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Mortality and morbidity after retransplantation after primary heart transplant in childhood: An analysis from the registry of the International Society for Heart and Lung Transplantation Jennifer Conway, MD,a Cedric Manlhiot, MSc,a Richard Kirk, MD,b Leah B. Edwards, PhD,c Brian W. McCrindle, MD,a and Anne I. Dipchand, MDa From the aLabatt Family Heart Center, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; bInstitute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK; and the cInternational Society of Heart and Lung Transplantation, Addison, Texas, USA.

KEYWORDS: retransplant; pediatrics; outcomes; morbidity; allograft vasculopathy; renal dysfunction; rejection; cancer

BACKGROUND: Retransplantation for graft failure in the pediatric population is rare with reports of decreased survival compared with primary transplantation. Little is known about the risk factors for retransplantation or death after retransplantation; in addition, there is a paucity of data in the literature on transplant-related morbidities in this patient population. The purpose of this analysis of the registry of the International Society of Heart and Lung Transplant (ISHLT) was to describe outcomes after retransplantation as compared with primary transplantation, including identifying risk factors leading to retransplantation and both transplant-related morbidities and mortality after retransplantation. METHODS: Data from 1998 to 2010 were used to identify all patients whose primary transplantation was performed at o18 years of age. Of the 9,966 transplants reviewed, 9,248 primary transplants and 602 retransplants were analyzed. RESULTS: The median age for retransplantation was 14 (range 1 to 26) years, with the most common indication being allograft vasculopathy (58.5%). After retransplantation, early time-related risk of mortality was similar to that after primary transplantation (HR 1.07 [0.92 to 1.25], p ¼ 0.40), but both late-phase time-related risk of mortality (HR 1.67 [1.40 to 1.99], p o 0.001) and requirement of an additional graft (HR 1.69 [1.18 to 2.43], p ¼ 0.004) were higher. Long-term morbidities were significantly more common after retransplantation than with primary transplantation. These included allograft vasculopathy (HR 2.8 [2.37 to 3.38], p o 0.001), late rejection (HR 2.0 [1.65 to 2.40], p o 0.001) and late renal dysfunction (HR 2.6 [2.18 to 3.12], p o 0.001), but not cancer (HR 1.16 [0.74 to 1.82], p ¼ 0.52). Numerous patient-, donor- and transplant-related risk factors were identified that increased both the risk of mortality and transplant-related morbidities after retransplantation. CONCLUSIONS: Retransplantation after primary transplant in the pediatric age group, although feasible with similar early survival, is associated with decreased long-term survival and an increase in transplantrelated morbidities. The results of this study highlight the ongoing challenges of managing patients after retransplant and also suggest some modifiable risk factors, for both the donor and recipient, which may improve survival and decrease the burden of morbidities. J Heart Lung Transplant 2014;33:241–251 r 2014 International Society for Heart and Lung Transplantation. All rights reserved.

Reprints requests: Anne I. Dipchand, MD, Labatt Family Heart Center, The Hospital for Sick Children, Department of Paediatrics, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Telephone: 416-813-6674. Fax: 416-813-7547. E-mail address: [email protected]

Retransplantation for graft failure in the pediatric population is rare, accounting for only 5% of the transplants reported to the registry of the International Society for Heart and Lung Transplantation (ISHLT).1 Retransplantation

1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2013.11.006

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more commonly occurs in children 411 years of age (9%) compared with infants (o1%) and occurs more frequently in North America (6% of all transplants) compared with the rest of the world (o2%).1 Approximately half of all retransplants occur Z5 years after the primary transplant, with allograft vasculopathy, rejection and primary graft failure being the most common reasons.1–3 There is limited information in the literature on the risk factors that increase the likelihood of retransplantation in childhood.2 Reported outcomes after retransplantation show 1-year survival rates ranging between 78% and 83%4–6 in predominantly single-center series with small patient numbers. Other multi-institutional registry studies have shown survival to be inferior to that of primary transplantation.2,3 Risk factor analyses for mortality after retransplantation are limited to three pediatric studies with inconsistent findings.2,5,7 Finally, there is a paucity of information about morbidities after retransplantation. The purpose of our analysis of the ISHLT registry was to describe the outcomes after retransplantation as compared with primary transplantation, and to identify risk factors for retransplantation as well as transplant-related morbidities and mortality.

Methods This investigation was a retrospective cohort analysis of transplants performed (from 1988 to 2010) using the International Society of Heart and Lung Transplant (ISHLT) registry, an international longitudinal voluntary database that collects data from the time of transplant and throughout follow-up. There were 273 institutions from 32 countries that contributed data during this time period (albeit not all institutions started participation in 1988). The ISHLT registry collects pre-transplantation data, additional data points at the time of hospital discharge after transplantation and yearly follow-up data until graft loss (i.e., relisting for transplantation or death). Standard variable definitions as per ISHLT protocols were used throughout the study.

Study population Heart transplant recipients whose primary transplant was performed at o18 years of age were included. We identified the subset of patients who underwent second, third or even fourth transplantation, regardless of age. Patients undergoing retransplantation for the first time were the focus of this analysis. Undergoing a second retransplantation (third graft) was considered an outcome for the first retransplantation; however, outcomes and risk factors for a third (n ¼ 29) or fourth (n ¼ 2) graft (second or third retransplantation) were excluded from the analysis because of the small number. The comparison group were all primary transplantations within the registry over the same period of time. Patients who were reported to have undergone multiple-organ transplantation were included in this analysis.

