Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Interferon Gamma ELISPOT Testing as a Risk-Stratifying Biomarker for Kidney Transplant Injury: Results From the CTOT-01 Multicenter Study.

Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell-depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNγELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNγELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells.

Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury.

Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5-99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.

Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Sarcoma of the mitral valve causing coronary arterial occlusion in children.

Primary tumors of the cardiac valves are rare. One of the most common reasons that left-sided cardiac tumors come to clinical attention is embolization to the systemic circulation. We present two children who suffered left coronary arterial occlusion due to embolization of a sarcoma of the mitral valve. A 6-year-old female who had been admitted to the hospital after cerebrovascular embolization of a fragment of sarcoma of the mitral valve experienced sudden cardiovascular collapse due to occlusion of the left coronary artery. She was placed on extracorporeal membrane oxygenation, and underwent coronary embolectomy and resection of the tumor from the mitral valve and its tendinous cords. Left ventricular function did not improve, and she underwent orthotopic heart transplantation. On follow-up 32 months after transplant, the patient is well, with no evidence of recurrence of or metastasis from the tumor. The tumor arose from the leaflets and tendinous cords of the mitral valve, and was composed grossly of multiple white nodules. Histopathologic evaluation disclosed fragments composed predominantly of peripheral spindle cells in an extensive fibromyxoid stroma. The mildly pleomorphic cells of the tumor gradually blended with adjacent pieces of the mitral valvar leaflet and tendinous cords. Immunohistochemical studies revealed strong staining for vimentin, smooth muscle actin, muscle specific actin, and myoglobin, suggesting myogenic differentiation. The other patient was a 2 1/2-year-old female who died suddenly at home. Grossly and histologically, the tumor was essentially identical to the first case, and there was a 3 cm string-like extension passing into the orifice of the left coronary artery. To put the cases in context, we compare them with other descriptions of this rare type of tumor.

Arrhythmias after pediatric lung transplantation.

Atrial arrhythmias have been reported after congenital heart surgery involving extensive atrial suture lines. Experimental studies involving bilateral lung transplantation (Tx) suggest that the left atrial suture lines predispose to atrial flutter. The overall incidence and type of arrhythmias after pediatric lung Tx have not previously been described and therefore the purpose of this study was to prospectively screen and describe arrhythmias in a subset of our lung transplant population. Over a 1-yr study period, all recipients of bilateral lung Tx were admitted to a full-disclosure telemetry unit. Single-lead electrocardiograms were recorded continuously and reviewed daily via a beat-by-beat analysis. A total of 314 patient days (range 9-93, median 43 days) were recorded from seven patients. The incidence of arrhythmias observed per total patient days included junctional escape rhythm (4.8%), non-sustained ventricular tachycardia (4.1%), accelerated junctional (2.5%), sinus bradycardia (2.2%), non-sustained supraventricular tachycardia (1.3%), ectopic atrial tachycardia (1.0%), sustained ventricular tachycardia (0.3%), junctional ectopic tachycardia (0.3%), and second degree heart block (0.3%). No patient had sustained supraventricular tachycardia, atrial flutter, atrial fibrillation, or complete heart block. Arrhythmias were treated in two patients. During the follow-up period, one patient received amiodarone for ventricular tachycardia (which was also noted and treated prior to transplant). We conclude that among pediatric lung transplant recipients admitted for their transplant surgery, arrhythmia is uncommon and rarely requires therapy.

Airway growth after pediatric lung transplantation.

BACKGROUND: Lung transplantation (LT) has been successfully offered to pediatric patients. Very little is known about the growth of the transplanted lung, especially in the infant population. Computerized tomography (CT) scanning is a simple method for studying pediatric patients who have undergone LT. We evaluated the use of CT scans to assess airway growth after pediatric LT, compare airway diameter indexed to somatic growth between LT patients and normals, and compare the growth of pre-anastomotic and post-anastomotic airways indexed to somatic growth in pediatric LT patients. METHODS: We reviewed CT scans on all pediatric patients who underwent primary LT before their fifteenth birthday between January 1995 and September 1998. Uniform measurements of diameter were made in pre-anastomotic (trachea, and proximal right and left bronchi) and post-anastomotic (distal right and left bronchi) sites. These measurements were then correlated with height and compared to previously published normal values. RESULTS: Of the 16 patients who underwent LT during the study period, 11 had at least 2 sequential CT scans (LT age 3 months to 14 years, median 2 years). Thirty-one CT scans were reviewed. Inter-observer variability was within 1 standard deviation (2 mm) in 93% of the measurements and inter-observer reliability was 0.91 by analysis of variance. Tracheal transverse diameter plotted against body height (slope 0.0072, correlation coefficient 0.88) was virtually identical to previously published norms. A similar relationship between airway diameter and height was observed in pre-anastomotic and post-anastomotic segments. CONCLUSION: CT scanning is a reliable method for assessing airway growth in pediatric LT recipients. Tracheal growth in pediatric LT recipients is similar to that of normal children. Post-anastomotic large airways grow similarly to native, pre-anastomotic airways.

