Jeffrey D. Hosenpud

The registry of the international society for heart and lung transplantation: eighteenth official report—2001

In this last report of the Registry’s current administration, it is appropriate to review the changes and growth of the Registry during our 7-year stewardship. The total number of thoracic transplant recipients listed in the Registry has grown from 35,972 to more than 73,000 (see Table I). In addition to the increase in sheer volume of data, the breadth and sophistication of the analyses increased, from descriptive and univariate survival analyses to complex multivariate, risk-stratified data that investigate mortality as well as morbidity end-points. In 1993, the number of slides showing thoracic transplant data offered as a service to the members of the International Society for Heart and Lung Transplantation (ISHLT) was in the mid-30s. This year’s slide set offered free as a PowerPointTM file on the ISHLT website will contain 65 data slides. The health of the Registry will continue with a smooth transition to the new directorship.

Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease

BACKGROUND Although certain forms of end-stage lung disease are debilitating, whether the associated mortality rate exceeds that of transplantation is unclear. We undertook analysis to clarify the survival benefit of lung transplantation for various types of end-stage lung disease. METHODS We analysed data for all patients listed for transplantation in the USA for emphysema, cystic fibrosis, or interstitial pulmonary fibrosis in the years 1992-94. The numbers of patients entered on the waiting list, post-transplantation, died waiting, and currently waiting were: emphysema group 1274, 843, 143, and 165; cystic fibrosis group 664, 318, 193, and 59; interstitial pulmonary fibrosis group 481, 230, 160, and 48. A time-dependent non-proportional hazard analysis was used to assess the risk of mortality after transplantation relative to that for patients on the waiting list. FINDINGS The clearest survival benefit from lung transplantation occurred in the cystic fibrosis group. The relative risks of transplantation compared with waiting were 0.87, 0.61, and 0.61 at 1 month, 6 months, and 1 year (p = 0.008), respectively. For interstitial pulmonary fibrosis, the corresponding relative risks were 2.09, 0.71, and 0.67 (p = 0.09). No survival benefit was apparent in the emphysema group. The risks of transplantation relative to waiting were 2.76, 1.12, and 1.10 at 1 month, 6 months, and 1 year, respectively, and the relative risk did not decrease to below 1.0 during 2 years of follow-up. INTERPRETATION These findings suggest that lung transplantation does not confer a survival benefit in patients with end-stage emphysema by 2 years of follow-up. Other benefits not accounted for in this analysis such as improved quality of life, however, may justify lung transplantation for these patients.

The Registry of the International Society for Heart and Lung Transplantation: Seventeenth Official Report—2000

The Registry of the International Society for Heart and Lung Transplantation has grown substantially during the past 5 years, from a little more than 43,000 registered procedures at the end of 1994 to almost 70,000 registered procedures by the end of 1999 (see Table I). The substantial increase during this 5-year period occurred despite overall annual transplant numbers that were flat or that declined. We attribute this increase to obtaining more complete data from national and multinational registries, from capturing new centers that did not previously report, and finally, from direct Internetbased data reporting by individual centers. During this same 5-year period, excluding the annual reports, the Registry has peer reviewed 23 publications, reviews, and book chapters. J Heart Lung Transplant 2000;19:909.

The Registry of the International Society for Heart and Lung Transplantation : Sixteenth Official Report-1999

Over the past 12 months, The Registry of the International Society for Heart and Lung Transplantation added a total of 3673 additional thoracic organ recipients, the smallest number over the past 5 years. In addition, we added 10 new transplant programs to those reporting data. We continue to be in sharing discussions with 4 newer national/ regional databases, and electronic data submission via the Internet has been instituted with approximately 25% of the non-US centers submitting data using the new system. We continue to use the entire data set to calculate multivariate risks rather than the U.S. data set alone, and we have continued to extend the time frame for both univariate and multivariate analyses.

The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Official Report—1998

Over the past 12 months, The Registry of the International Society for Heart and Lung Transplantation added 20 new transplantation programs and a total of 7073 additional thoracic organ recipients. All of the national and multinational registries are now fully integrated into our registry, and electronic data submission via the Internet will be instituted by mid 1998 for those centers not participating in larger registries. For the first time, the entire data set was used to calculate multivariate risks rather than the U.S. data set alone, and we have continued to extend the time frame for both univariate and multivariate analyses. For this report, risk factors for 5-year outcome and morbidity at 3 years are presented.