Data collection All patients who received a retransplant had contemporary preretransplant data entered. Risk factors for outcomes after a given transplant were divided into patient characteristics, pre-transplant characteristics (those preceding the transplantation of interest), transplant characteristics (which related directly to the transplantation of interest) and post-transplantation complications (which also related directly to the transplantation of interest).

Thus, the risk factor and outcomes analysis outlined in what follows related to data relevant to the retransplantation, and recorded data for past medical history could be before or after a primary transplant for the retransplantation group.

Outcomes Early rejection was defined as rejection o1 year after transplantation (or retransplantation), whereas late rejection was defined as a rejection episode 41 year post-transplantation. Late renal dysfunction was defined as renal dysfunction at any time after hospital discharge post-transplantation (or retransplantation). Malignancy was defined as either post-transplant lymphoproliferative disorders/lymphoma or solid-organ tumors. Outcomes were evaluated at the time of yearly follow-up, with the specific date of outcome recorded if the outcome occurred. Follow-up duration for each outcome was censored at the time of the last follow-up, graft loss or death.

Statistical analysis All variables in the ISHLT registry were examined. Variables with a high level of missing data (475%), or where event rates were o1%, were excluded from any further analyses. Distributions were examined for extreme outliers (43 times the interquartile range) and data points outside the physiologic range were censored. Data are presented as mean and standard deviation, median with 5th and 95th percentiles and frequencies as appropriate. Statistical significance of differences between primary transplantation and retransplantation were assessed using Student’s t-test, assuming unequal variance between study groups, and Fisher’s exact chisquare test; based on these, odds ratios with 95% confidence intervals were calculated. Freedom from time-dependent outcomes was modeled in parametric survival models (using maximumlikelihood estimates to resolve hazard), which divide hazard over time in up to three distinct phases of hazard (early, constant and late) using standard mathematical algorithms for the HAZARD procedure (http://my.clevelandclinic.org/professionals/software/ hazard/default.aspx). The parametric survival models were com bined in competing risk models to obtain prevalence of mutually exclusive outcomes, including mortality, retransplantation and prevalence of outcomes. Associations between patients’ character istics (Tables 1 and 2) and outcomes were first tested at the univariable level. Associations with p o 0.10 were then included in a bootstrap bagging algorithm (1,000 resamples); variables with reliability (defined as percent of resample in which a given variable is selected) were then included in a multivariable regression model with backward selection of variables to obtain a final model. All hazard factors analyses were performed using a unified phase of hazard given the limited number of events in some phases of hazard after retransplantation. Mean imputation was used to account for missing variables. All statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC).

Results Patients’ demographics A total of 9,966 heart transplants were performed during the study period, of which 84 were excluded because no clinical outcomes were reported. Of the remaining 9,882 heart transplants, 9,248 (93.6%) were primary transplants, 602

Conway et al. Table 1

Mortality and Morbidity After Retransplantation After Primary Heart Transplant in Childhood

243

Patient and Donor Characteristics Stratified by Primary Transplantation vs Retransplantation (Second Graft) Primary transplantation N

Transplant characteristics Transplant year 1988-1992 1993-1997 1998-2002 2003-2006 2007-2010 ABO-incompatible transplantation Multiple-organ transplant Pre-transplantation patient characteristics Age at transplantation, in years Recipient age category o1 year old 1–10 years old 11–18 years old 418 years old Gender (male) Primary diagnosis Congenital heart disease Valvular heart disease Dilated cardiomyopathy Restrictive cardiomyopathy Hypertrophic cardiomyopathy Myocarditis Coronary artery abnormalities/Kawasaki disease Left ventricular non-compaction Cardiac tumour Rejection Primary graft failure Non-specific graft failure Allograft vasculopathy Other Unknown Recipient ABO blood group A, A1, A2 B AB, A2B O Pre-transplantation comorbidities Anti-arrhythmic use Angina Symptomatic cerebrovascular disease Cerebrovascular event Dialysis Implantable defibrillator Drug-treated systemic hypertension Infection requiring IV therapy (o2 weeks before) Malignancy Allogeneic blood transfusions Cardiorespiratory arrest Positive IgG Epstein–Barr virus Positive IgM Epstein–Barr virus Positive IgG cytomegalovirus Positive IgM cytomegalovirus Patient sensitized (PRA 410) Sensitization level None (PRA 0)

Value

9,248

8,896 9,248 9,248 9,248

9,247 9,248

Retransplantation N

Value

OR (95% CI)

p

602 1,707 2,024 2,001 1,745 1,771 176 32

(18.5%) (21.9%) (21.6%) (18.9%) (19.2%) (2.0%) (0.4%)

7.0 (0.0–17.0) 2,363 3,254 3,631 0 5,290

(25.6%) (35.2%) (39.3%) (0.0%) (57.2%)

589 602 602 602

602 602

(0.31–0.55) (0.49–0.78) (0.94–1.38) (1.09–1.61) (1.45–2.10) (0.04–0.68) (5.63–17.4)

o0.001 o0.001 0.19 0.006 o0.001 0.002 o0.001

14.0 (1.0–26.0)

1.16 (1.14–1.17)

o0.001 o0.001

25 173 265 139 325

0.13 (0.08–0.19) 0.74 (0.62–0.89) 1.22 (1.03–1.44) — 0.88 (0.74–1.04)

51 89 144 142 176 2 20

(8.5%) (14.8%) (23.9%) (23.6%) (29.4%) (0.3%) (3.3%)

(4.2%) (28.7%) (44.0%) (23.1%) (54.0%)

0.41 0.62 1.14 1.33 1.74 0.17 9.90

— — — — — —

3,812 (41.2%) 69 (0.8%) 3,845 (41.6%) 442 (4.8%) 234 (2.5%) 403 (4.4%) 75 (0.8%) 25 (0.3%) 29 (0.3%) — — — — 244 (2.6%) 70 (0.8%)