Effectiveness of pharmacomechanical thrombolysis in infants and children.

Between March 1995 and February 2000, 10 children with major thromboses were treated with local pharmacomechanical thrombolysis. Clinical improvement was found in 8 patients: follow-up angiography showed complete thrombus resolution in 5 patients and subtotal resolution in 4.

Modifications to the cavopulmonary anastomosis do not eliminate early sinus node dysfunction.

OBJECTIVE: To determine whether operations that theoretically jeopardize the sinus node (hemi-Fontan and/or lateral tunnel Fontan procedures) are associated with a greater risk of sinus node dysfunction than those that theoretically spare the sinus node (bidirectional Glenn and/or extracardiac conduit). METHODS: Between January 1, 1996, and December 31, 1999, a prospective cohort study was conducted evaluating the incidence of sinus node dysfunction in patients undergoing a bidirectional Glenn or hemi-Fontan procedure and those in whom the Fontan repair was completed with either an extracardiac conduit or a lateral tunnel. Sinus node dysfunction was defined (1) as a heart rate more than 2 SD below age-adjusted norms or (2) as a predominant junctional rhythm and/or a sinus pause of more than 3 seconds as determined by the resting electrocardiogram and/or ambulatory monitoring at hospital discharge. RESULTS: Fifty-one patients had a bidirectional Glenn shunt (mean age 7.8 +/- 5.1 months) and 79 a hemi-Fontan procedure (mean age 6.9 +/- 2.8 months). The incidence of sinus node dysfunction on postoperative day 1 was significantly higher after the hemi-Fontan (36%) than after the bidirectional Glenn shunt (9.8%); however, by hospital discharge this difference was no longer apparent (hemi-Fontan [8%]; bidirectional Glenn [6%]; P = not significant). No difference in early sinus node dysfunction was discernible after the extracardiac conduit (4/30 [13%]) compared with the lateral tunnel Fontan procedure (6/46 [13%]) (P = not significant). No diagnostic or perioperative variables were predictive of sinus node dysfunction. CONCLUSIONS: Avoidance of surgery near the sinus node has no discernible effect on the development of early sinus node dysfunction. Thus, concerns about early sinus node dysfunction should not override patient anatomy or surgeon preference as determinants of which cavopulmonary anastomosis to perform.

Bilateral sequential lung transplant for ectodermal dysplasia.

A case of bilateral sequential lung transplantation for anhidrotic ectodermal dysplasia is presented. The patient was a 16-year-old male with end-stage lung disease secondary to chronic severe respiratory infection. Although a relatively rare disease, the common association of fatal pulmonary compromise in those affected with this disorder warrants consideration of lung transplantation as a viable therapeutic option.

Congenital Heart Surgery Nomenclature and Database Project: end-stage lung disease.

The extant nomenclature for end-stage lung disease is reviewed for the purpose of establishing a unified reporting system. The subject was debated and reviewed by members of the STS-Congenital Heart Surgery Database Committee and representatives from the European Association for Cardiothoracic Surgery. All efforts were made to include all relevant nomenclature categories, using synonyms where appropriate. Indications for lung transplantation are coded under a broad category called pulmonary failure. The proposed hierarchical scheme also allows classification of complications of lung transplantation under a category called status post lung transplant. A comprehensive database set is presented which is based on a hierarchical scheme. Data are entered at various levels of complexity and detail, which can be determined by the clinician. These data can lay the foundation for comprehensive risk stratification analyses. A minimum database set is also presented, which will allow for data sharing and would lend itself to basic interpretation of trends. Outcome tables relating diagnoses, procedures, and various risk factors are presented.

Prolonged extracorporeal membrane oxygenation as a bridge to cardiac transplantation.

Cardiac transplantation provides the best option for neonates with congenital heart disease that is not amenable to surgical repair or palliation. The scarcity of suitable organs for this group has resulted in prolonged waiting times; many infants die awaiting transplantation. We present the case of a newborn with severe Ebstein's anomaly and low cardiac output who was supported with extracorporeal membrane oxygenation for 1,126 hours, until an appropriate organ became available.

Survival after acute graft failure in pediatric thoracic organ transplant recipients.