Neurological events during long-term mechanical circulatory support for heart failure ; the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) experience

Background—Progression of heart failure can lead to cardiac transplantation, but when patients are ineligible, long-term mechanical circulatory support may improve survival. The REMATCH trial showed that left ventricular assist devices (LVADs) prolonged survival in patients with end-stage disease, but with a significant number of adverse events. We report on the neurological outcomes in the REMATCH trial. Methods and Results—We examined new neurological events in the 129 patients randomized to either LVAD placement (n= 68) or medical management (n= 61), classified as stroke, transient ischemic attack, toxic-metabolic encephalopathy, and other. There were 46 neurological events: 42 in 30 LVAD patients and 4 in 4 patients in the medical arm (χ2, 30/68 versus 4/61, P < 0.001). Sixteen percent of the LVAD patients had a stroke, with a rate of 0.19 per year (95% CI, 0.10 to 0.33), many occurring in the postoperative period. The stroke rate in the medical arm was 0.052. A Kaplan-Meier survival analysis showed a 44% reduction in the risk of stroke or death in the LVAD group versus the optimal medical group (P = 0.002). The mean interval from implantation to stroke was 221.8 days (± 70.4 days). History of stroke, age, and sepsis were not stroke risk factors in the LVAD group. Conclusions—Fewer than half of the patients in the LVAD group had a neurological event, and there were few neurological deaths. Survival analysis combining stroke or death demonstrated a significant benefit for long-term circulatory support with an LVAD over medical therapy. Future trials will need to address prospectively all neurological outcomes, including neurocognitive function, and the role of long-term neuroprotection.

Abnormal pulmonary function specifically related to congestive heart failure: Comparison of patients before and after cardiac transplantation

PURPOSE A variety of abnormalities in pulmonary function have been attributed to, or are believed to be, exacerbated by congestive heart failure. Separating out specific contributions from cardiac versus pulmonary disease is difficult. In order to investigate the impact of cardiac disease on pulmonary function, we performed spirometry on patients immediately before and after cardiac transplantation. PATIENTS AND METHODS Seventeen patients (13 men, 4 women) with a mean age of 44 years (range: 20 to 62 years) were studied before and 15 +/- 10 (mean +/- SD) months after cardiac transplantation. Eleven patients had a significant smoking history. RESULTS In comparing pre- and post-transplant spirometric results, forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) increased substantially after transplant (3.34 +/- 0.96 L versus 3.89 +/- 1.00 L, p = 0.0054, and 2.63 +/- 0.80 L versus 2.95 +/- 0.83 L, p = 0.042, respectively). FEV1/FVC was not significantly different between study states in the entire group (0.78 +/- 0.10 versus 0.76 +/- 0.10, p = NS), nor was it different in those patients with and without a smoking history (0.76 +/- 0.11 versus 0.72 +/- 0.10, p = NS, and 0.87 +/- 0.06 versus 0.84 +/- 0.02, p = NS, respectively). Furthermore, normal lung volumes were obtained after transplant in those patients without a smoking history in contrast to those with a smoking history. Finally, the increase in FVC after cardiac transplantation directly correlated with the decrease in cardiac volume with cardiac replacement (r = 0.83, p less than 0.0001). CONCLUSION We conclude that in patients selected as cardiac transplant candidates (those without severe obstructive lung disease), restrictive but not obstructive pulmonary physiology can be attributed in part to congestive heart failure, and a major part of the reduction in lung volumes is secondary to the space occupied by a large heart. Other factors, such as accompanying pleural effusions and interstitial edema, likely contribute to the reduction in lung volumes. Abnormal pulmonary function secondary to chronic congestive heart failure in this selected population is completely reversible with normalization of cardiovascular physiology and anatomy.

Influence of graft ischemic time and donor age on survival after lung transplantation