49 39 52 352 106 4

— — (8.1%) (6.5%) (8.6%) (58.5%) (17.6%) (0.7%)

— — — — — —

0.13 —

— — — — — — — —

9,163 9,163 9,163 9,163

3,758 1,089 3,792 524

(41.0%) (11.9%) (41.4%) (5.7%)

602 602 602 602

275 68 221 39

(45.5%) (11.3%) (36.7%) (6.5%)

1.20 0.94 0.82 1.14

(1.02–1.42) (0.73–1.23) (0.69–0.98) (0.82–1.60)

0.03 0.70 0.03 0.42

5,126 4,610 5,104 4,673 4,776 2,170 5,119 4,688 5,461 3,473 4,817 2,171 1,736 3,488 2,908 3,687 3,687

985 106 97 163 135 285 560 797 111 2,301 1,039 1,260 103 1,498 218 353

(19.2%) (2.3%) (1.9%) (3.5%) (2.8%) (13.1%) (10.9%) (17.0%) (2.0%) (66.3%) (21.6%) (58.0%) (5.9%) (43.0%) (7.5%) (9.6%)

411 364 415 379 391 187 407 392 432 252 396 166 143 290 230 230 230

62 110 14 10 45 20 156 47 22 223 110 129 20 171 25 69

(15.1%) (30.2%) (3.4%) (2.6%) (11.5%) (10.7%) (38.3%) (12.0%) (5.1%) (88.5%) (27.8%) (77.7%) (14.0%) (59.0%) (10.9%) (30.0%)

0.75 18.4 0.75 1.80 4.47 0.79 5.06 0.67 2.59 3.91 1.40 2.52 2.58 1.91 1.51 4.05

(0.57–0.99) (13.7–24.7) (0.39–1.43) (1.02–3.19) (3.13–6.38) (0.49–1.28) (4.07–6.29) (0.49–0.91) (1.62–4.13) (2.64–5.80) (1.11–1.76) (1.73–3.67) (1.54–4.31) (1.50–2.44) (0.97–2.33) (2.99–5.80)

0.04 o0.001 0.05 0.46 o0.001 0.43 o0.001 0.01 o0.001 o0.001 0.005 o0.001 o0.001 o0.001 0.07 o0.001 o0.001

2,853 (77.4%)

128 (55.7%)

0.37 (0.28–0.49)

Continued on page 244

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Table 1 (Continued) Primary transplantation N Pre-sensitized (PRA 1–10) Sensitized (PRA 11–80) Highly sensitized (PRA 81–100) Medical condition at transplantation Hospitalization Not hospitalized Inpatient but not in the ICU In ICU Life support at the time of transplantation ECMO Inotropes Prostaglandin E Ventilation Ventricular assist device Total ischemic time (hours) Donor characteristics Donor age (years) Gender (male) Donor cause of death Anoxia Cerebrovascular/stroke Central nervous system tumor Head trauma Other Unknown Donor ABO blood group A, A1, A2 B AB, A2B O History of diabetes History of hypertension Left ventricular ejection fraction (%) Clinical infection at the time of donation Positive anti-CMV antibody

Value

Retransplantation N

481 (13.1%) 289 (7.8%) 64 (1.7%) 6,464

6,415 6,410 6,603 6,256 6,347 4,605 7,245 9,021 8,978 9,248

OR (95% CI) 1.29 (0.86–1.93) 4.37 (3.09–6.17) 4.19 (2.20–7.85)

8.0 (0.0–39.0) 3,826 (42.6%)

464 466 468 458 464 374 459 590 589 602

(16.7%) (12.3%) (0.8%) (41.5%) (15.7%) (13.2%)

2,847 (32.0%) 673 (7.6%) 5,145 (57.8%) 233 (2.6%) 45 (0.9%) 103 (2.0%) 63 ⫾ 10 1,210 (25.4%) 3,439 (50.7%)

589 589 589 589 440 442 293 399 467

p

o0.001

465 2,108 (32.6%) 822 (12.7%) 3,534 (54.7%) 3,786 (59.0%) 370 (5.8%) 2,848 (43.1%) 375 (6.0%) 1,352 (21.3%) 571 (12.4%) 3.30 ⫾ 1.58

1,540 1,138 74 3,733 1,447 1,216 8,898 8,898 8,898 8,898 5,282 5,274 2,974 4,770 6,785

Value 33 (14.4%) 55 (23.9%) 14 (6.1%)

209 (45.0%) 63 (13.6%) 193 (41.5%) 231 (49.8%) 28 (6.0%) 194 (41.5%) 0 (0.0%) 86 (18.5%) 23 (6.2%) 3.27 ⫾ 1.37

1.69 1.08 0.59 0.69 1.04 0.93

(1.39–2.05) (0.81–1.43) (0.48–0.72) (0.57–0.83) (0.70–1.55) (0.77–1.13) . 0.84 (0.66–1.07) 0.46 (0.30–0.71) 0.99 (0.93–1.05)

o0.001 0.84 0.50 o0.001 0.18 o0.001 0.68

16.0 (1.0–46.0) 235 (39.9%)

1.04 (1.03–1.04) 1.12 (0.94–1.33)

o0.001 0.21

80 86 5 302 57 72

(13.3%) (14.3%) (0.8%) (50.2%) (9.5%) (12.0%)

0.77 1.19 1.04 1.42 0.56 0.90

(0.60–0.98) (0.94–1.51) (0.42–2.58) (1.21–1.68) (0.43–0.75) (0.70–1.16)

