripartum patients.

ISHLT consensus statement on the perioperative use of ECLS in lung transplantation: Part II: Intraoperative considerations.

The use of extracorporeal life support (ECLS) throughout the perioperative phase of lung transplantation requires nuanced planning and execution by an integrated team of multidisciplinary experts. To date, no multidisciplinary consensus document has examined the perioperative considerations of how to best manage these patients. To address this challenge, this perioperative utilization of ECLS in lung transplantation consensus statement was approved for development by the International Society for Heart and Lung Transplantation Standards and Guidelines Committee. International experts across multiple disciplines, including cardiothoracic surgery, anesthesiology, critical care, pediatric pulmonology, adult pulmonology, pharmacy, psychology, physical therapy, nursing, and perfusion, were selected based on expertise and divided into subgroups examining the preoperative, intraoperative, and postoperative periods. Following a comprehensive literature review, each subgroup developed recommendations to examine via a structured Delphi methodology. Following 2 rounds of Delphi consensus, a total of 39 recommendations regarding intraoperative considerations for ECLS in lung transplantation met consensus criteria. These recommendations focus on the planning, implementation, management, and monitoring of ECLS throughout the entire intraoperative period.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

Variation in PTX3 is associated with primary graft dysfunction after lung transplantation.

RATIONALE: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis. OBJECTIVES: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD. METHODS: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis. CONCLUSIONS: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.

HLA Sensitization in Patients Bridged to Lung Transplantation With Extracorporeal Membrane Oxygenation.

Lung transplantation is a definitive therapy for many end-stage lung pathologies. Extracorporeal membrane oxygenation (ECMO) is increasingly being used as a bridge to lung transplantation (BTT). HLA sensitization is a major barrier to lung transplantation. The development of HLA sensitization while undergoing ECMO support as a BTT has recently been reported in a 2-patient series. Methods: We performed a retrospective analysis of patients undergoing ECMO as a BTT at a single large academic medical center from January 2016 to April 2022. The study was approved by the institutional review board. We selected patients who had undergone ECMO support for at least 7 d with either negative HLA before cannulation or initial negative HLA on ECMO (3 patients). Results: We identified 27 patients bridged to lung transplantation with available HLA data. Of this group, 8 patients (29.6%) developed significant HLA sensitization (>10%). We did not identify any factors predisposing to sensitization, including infection episodes or blood product transfusion. Sensitized patients demonstrated a trend toward an increased primary graft dysfunction rate, a need for posttransplant ECMO support, and a decreased 1-y survival; however, these did not meet statistical significance. Conclusions: Our study is the largest series today describing the association between HLA sensitization and ECMO therapy. We suggest that interaction between the immune system and ECMO circuit contributes to allosensitization pretransplant, similar to that occurring with ventricular assist device. Further work is needed to better characterize the incidence of HLA sensitization in a multicenter cohort and to identify potentially modifiable factors associated with HLA sensitization.

Bilateral Lung Transplantation With Donor Positive for COVID-19 Infection on Bronchoalveolar Lavage: A Case Report.

Initial experience with lung transplant of COVID-19-positive donors was marked by disappointing results, including a reported case of mortality through donor to recipient transmission of infection. However, since that time a number of improvements in preventative and therapeutic measures against COVID-19 have been developed. We present the case of a 51-year-old woman with scleroderma-associated interstitial lung disease who was awaiting lung transplant. A potential donor with excellent lung physiology was located; however, initial testing on bronchoalveolar lavage (BAL) was positive for COVID-19. The donor had tested positive 2 weeks prior and had symptomatically recovered. Our patient had been fully vaccinated but not seroconverted. Given the history of a donor with recovering COVID infection and a fully immunized recipient, our multidisciplinary team elected to proceed with the transplant. The patient successfully underwent bilateral lung transplant with standard induction immunosuppression. Bebtelovimab was given post-transplant day 1 because the recipient remained seronegative to COVID-19. Serial bronchoalveolar lavages post transplant have been negative for COVID-19. The patient has done well after transplant. She was seen in the clinic 2 months post transplant and is ambulatory without supplemental oxygen requirements. To our knowledge, this represents the first reported successful case of lung transplant with a donor positive for COVID-19 on lower respiratory tract sampling.

Solute clearance in CRRT: prescribed dose versus actual delivered dose.

BACKGROUND: Substantial efforts have been made toward defining the dose threshold of continuous renal replacement therapy (CRRT) associated with improved survival in critically ill patients with acute kidney injury. Published studies have used prescribed effluent rates, expressed as total effluent volume (TEV) per weight and unit time (mL/kg/h), as a surrogate for dose. The purpose of this study was to compare differences in CRRT dose based on prescribed effluent rate, measured TEV and direct measurement of urea and creatinine clearance. METHODS: We analyzed data that had been prospectively collected on 200 patients enrolled in a randomized trial comparing survival with a prescribed effluent rate of 20 mL/kg/h (standard dose) to 35 mL/kg/h (high dose) using pre-dilution continuous venovenous hemodiafiltration (CVVHDF). Filters were changed every 72 h. Blood urea nitrogen (BUN), serum creatinine (SCr), effluent urea nitrogen (EUN) and effluent creatinine (ECr) were collected daily. Actual delivered dose was calculated as: (EUN/BUN)*TEV for urea and (ECr/SCr)*TEV for creatinine. Data were available for 165 patients. RESULTS: In both groups, prescribed dose differed significantly from the measured TEV dose (P < 0.001). In the standard dose group, there was no difference between the measured TEV dose and actual delivered urea and creatinine clearances. However, in the high-dose group, measured TEV dose differed significantly from delivered urea clearance by 7.1% (P < 0.001) and creatinine clearance by 13.9% (P < 0.001). CONCLUSIONS: Dose based on prescribed effluent rate or measured TEV is a poor substitute for actual CVVHDF creatinine and urea clearance.

Advances in continuous renal replacement therapy: citrate anticoagulation update.

Because of the potential side effects of heparin, methods of regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) have been gaining wider acceptance with the development of simplified and safer protocols. Advantages of RCA include the avoidance of systemic anticoagulation and heparin-induced thrombocytopenia. The disadvantage is that citrate can add complexity and labor intensity to CRRT. Frequent monitoring of electrolytes, ionized calcium, and acid-base status is required, due to the potential for hypernatremia, metabolic alkalosis, and systemic ionized hypocalcemia. If properly monitored, complications associated with RCA are uncommon. A variety of methods of delivering RCA are described in the literature. Overall, studies of RCA, as compared to unfractionated heparin, report better filter survival times and less bleeding. In this section, we summarize the characteristics of citrate as an anticoagulant and provide an update of citrate use in CRRT.

Obesity and primary graft dysfunction after lung transplantation: the Lung Transplant Outcomes Group Obesity Study.

RATIONALE: Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation. OBJECTIVES: To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation. METHODS: We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios. MEASUREMENTS AND MAIN RESULTS: Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30­50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass. CONCLUSIONS: Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

Contemporary trends in PGD incidence, outcomes, and therapies.

BACKGROUND: We sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation. METHODS: Patients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders. RESULTS: A total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p = .0002), median LAS (38.0-47.7 p = .009) and the use of ECMO salvage for PGD (5.7%-20.9%, p = .007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p = .0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p = .66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p = .0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]). CONCLUSIONS: PGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.