BACKGROUND Increased graft ischemic time and donor age are risk factors for early death after heart transplantation, but the effect of these variables on survival after lung transplantation has not been determined in a large, multinational study. METHODS All recipients of cadaveric lung transplantations performed between October 1, 1987 and June 30, 1997 which were reported to the United Network for Organ Sharing/International Society for Heart and Lung Transplantation (UNOS/ISHLT) Registry were analyzed. Patient survival rates were estimated using Kaplan-Meier methods. Multivariate logistic regression was used to determine the impact of donor and recipient characteristics on patient survival after transplantation. To examine whether the impact of donor age varied with ischemic time, interactions between the 2 terms were examined in a separate multivariate logistic regression model. RESULTS Kaplan-Meier survival did not differ according to the total lung graft ischemia time, but recipient survival was significantly adversely affected by young (-10 years) or old (-51 years) donor age (p = 0.01). On multivariate analysis, neither donor age nor lung graft ischemic time per se were independent predictors of early survival after transplantation, except if quadratic terms of these variables were included in the model. The interaction between donor age and graft ischemia time, however, predicted 1 year mortality after lung transplantation (p = 0.005), especially if donor age was greater than 55 years and ischemic time was greater than 6 to 7 hours. CONCLUSIONS Graft ischemia time alone is not a risk factor for early death after lung transplantation. Very young or old donor age was associated with decreased early survival, whereas the interaction between donor age and ischemic time was a significant predictor of 1 year mortality after transplantation. Cautious expansion of donor acceptance criteria (especially as regards ischemic time) is advisable, given the critical shortage of donor lung grafts.

Transforming growth factor (TGF)-β mimics and anti-TGF-β antibody abrogates the in vivo effects of cyclosporine : Demonstration of a direct role of TGF-β in immunosuppression and nephrotoxicity of cyclosporine

BACKGROUND Cyclosporine (CsA) has been shown to induce the expression of transforming growth factor (TGF)-beta both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-beta. This study was planned to investigate whether anti-TGF-beta mitigated and TGF-beta reproduced the in vivo effects of CsA to directly prove this hypothesis. METHODS B6AF1 (H2b/k.d) mice were divided into groups and received the following: CsA, vehicle (olive oil), CsA + anti-TGF-beta1 antibody, TGF-beta1, or vehicle phosphate-buffered saline/bovine serum albumin. All studies were carried out at 10 and 28 days after the last day of CsA administration with the exception of the exogenous TGF-beta experiments, which were performed 5 days after exogenous TGF-beta administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [3H]thymidine uptake; TGF-beta protein levels were quantified by ELISA. TGF-beta, collagen, and fibronectin gene expression was studied using reverse transcriptase-polymerase chain reaction, and histopathological analysis was made on periodic acid-Schiff- and trichrome C-stained thin kidney sections. RESULTS CsA treatment resulted in decreased ex vivo proliferation of splenocytes, an increase in TGF-beta protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-beta, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-beta antibody. CONCLUSION The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-beta levels and suggests that TGF-beta at least in part mediates CsAs beneficial and detrimental effects.

Single vs bilateral, sequential lung transplantation for end-stage emphysema: influence of recipient age on survival and secondary end-points

BACKGROUND The appropriate age to perform bilateral, sequential lung transplants (BSLT) in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Although single lung transplant (SLT) offers an advantage in terms of organ availability, the long-term survival may not warrant this strategy in all age groups. METHODS We analyzed 2,260 lung transplant recipients (1835 SLT, 425 BSLT) with COPD recorded in the International Society for Heart and Lung Transplantation/United Network for Organ Sharing thoracic registry between January 1991 and December 1997. To assess mortality, we performed univariate (Kaplan-Meier method and the chi-square statistic) and multivariate analyses (proportional hazards method). Because of incomplete morbidity data in the international registry, only data from U.S. centers (n = 1778, 1467 SLT, 311 BSLT) were used in the morbidity analysis. RESULTS Survival rates (%) computed using the Kaplan-Meier method at 30 days, 1 year, and 5 years for the patients aged < 50 years were 93.6, 80.2, and 43.6, respectively, for the SLT patients, and 94.9, 84.7, and 68.2, respectively, for the BSLT patients. For patients aged 50 to 60 years, survival rates (%) were 93.5, 79.4, and 39.8 for the SLT patients compared with 93.0, 79.7, and 60.5 for the BSLT patients. For those aged > 60 years, SLT survival (%) was 93.0, 72.9, and 36.4, compared with 77.8 and 66.0 for the BSLT group (a 5-year rate could not be completed in this group). The multivariate model showed a higher risk ratio for mortality in patients aged 40 to 57 years who received SLT vs BSLT. Recipient age and procedure type did not appear to affect the development of rejection, bronchiolitis obliterans, bronchial stricture, or lung infection. CONCLUSIONS Single lung transplant may offer acceptable early survival for patients with end-stage respiratory failure. However, long-term survival data favors BSLT in recipients until approximately age 60 years. These data suggest that a BSLT approach offers a significant survival advantage to recipients younger than 60 years of age.