0.03 0.16 0.81 o0.001 o0.001 0.45

213 (36.2%) 49 (8.3%) 310 (52.6%) 17 (2.9%) 6 (1.4%) 13 (2.9%) 61 ⫾ 10 122 (30.6%) 280 (60.0%)

1.20 1.11 0.81 1.11 1.61 1.52 0.99 1.30 1.45

(1.01–1.43) (0.82–1.50) (0.69–0.96) (0.67–1.82) (0.68–3.79) (0.85–2.73) (0.97–1.00) (1.04–1.62) (1.20–1.76)

0.04 0.52 0.01 0.69 0.28 0.16 0.007 0.02 o0.001

Data presented as mean with standard deviations, median with 5th and 95th percentile or frequency. CI, confidence interval; CMV, cytomegalovirus; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; Ig, immunoglobulin; IV, intravenous; OR, odds ratio; PRA, panel-reactive antibodies.

(6.1%) were retransplants (second graft), and 32 (0.3%) were third or fourth grafts and were not included in the analysis. This resulted in a final analysis cohort of 9,850 transplants. Patient characteristics stratified by primary transplantation vs retransplantation are summarized in Table 1. Patients undergoing retransplantation were, on average, older, with 139 (23.1%) 418 years of age. Median follow-up was 4.0 (range 0.003 to 17.6) years for primary transplantation and 3.0 (0.003 to 13.7) years for retransplantation (p o 0.001). The mean inter-transplant interval was 6.8 ⫾ 5.1 years after primary transplant. The retransplantation cohort was less likely to have been hospitalized at the time of transplantation but had a higher overall burden of comorbidities.

Timing and hazard of retransplantation Looking at all transplantations (for this analysis only), freedom from retransplantation decreased with time post-transplantation, and timing of retransplantation was

characterized by a short but significant early phase of hazard followed by an increasing hazard over time post-transplant (Figure 1). At 1-year post-retransplantation, 83% were alive and free from retransplantation, 16% had died, and 1% had been retransplanted (Figure 2). Respective proportions were 69%, 28% and 3% at 5 years; 54%, 40% and 7% at 10 years; and 31%, 55% and 14% at 20 years.

Post-transplant complications Post-transplantation complications are reported in Table 2. Early complications were similar between primary transplantation and retransplantation with the exception of cardiac reoperation before discharge (odds ratio [OR] 1.54 [1.04 to 2.72], p ¼ 0.04) and dialysis before discharge (OR 3.07 [2.32 to 4.06], p o 0.001), being more common in patients undergoing retransplantation. In longer term followup, the retransplantation patients were more often treated for hyperlipidemia and hypertension and were more likely to

Conway et al. Table 2

Mortality and Morbidity After Retransplantation After Primary Heart Transplant in Childhood

245

Short- and Long-term Complications After Pediatric Heart Transplantation Stratified by Primary Transplantation vs Retransplantation Primary transplantation N

Early post-transplantation complicationsa Cardiac reoperation Chest drain 42 weeks Dialysis Drug-treated infection Pacemaker implantation Stroke Acute rejection Time on inotropic support (days) Duration of hospital stay (days) Long-term outcomes and complicationsb Evidence of non-compliance Any documented drug-treated hyperlipidemia Pacemaker implantation Drug-treated hypertension Stroke Lowest EF recorded during follow-up 455% 45–55% o45% Early rejectionc Late rejectiond Documented graft failure during follow-up Time to graft failure (years) Graft vasculopathy Late renal dysfunction Any cancer Lymphoma/PTLD Solid tumor Hospitalization for infection

Value

Retransplantation N

Value

OR (95% CI)

p

3,462 1,934 5,150 3,654 5,088 5,022 5,008 1,541 3,615

278 151 328 958 74 128 1,083 5 17

(8.0%) (7.8%) (6.4%) (26.2%) (1.5%) (2.6%) (21.6%) (1–30) (7–74)

270 178 411 276 410 403 410 157 321

32 15 71 69 9 9 94 5 15

(11.9%) (8.4%) (17.3%) (25.0%) (2.2%) (2.2%) (22.9%) (1-25) (7-63)

1.54 1.09 3.07 0.94 1.52 0.87 1.08 0.99 1.00

(1.04–2.72) (0.62–1.89) (2.32–4.06) (0.71–1.24) (0.76–3.06) (0.44–1.73) (0.85–1.37) (0.98–1.01) (0.99–1.00)

0.04 0.77 o0.001 0.72 0.21 0.87 0.53 0.37 0.40

7,696 7,696 7,696 7,696 9,248 4,167

793 1,646 289 3,065 110

(10.3%) (21.4%) (3.8%) (39.8%) (1.2%)

504 504 504 504 602 299

55 196 29 256 9

(10.9%) (38.9%) (5.8%) (50.8%) (1.5%)

1.07 2.34 1.57 1.56 1.26

(0.80–1.42) (1.94–2.82) (1.06–2.32) (1.30–1.87) (0.64–2.50)

0.65 o0.001 0.03 o0.001 0.44 0.05

2,525 754 888 1,307 1,234 873 4.7 1,265 1,229 397 360 47 85

(60.6%) (18.1%) (21.3%) (15.9%) (16.0%) (9.4%) (0.0–16.7) (13.7%) (13.3%) (4.3%) (3.9%) (0.5%) (1.1%)

181 68 50 120 120 75 2.0 135 135 21 18 4 7

(60.5%) (22.7%) (16.7%) (22.1%) (23.8%) (12.5%) (0.0–11.6) (22.4%) (22.4%) (3.5%) (3.0%) (0.7%) (1.4%)