Survival among recipients of repeat thoracic organ transplantation, particularly in the setting of acute graft failure (AGF), is lower than survival after a primary transplant. This has created controversy over the fair allocation of scarce organs. We reviewed our experience to assess the effectiveness of aggressive therapy and retransplantation in pediatric patients with AGF. Between November 1994 and March 1998, 52 patients aged 49 days to 16.9 years (median age 4.7 years) underwent thoracic organ transplantation (32 primary and 4 repeat heart, 16 primary and 4 repeat lung, and 3 primary heart-lung transplants). Acute graft failure occurred in nine (4 heart, 3 lung, 2 heart-lung transplants), six of whom were supported with extracorporeal membrane oxygenation (ECMO), and four of whom underwent repeat transplant. Six of the nine survived, including all of those who were retransplanted, and five of the nine were alive 1 year later. The average postoperative hospital stay after receiving a second organ was 46.5 days vs. a postoperative 22-day stay in recipients without AGF (p = 0.07). We conclude that the decision to allocate institutional and professional resources to the aggressive support of patients with AGF must be made at the level of the individual transplant center. However, we feel that the outcome of aggressive support and retransplantation justifies the allocation of organs to these patients and suggests that the current policies governing organ allocation for patients with early graft failure should be re-examined.

Outcome of infants listed for lung or heart/lung transplantation.

BACKGROUND: Little is known about outcome, characteristics, or organ availability for infants listed for lung or heart/lung transplantation. METHODS: Within a 45-month period at one institution, all pediatric patients who were listed for primary lung or heart/lung transplantation and who reached the end point of either transplant or death prior to transplant were identified. Outcomes for those patients listed as younger than and older than 1 year of age were compared. RESULTS: Among 48 pediatric patients, 19 were infants less than one year of age. The median age among infants at listing was 3.7 months (range 0.5 to 8.9 months). Death before transplant occurred in 10 of 19 infants (53%) compared with 14 of 29 (48%) children. When comparing those infants who died prior to transplant with those who received organs, there were no significant differences with respect to size, blood type, age at listing, presence of pulmonary hypertension, or type of transplant for which the patient was listed. There was a trend toward poorer pre-transplant survival for infants when compared with children. Waiting times were significantly shorter for infants vs children (p = 0.02). The incidence of acute cellular rejection and serious infection was similar in the 2 groups. Infants had significantly longer hospitalization post-transplant and a trend toward poorer hospital survival, although survival at 1 year was comparable between the 2 groups. CONCLUSION: The outcome for infants listed for lung or heart/lung transplantation is similar to that of children; thus, very young age should not be considered a contraindication to lung or heart/lung transplantation. Earlier diagnosis and listing may decrease pre-transplant mortality.

Early survival of infants weighing 2.5 kilograms or less undergoing first-stage reconstruction for hypoplastic left heart syndrome.

BACKGROUND: Results of staged palliation for hypoplastic left heart syndrome (HLHS) have improved in recent years; however, certain risk factors have been associated with decreased survival rates. METHODS AND RESULTS: We retrospectively reviewed the medical records of 67 patients weighing

Impact of early ventricular unloading on exercise performance in preadolescents with single ventricle Fontan physiology.

OBJECTIVES: We sought to determine if early ventricular volume unloading improves aerobic capacity in patients with single ventricle Fontan physiology. BACKGROUND: Surgical strategies for patients with single ventricle include intermediate staging or early Fontan completion to reduce the adverse affects of prolonged ventricular volume load. The impact of this strategy on exercise performance has not been evaluated. METHODS: Retrospectively, we reviewed the exercise stress test results of all preadolescents with single ventricle Fontan physiology. "Volume unloading" was considered to have occurred at the time of bidirectional cavopulmonary anastomosis or at the time of Fontan surgery in those patients who did not undergo intermediate staging. Potential predictors of aerobic capacity were analyzed using multivariate regression. RESULTS: The patients (n = 46) achieved a mean percentage predicted of maximal oxygen consumption (VO2max) of 76.1% +/- 21.1%. The mean age at the time of volume unloading was 2.7 +/- 2.4 years, and the mean age at testing was 8.7 +/- 2 years. Intermediate staging was performed in 16 of 46 patients (35%). In multivariate analysis, younger age at volume unloading was associated with increased aerobic capacity (p = 0.003). Other variables were not predictive. The subgroup of patients who underwent volume unloading before two years of age achieved a mean percentage predicted VO2max of 88.6% +/- 24.1%. CONCLUSIONS: Preadolescents with single ventricle who undergo volume unloading surgery at an early age demonstrate superior aerobic capacity compared with those whose surgery is delayed until a later age.