1.00 1.33 0.74 1.50 1.64 1.37 0.91 1.82 1.89 0.81 0.76 1.31 1.26

(0.78–1.28) (1.00–1.78) (0.54–1.02) (1.22–1.86) (1.32–2.03) (1.06–1.76) (0.87–0.97) (1.49–2.23) (1.54–2.31) (0.52–1.26) (0.47–1.23) (0.47–3.65) (0.58–2.74)

8,210 7,696 9,248 859 9,248 9,248 9,248 9,248 9,248 7,696

542 504 602 75 602 602 602 602 602 504

o0.001 o0.001 0.02 o0.001 o0.001 o0.001 0.40 0.32 0.55 0.51

CI, confidence interval; EF, ejection fraction; OR, odds ratio; PTLD, post-transplant lymphoproliferative disorder. a Up to hospital discharge. b After hospital discharge, at any time during follow-up but before terminal outcomes (retransplantation or death). c Early rejection: after hospital discharge but o1 year after transplantation. d Late rejection: Z1 year after transplantation.

require a pacemaker. In addition, these patients had an increased incidence of early and late rejection, graft failure, allograft vasculopathy and late renal dysfunction. In those who developed graft failure, it occurred earlier after retransplantation than after primary transplantation (2.0 vs 4.7 years, p o 0.001).

Figure 1 Freedom from and hazard function for retransplantation (all transplantations combined [N ¼ 9,248/event ¼ 560]). Solid lines: estimates; dotted lines: 95% confidence intervals.

Figure 2 Competing outcomes after transplantation (all transplantations combined). Solid lines: estimates; dotted lines: 95% confidence intervals.

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Factors associated with retransplantation As expected, graft failure (hazard raio [HR] 7.96 [6.50 to 9.08], p o 0.001) and allograft vasculopathy (HR 2.43 [2.05 to 2.99], p o 0.001) after primary transplantation were strongly associated with the need for retransplantation in univariable analysis. These two factors were excluded from the multivariable model as they are indications for retransplantation. Table 3 shows the recipient, donor and clinical factors found to be significantly associated with increased risk of retransplantation in this model.

Mortality and graft loss after retransplantation After retransplantation, the early time-related risk of mortality was similar to that after primary transplantation (HR 1.07 [0.92 to 1.25], p ¼ 0.40); however, late-phase time-related risk of mortality was higher (HR 1.67 [1.40 to 1.99], p o 0.001) (Figure 3). After primary transplantation, survival was 84% at 1 year, 72% at 5 years, 60% at 10 years and 42% at 20 years, compared with 81% at 1 year, 63% at 5 years, 46% at 10 years and 26% at 20 years after Table 3 Multivariable Factors Associated With Increased Hazard of Retransplantation After Primary Transplantation (N ¼ 9,248/event ¼ 560) Parameter Recipient factors Patient sensitized (PRA 410) Female gender Patient diagnosis ¼ coronary artery abnormalities AICD implantation prior to transplantation Patient diagnosis ¼ restrictive cardiomyopathy Positive cytomegalovirus IgG result prior to transplantation Donor factors Donor cause of death ¼ trauma Donor blood group O (protective) Donor cause of death ¼ cardiovascular stroke Post-transplant complications Cardiac reoperation prior to hospital discharge Late rejection episode (Z1 year after transplantation) Lower post-transplant ejection fraction category Pacemaker implantation after transplantation

Hazard ratio (95% confidence interval)

p

Figure 3 Patient survival after transplantation stratified by primary transplantation vs retransplantation.

retransplantation. The median survival was longer in primary transplant recipients, reaching 15 years, compared with 8.7 years after retransplantation. Patients undergoing retransplantation were more likely to die from cardiovascular causes (HR 1.69 [1.29 to 2.21], p o 0.001); other causes of death were similar between the two groups (Table 4). Multivariable risk factors for mortality after retransplantation are listed in Table 5. Longer intertransplant interval was associated with a decreased hazard of mortality after retransplantation at the univariable level (HR 0.76 [0.65 to 0.89], p ¼ 0.001). Once adjusted for confounding factors in multivariable modeling, intertransplant interval was no longer associated with hazard of mortality after retransplantation (HR 0.89 [0.74 to 1.08], p ¼ 0.23). The time-related risk of requiring retransplantation was significantly higher after retransplantation (e.g., need for a third graft) compared with primary transplant (HR 1.69 [1.18 to 2.43], p ¼ 0.004) (Figure 4); after primary transplantation, freedom from retransplantation was 99% at 1 year, 96% at 5 years, 91% at 10 years and 75% at 20 years, compared with 99% at 1 year, 96% at 5 years, 87% at 10 years and 63% at 20 years for patients who had already undergone retransplantation.

1.71 (1.22–2.39) 1.28 (1.08–1.52) 2.27 (1.27–4.06)

0.002 0.004 0.005

1.82 (1.13–2.92)

0.01

1.46 (1.01–2.10)

0.04

1.42 (1.02–1.97)

0.04

1.36 (1.13–1.63)

0.001

Allograft vasculopathy

0.84 (0.71–1.00)

0.04

1.33 (1.02–1.73)

0.04

2.89 (2.03–4.14)

o0.001

1.52 (1.23–1.86)

o0.001

1.24 (1.11–1.39)

o0.001

The time-related risk of allograft vasculopathy was significantly higher after retransplantation than after primary transplantation (HR 2.83 [2.37 to 3.38], p o 0.001) (Figure 5). Freedom from allograft vasculopathy was 99% at 1 year, 91% at 5 years, 77% at 10 years and 49% at 20 years for primary transplantation, compared with 98% at 1 year, 77% at 5 years, 48% at 10 years and 14% at 20 years for patients after retransplantation. Table 6 lists multivariable factors associated with increased risk of developing allograft vasculopathy after retransplantation.

1.63 (1.22–2.17)

0.001

AICD, automatic implantable cardioverter-defibrillator; IgG, immunoglobulin; PRA, panel-reactive antibodies.

Late renal dysfunction After retransplantation, the time-related risk of late renal dysfunction was significantly higher than after primary

Conway et al. Table 4

Mortality and Morbidity After Retransplantation After Primary Heart Transplant in Childhood

247

Causes of Death Stratified by Primary Transplantation (N ¼ 3,061) vs Retransplantation (N ¼ 236)

Primary cause of death

Primary transplantation [N (%)]

Retransplantation [N (%)]

OR (95% CI)

Cardiovascular other than graft vasculopathy Graft vasculopathy Cerebrovascular Graft failure Hemorrhage Infection Malignancy Non-medical Organ failure (non-cardiac) Pulmonary Rejection Other Unknown

619 178 107 411 57 275 132 37 209 115 110 115 377

65 10 2 24 5 20 7 3 20 9 8 9 39

1.69 0.86 0.29 0.89 1.35 1.12 0.81 1.25 1.49 1.12 0.84 1.21 1.41

(20.2%) (5.8%) (3.5%) (13.4%) (1.9%) (9.0%) (4.3%) (1.2%) (6.8%) (3.8%) (3.6%) (3.8%) (12.3%)

(27.5%) (4.2%) (0.8%) (10.2%) (2.1%) (8.5%) (3.0%) (1.3%) (8.5%) (3.8%) (3.4%) (3.8%) (16.5%)

(1.29–2.21) (0.45–1.64) (0.07–1.16) (0.59–1.36) (0.54–3.38) (0.71–1.78) (0.38–1.75) (0.38–4.06) (0.93–2.37) (0.54–2.30) (0.55–1.28) (0.61–2.39) (0.97–2.05)

p o0.001 0.76 0.07 0.68 0.43 0.62 0.72 0.73 0.10 0.70 0.49 0.57 0.07

CI, confidence interval; OR, odds ratio.

transplantation (HR 2.61 [2.18 to 3.12], p o 0.001) (Figure 6). After primary transplantation, freedom from renal dysfunction was 95% at 1 year, 89% at 5 years, 77% at 10 years and 56% at 20 years, compared with 88% at 1 year, 74% at 5 years, 51% at 10 years and 22% at 20 years for Table 5 Multivariable Factors Associated With Increased Hazard of Mortality After Retransplantation (N ¼ 602/Event ¼ 236) Parameter Patient factors Patient diagnosis ¼allograft vasculopathy (protective) Pre-retransplant history of drug-treated arrhythmia Patient diagnosis ¼ nonspecific graft failure In ICU prior to transplantation

Hazard ratio (95% CI) 0.58 (0.43–0.80)

0.001

1.64 (1.11–2.43)

0.01

1.59 (1.04–2.43)

0.03

1.54 (1.06–2.25)

0.03

Donor factors Donor history of diabetes 5.11 (1.85–14.07) Positive donor anti1.45 (1.07–1.96) cytomegalovirus antibody Donor cause of death ¼ central 3.86 (1.37–10.84) nervous system tumour Post-retransplant factors Post-retransplant dialysis (prior to hospital discharge) Documented graft failure (at any time after retransplant) Later year of retransplantation (protective) Drug-treated infection before hospital discharge Any hospitalization for infection after hospital discharge Cardiac reoperation prior to hospital discharge

p

0.002 0.02

Late rejection The time-related risk of late rejection was also significantly higher after retransplantation than after primary retransplantation (HR 1.99 [1.65 to 2.04], p o 0.001) (Figure 7). After primary transplantation, freedom from late rejection was 85% at 5 years, 78% at 10 years and 69% at 20 years, compared with 73% at 5 years, 61% at 10 years and 47% at 20 years for patients after retransplantation. Multivariable factors associated with increased hazard of late rejection after retransplantation are listed in Table 8.

Malignancy Freedom from malignancy after retransplantation was comparable to that for primary transplantation (HR 1.16 [0.74 to 1.82], p ¼ 0.52). After primary transplantation,

0.01

2.18 (1.50–3.16)

o0.001

2.96 (2.12–4.12)

o0.001

0.96 (0.94–0.99)

0.004

1.60 (1.07–2.40)

0.02

2.78 (1.13–6.85)

0.03

1.75 (1.05–2.93)

0.03

CI, confidence interval; ICU, intensive care unit.

patients after retransplantation. Multivariable factors associated with increased hazard of late renal dysfunction after retransplantation are listed in Table 7.

Figure 4 Freedom from receiving an additional cardiac graft after transplantation stratified by primary transplantation vs retransplantation.

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Figure 5 Freedom from allograft vasculopathy after transplantation stratified by primary transplantation vs retransplantation.

Figure 6 Freedom from late renal dysfunction after transplantation stratified by primary transplantation vs retransplantation.

freedom from malignancy was 99% at 1 year, 97% at 5 years, 93% at 10 years and 84% at 20 years, compared with 99% at 1 year, 96% at 5 years, 91% at 10 years and 82% at 20 years for patients after retransplantation. Multivariable factors associated with increased hazard of malignancy after retransplantation are listed in Table 9.

Previous studies have reported factors associated with a higher likelihood of retransplantation, including a higher creatinine level, the need for ventilator support at the time of primary transplant, recipient ethnicity and early primary graft failure.2,3 These were not borne out in this registrybased analysis of a larger cohort of patients; however, a number of factors not previously described in the pediatric population were identified. Sensitization increased the risk of retransplantation by 1.7-fold, which is not surprising given the reported increased risk of rejection, allograft vasculopathy and graft loss in these recipients.8–12 Underlying coronary artery abnormalities have not been reported previously, but in a small series of patients transplanted for Kawasaki disease, more significant refractory rejection was observed,13 providing a hypothesis for graft failure and identifying an interesting subgroup for further study. Restrictive cardiomyopathy theoretically may also be a risk factor due to the potential for elevated pulmonary artery pressures and resulting effect on the right ventricular

Discussion In this contemporary analysis from the registry of the ISHLT, retransplantation, although feasible with similar early mortality compared with primary transplantation, is associated with decreased long-term survival and a greater risk of post-transplant morbidities, including late renal dysfunction, late rejection and allograft vasculopathy. Table 6 Multivariable Factors Associated With Increased Hazard of Allograft Vasculopathy After Retransplantation (N ¼ 602/Event ¼ 135) Parameter Patient factors Pre-retransplantation history of systemic hypertension Patient diagnosis ¼ allograft vasculopathy Donor factors Donor history of hypertension Donor blood group O (protective) Donor history of diabetes Donor history of cocaine use Male donor in female recipient Post-retransplant factors Documented renal dysfunction during follow-up Hospitalization for infection during follow-up Drug-treated hypertension during follow-up

Hazard ratio (95% CI) 1.78 (1.22–2.61) 1.96 (1.26–3.06)

5.69 0.57 5.68 2.62 1.52

(2.18–14.85) (0.40–0.82) (1.70–18.97) (1.16–5.96) (1.05–2.19)

p

Table 7 Multivariable Factors Associated With Increased Hazard of Late Renal Dysfunction After Retransplantation (N ¼ 602/Event ¼ 120)

0.003 0.003

0.001 0.002 0.005 0.02 0.02

1.83 (1.26–2.65)

0.002

2.71 (1.07–6.85)

0.04

1.61 (1.00–2.61)

0.05

Parameter Patient factors Higher pre-retransplant creatinine (per unit) Later year of transplantation (per year) Post-retransplant factors Post-retransplant dialysis before discharge Drug-treated hypertension during follow-up Allograft vasculopathy during follow-up Any hospitalization for infection during follow-up CI, confidence interval.

Hazard ratio (95% CI)

p

1.32 (1.16–1.49)

o0.001

1.10 (1.05–1.15)

o0.001

4.02 (2.54–6.35)

o0.001

3.38 (2.10–5.43)

o0.001

1.74 (1.21–2.51)

0.003

4.05 (1.44–11.44)

0.008

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Mortality and Morbidity After Retransplantation After Primary Heart Transplant in Childhood

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Table 9 Multivariable Factors Associated With Increased Hazard of Malignancy After Retransplantation (N ¼ 602/ Event ¼ 21) Parameter

Hazard ratio (95% CI)

p

Patient factors Patient diagnosis ¼ non-specific 3.85 (1.34–11.04) 0.01 graft failure Positive EBV IgG before transplant 0.21 (0.04–1.03) 0.05 (protective) Cancer history before transplant 3.38 (0.93–12.31) 0.06

Figure 7 Freedom from late rejection after transplantation stratified by primary transplantation vs retransplantation.

function in the post-transplant period. The finding of a positive cytomegalovirus (CMV) recipient status is plausible in the context of reactivation of a latent infection, the indirect effects of CMV, and the possible role in allograft injury.14 Cardiac-related factors developing after primary transplant (e.g., the need for cardiac operation prior to discharge, documented late rejection, lower ejection fraction and the need for a pacemaker) may all be surrogates for allograft vasculopathy or primary/non-specific graft failure. Many single-center reports have suggested promising early survival after retransplantation in the pediatric population5,6; however, these findings have not been confirmed by larger multicenter or registry-based studies.2,3 Using the United Network Organ Sharing database (n ¼ 219), Mahle et al reported inferior results with a 1-, 5- and 10-year survival rates of 79%, 53% and 44%, respectively3; similar numbers were reported by the Paediatric Heart Transplant Study (PHTS, n ¼ 62) with 1-, 3- and 5-year survival rates of 80%, 69% and 60%.2 In our study, early Table 8 Multivariable Factors Associated With Increased Risk of Late Rejection After Retransplantation (N ¼ 602/Event ¼ 120)

Parameter

Hazard ratio (95% CI)

p

Patient factor Later year of transplantation (per year)

1.32 (1.24–1.41) o0.001

Donor factor Donor positive anticytomegalovirus antibody

1.77 (1.05–2.27)

Post-retransplant factors Suspected non-adherence in follow-up Early rejection (before hospital discharge) Positive cytomegalovirus IgG results before transplantation

0.007

3.62 (2.29–5.72) o0.001 1.55 (1.04–2.66)

0.03

1.67 (1.16–2.66)

0.03

CI, confidence interval; IgG, immunoglobulin.

Post-retransplant factors Drug-treated infection before hospital discharge Drug-treated hypertension during follow-up

3.27 (1.04–10.31) 0.04 3.41 (0.98–11.80) 0.05

CI, confidence interval; EBV, EpsteinBarr virus; Ig, immunoglobulin.

mortality after retransplantation was encouragingly similar to that for primary transplantation (81% and 84% survival at 1 year), although later phase mortality was higher (46% vs 60% survival at 10 years). Studies have also suggested that retransplantation for early primary graft failure tends to have a poorer prognosis than late graft failure or allograft vasculopathy.2,3 ISHLT registry data for the most recent era (2000 to 2009) indicate a survival difference that varied based on inter-transplant interval; that is, if the inter-transplant interval was 45 years, then 5-year survival was comparable to primary transplant recipients (71%). However, an inter-transplant interval of o3 years was associated with a 5-year survival of only 50%.1 This larger analysis of the ISHLT registry, with further adjustment for confounding variables, did not show a difference in mortality among retransplants based on intertransplant interval. However, surrogates for longer intertransplant interval were associated with decreased mortality, including allograft vasculopathy and later year of retransplantation. Currently, the American Heart Association guidelines recommend retransplantation in those children with normal (Class IIA, Level of Evidence B) or abnormal ventricular function (Class I, Level of Evidence B) associated with moderate allograft vasculopathy, but not in children with acute allograft rejection or within the first 6 months after primary transplant (Class III, Level of Evidence B). Our current analysis would support the role of retransplantation in those with allograft vasculopathy, but it does raise the question of whether time post-transplantation is a key factor in predicting outcomes or if it is more dependent on the underlying etiology. Future subgroup analysis will focus on etiology-specific outcomes in retransplantation to help inform decision-making.15 Other factors identified in the literature to impact survival after retransplantation have included younger age, need for mechanical ventilation before retransplantation, and rejection during the primary transplant.2,5,7 Additional factors identified herein reflect a sicker patient at the time of retransplantation (e.g., the requirement for intensive care prior to retransplantation, the need for dialysis prior to

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hospital discharge, development of an infection, and a cardiac reoperation). Thus, there are factors that should be considered in determining recipient candidacy for retransplantation. Interestingly, some donor factors were also identified that impacted survival post-retransplantation including donor cause of death (central nervous system tumor), donor history of diabetes and CMV serology status. These findings highlight the possibility that we can improve outcomes after retransplantation through judicious donor selection. There is a paucity of information in the literature on development of post-retransplant morbidities. Previous adult studies have been inconsistent in their findings with regard to the rate of malignancy, rejection and infections after a second graft.16,17 The pediatric literature is sparse with only one report from the PHTS, which showed no significant difference between the time to first rejection episode or infection.2 In this analysis, there were a number of early complications seen more frequently in the retransplantation group including the need for dialysis and reoperation prior to discharge and the development of rejection within in the first post-retransplant year. In longer term follow-up, the retransplantation group was more likely to require treatment for hypercholesterolemia and hypertension and to develop rhythm disturbances requiring a pacemaker. Long-term morbidities, such as allograft vasculopathy, late rejection and late renal dysfunction, were significantly more common after retransplantation than primary transplant. A concerning observation is the earlier progression of allograft vasculopathy after retransplantation (77% freedom at 10 years for primary transplant vs 48% for retransplant), as reported elsewhere.1,18 Significant donor factors identified have been associated with cardiovascular disease in the general adult population, including hypertension, diabetes mellitus and cocaine use.19,20 Older donor age, male donor and history of donor hypertension have also been associated with early-onset angiographic evidence of allograft vasculopathy in adult transplant recipients.21 Thus, the question remains whether there is the potential for further risk modification with judicious donor selection (e.g., with a low-risk profile for atherosclerotic disease). An association between allograft vasculopathy and renal dysfunction was observed that has not been reported previously. However, in adults and children with chronic kidney disease, both traditional and uremicrelated factors are associated with increased risk of cardiovascular disease, and therefore this association is not unexpected.22 It remains to be determined whether early and aggressive management of these risk factors, such as hypertension and renal dysfunction before and after retransplantation, would reduce the development of allograft vasculopathy. Late renal dysfunction was also more common after retransplantation. This phenomenon of decreased renal function over time is not unexpected as it has been reported in previous studies.1,23 The development of late renal dysfunction is not surprising as pre-existing renal dysfunction (higher pre-transplant creatinine) and the requirement for dialysis in the early post-transplant period were identified risk factors. The development of renal dysfunction was independent of duration of the primary transplant.

By 10 years post-transplant, 39% of patients who underwent retransplantation had documented late rejection, which increased to 450% by 15 years post-retransplantation. This was markedly increased compared with primary transplantation (22% and 31%, respectively). Many factors have been suggested to be associated with rejection and are not easily modifiable, such as later year of transplant, documented early rejection and both donor and recipient CMV status.24–27 However, an important and potentially modifiable factor that increased the risk of late rejection by 3.6-fold was suspected non-adherence. Although not surprising, given the average age of patients undergoing retransplantation, there is clearly an ongoing need for further study and intervention to deal with the challenges of non-adherence and its detrimental impact on patient outcomes. This study has all the limitations inherent in being a retrospective review of a voluntary multi-institutional database, including incomplete data, variations in reporting of adverse events, and different patient data analyzed at different time-points. Despite these limitations, our study does represent the largest and most contemporary cohort of pediatric heart retransplant recipients in the literature. In addition, due to the nature of the database, we were able to include patients who underwent retransplantation after 18 years of age. Last, this is the first study to have examined risk factors for morbidities after retransplantation in this population. Retransplantation after primary transplant in the pediatric age group is associated with similar early survival but decreased long-term survival, with the best outcomes for those retransplanted for allograft vasculopathy. In addition, transplant-related morbidities are more common after retransplantation than after primary transplantation. We have highlighted the ongoing challenges of managing these patients long term and also suggested some modifiable risk factors, for both the donor and recipient that may lead to improved survival and decrease the burden of long-term morbidities.

Disclosure statement The authors have no conflicts of interest to disclose. This project was supported by an ISHLT Early Career Award.

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Mortality and Morbidity After Retransplantation After Primary Heart Transplant in Childhood

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